Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH2:16])[CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][C:5]=1[O:17][CH2:18][CH3:19].CCN(CC)CC.C[O:29][C:30](=O)[C:31]1[C:36]([NH:37][C:38]([CH:40]2[CH2:42][CH2:41]2)=[O:39])=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:43]Br>CN(C=O)C>[F:20][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([N:16]2[C:30](=[O:29])[C:31]3[C:32](=[CH:33][CH:34]=[CH:35][C:36]=3[NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[CH2:43]2)[CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][C:5]=1[O:17][CH2:18][CH3:19]
Reactant: COC(=O)c1c(CBr)cccc1NC(=O)C1CC1
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C(CS(C)(=O)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Temperature: 90 °C
Yield: 25.5 %

Procedure:
To the DMF solution (20 ml) of 1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethylamine (0.80 g, 2.7 mmol) was added Et3N (1.6 ml, 12 mmol) followed by 2-bromomethyl-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (1.0 g, 3.2 mmol). The mixture was heated at 90° C. for 12 hours then cooled to room temperature. The mixture was extracted with EtOAc (50 ml) and water (50 ml). The organic layer was washed with water (50 ml) and brine (50 ml), dried over Na2SO4 and concentrated in vacuo. The resulted oil was purified by silica gel chromatography to give cyclopropanecarboxylic acid {2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (0.35 g, 30%): mp 115-117° C.; 1H NMR (CDCl3) δ 0.83-0.92 (m, 2H, c-CH2), 1.09-1.13 (m, 2H, c-CH2), 1.45 (t, J=7.0 Hz, 3H, CH3), 1.66-1.70 (m, 1H, c-CH), 2.98 (s, 3H, SO2CH3), 3.64 (dd, J=3.8, 14 Hz, 1H, CH2), 4.10 (q, J=6.8 Hz, 2H, OCH2), 4.33 (dd, J=10, 14 Hz, 1H, CH2), 4.37 (dd, J=5, 50 Hz, 2H, CH2N), 5.69-5.74 (m, 1H, NCH), 6.57 (t, JH-F=75 Hz, 1H, CF2H), 6.94-7.04 (m, 3H, Ar), 7.18 (d, J=7.5 Hz, 1H, Ar), 7.47 (t, J=7.5 Hz, 1H, Ar), 8.45 (d, J=8.5 Hz, 1H, Ar), 10.42 (s, 1H, NH); 13C NMR (CDCl3) δ 9.06, 15.3, 16.9, 42.4, 49.0, 52.5, 56.3, 65.6, 112.4, 113.9, 116.6, 117.5, 117.6, 118.7, 119.9, 120.7, 123.8, 134.5, 136.5, 138.9, 141.1, 141.9, 151.9, 170.9, 173.4; Anal Calcd for C24H26F2N2O6S: C, 56.68; H, 5.15; N, 5.51. Found: C, 56.72; H, 5.15; N, 5.38.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[Br:11]C1C(=O)C(Br)=CC(Br)(Br)C=1>C(Cl)Cl>[Br:11][C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=1
Reactant: O=C1C(Br)=CC(Br)(Br)C=C1Br
Reactant: Nc1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Product: Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
A solution of 2-nitroaniline (5 g, 36.2 mmol) in CH2Cl2 (100 ml) was cooled to -10° C., and treated by 90% 2,4,4,6-tetrabromo-2,5-cyclohexadienone (19.8 g, 43.5 mmol) in 5 portions. The mixture was stirred at -10° C.-0° C. for 1 hr. After being warmed to room temperature, the reaction mixture was washed by 2N NaOH (60 ml) and brine (50 ml), dried over Na2SO4 and evaporated. Flash chromatography on silica gel (5% EtOAc/Hexane) gave 7.40 g (94%) of 17 as a yellow solid: mp 109-110 (lit. mp 112°-113° C.); 1H NMR δ8.27 (1H, d, J=2.3), 7.43 (1H, dd, J=8.9, 2.4), 6.73 (1H, d, J=8.8), 6.09 (NH, brs).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([O:22][CH3:21])[CH:24]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: COc1cccc(CN)c1
Product: COc1cccc(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)c1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (200 mg, 0.57 mmol) and 3-methoxy benzylamine (104 mg, 0.68 mmol). The title compound was obtained as a yellow solid (35 mg, 14% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.37 (1H, m), 8.98 (2H, m), 8.47 (1H, s), 7.23 (1H, m), 6.83 (3H, m) 4.37 (2H, m), 3.72 (3H, s). MS m/z: 468.26, 470.28 [M+H]+.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[C:39]([CH3:46])[C:40](=[O:45])[N:41]([CH2:43][CH3:44])[CH:42]=1>>[CH2:43]([N:41]1[C:40](=[O:45])[C:39]([CH3:46])=[CH:38][C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)=[CH:42]1)[CH3:44]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CCn1cc(Br)cc(C)c1=O
Product: CCn1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc(C)c1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 5-bromo-1-ethyl-3-methylpyridin-2(1H)-one following a procedure analogous to that described in Example 6 Step 1. LC-MS Method 2 tR=1.314 min, m/z=489; 1H NMR (CDCl3) 1.09 (s, 3H), 1.15 (s, 3H), 1.35 (t, 3H), 1.50 (d, 3H), 2.15-2.25 (m, 7H), 2.35 (m, 1H), 2.86 (m, 1H), 4.03 (m, 2H), 5.66 (q, 1H), 6.96 (d, 2H), 7.13 (d, 2H), 7.25-7.36 (m, 7H).
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[C:3](=[O:33])[CH2:4][NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[C:10]([CH3:32])[CH:9]=1)=O.P(Cl)(Cl)(Cl)=O>O>[C:2]([C:3]1[O:33][C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([NH:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=3)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[C:10]([CH3:32])[CH:9]=2)=[N:5][CH:4]=1)([CH3:34])([CH3:1])[CH3:35]
Reactant: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(C(=O)NCC(=O)C(C)(C)C)cc2C)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(-c3ncc(C(C)(C)C)o3)cc2C)cc1
Temperature: 90 °C
Yield: 80.6 %

Procedure:
To methyl 4-((1-(4-((3,3-dimethyl-2-oxobutyl)carbamoyl)-2-methylphenyl)-4,4,4-trifluorobutyl)amino)benzoate (200 mg) was added phosphoryl chloride (0.5 ml) at room temperature. The reaction mixture was heated at 90° C. for 1 hr, and water was added at room temperature. The filtrate was extracted with ethyl acetate, and the extract was washed with 1M aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (155.4 mg).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([C:20]4([O:27][CH3:28])[CH2:25][CH2:24][O:23][CH2:22][CH:21]4[OH:26])[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[O:29].CI.[CH2:32]1OCCOCCOCCOCCOC1>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([C:20]4([O:27][CH3:28])[CH2:25][CH2:24][O:23][CH2:22][CH:21]4[O:26][CH3:32])[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[O:29]
Reactant: C1COCCOCCOCCOCCO1
Reactant: COC1(c2cccc(OCc3ccc4c(ccc(=O)n4C)c3)c2)CCOCC1O
Solvent: CI
Product: COC1COCCC1(OC)c1cccc(OCc2ccc3c(ccc(=O)n3C)c2)c1
Yield: 78 %

Procedure:
Using the methylation procedure described in the portion of Example 1 which is concerned with the preparation of starting materials, (3RS,4SR)-4-[3-(1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy)phenyl]-3-hydroxy-4-methoxytetrahydropyran was reacted with methyl iodide in the presence of 15-crown-5 to give (3RS,4SR)-4-[3-(1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy)phenyl]-3,4-dimethoxytetrahydropyran in 78% yield, as a glass.
Reaction SMILES: O[CH:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1[N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18].[C:19]([O:22]C(=O)C)(=[O:21])[CH3:20]>Cl(O)(=O)(=O)=O>[C:19]([O:22][C:11]1[S:12][C:4]2[CH:3]([N:13]3[CH2:17][CH2:16][CH2:15][C:14]3=[O:18])[CH2:2][C:7]([CH3:9])([CH3:8])[O:6][C:5]=2[CH:10]=1)(=[O:21])[CH3:20]
Reactant: CC1(C)Oc2ccsc2C(N2CCCC2=O)C1O
Reactant: CC(=O)OC(C)=O
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(=O)Oc1cc2c(s1)C(N1CCCC1=O)CC(C)(C)O2
Temperature: 0 °C

Procedure:
A solution of 5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran (2.0 g, 7.48 mmol) and perchloric acid (70%, 10 drops) in acetic anhydride (20 mL) were stirred for 1 h at 0°-5° C. The solution was poured into ice water (100 mL). The product was extracted into dichloromethane, washed with water (4x), and evaporated in vacuo. The resultant oil was purified by flash chromatography, using 1% methanol in dichloromethane as the eluant, then crystallized from hexanes to give the product, 2.12 g (92%), as a colorless solid: mp 92°-93° C.; IR(KBr): 1745 and 1684 cm-1 ; MS: 310 (MH+); 1H NMR (CDCl3): δ 1.37 (s, 3H), 1.38 (s, 3H), 1.98 (m, 2H), 2.10 (s, 3H), 2.37 (m, 2H), 3.24 (m, 1H), 3.40 (m, 1H), 5.15 (d, J=9.1 Hz, 1H), 5.44 (d, J=9.1 Hz, 1H), 6.58 (d, J=5.4 Hz, 1H) and 7.13 (d, J=5.4 Hz, 1H).
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[C:26]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH2:1]([C:4]1[C:13]([O:14][CH3:26])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)c(OC)cc2ncnc(Nc3ccc(Br)cc3F)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: C=CCc1c(OC)c(OC)cc2ncnc(Nc3ccc(Br)cc3F)c12
Temperature: 90 °C
Reaction time: 4.5 h

Procedure:
To a solution of 5-allyl-4-(4-bromo-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-ol (0.34 g, 0.84 mmol) (from Example 19, Step D, supra) in acetone (100 mL) was added K2CO3 (0.35 g, 2.52 mmol) and methyl iodide (1.19 g, 8.41 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 4.5 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:4:0.01) as eluent to give the desired (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(4-bromo-2-fluoro-phenyl)-amine as a yellow solid. (Yield 0.33 g, 94%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][NH:15]3)=[CH:11][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:18]1[CH:23]=[CH:22][C:21]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:17]=[C:16]4[C:12]([CH:13]=[CH:14][NH:15]4)=[CH:11][CH:10]=3)[CH:5]=[N:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: Clc1cncc(Nc2ccc3cc[nH]c3c2)n1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: c1cc(-c2cncc(Nc3ccc4cc[nH]c4c3)n2)ccn1
Yield: 36.4 %

Procedure:
A mixture of (6-chloro-pyrazin-2-yl)-(1H-indol-6-yl)-amine (0.070 g, 0.2868 mmol), pyridine-4-boronic acid (0.042 g, 0.344 mmol), sodium carbonate (0.150 g, 1.43 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0165 g, 0.0143 mmol) in DME:water (3:2, 5 mL) was heated at reflux for 20 h. The reaction mixture was concentrated under reduced pressure and the residue obtained was extracted with dichloromethane. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (5% methanol in CH2Cl2 as eluent) to yield N-(6-pyridin-4-ylpyrazin-2-yl)-1H-indol-6-amine (0.030 g, 36.5%) as a yellow solid. 1H NMR (CD3OD) δ 8.73-8.72 (d, J=5.68 Hz, 2H), 8.51 (s, 1H), 8.23-8.20 (m, 4H), 7.56-7.54 (d, J=8.46 Hz, 1H), 7.22 (d, J=2.99 Hz, 1H), 7.14 (dd, J=10.18, 1.74 Hz, 1H), 6.45 (d, J=2.75 Hz, 1H); MS (API-ES/Positive); m/z: 288 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH:5]=[N+]=[N-])[CH3:2].[CH:9]1([CH2:12][OH:13])[CH2:11][CH2:10]1.CC(=O)OCC>C(Cl)Cl>[CH:9]1([CH2:12][O:13][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:8])[CH2:11][CH2:10]1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: OCC1CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)COCC1CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
Diazoacetic acid ethyl ester (80.00 g, 0.70 mol) was added dropwise to cyclopropanemethanol (60.66 g, 0.84 mol) and [Rh(Ac2O)2]2 (3.1 g, 7.02 mmol) in anhydrous CH2Cl2 (800 mL) at 0° C. The mixture was stirred at 0° C. for 30 min and at room temperature for 4 h. CH2Cl2 extractive work up and silica gel chromatography (PE: EA=100:1-50:1) gave the title compound (100 g, 90.4% yield) as a colorless oil. 1H NMR: (CDCl3, 400 MHz) δ 4.23-4.19 (m, 2H), 4.09 (s, 2H), 3.38-3.36 (m, 2H), 1.27 (t, J=7.2 Hz, 3H), 1.10-1.07 (m, 1H), 0.57-0.52 (m, 2H), 0.24-0.20 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:16]([CH3:17])=[CH:15][C:14]([C:18]#[N:19])=[CH:13][C:3]=1[C:4]([O:6]CCCCCC)=O.[CH3:20][NH2:21].C[O-].[Na+]>>[NH2:1][C:2]1[C:16]([CH3:17])=[CH:15][C:14]([C:18]#[N:19])=[CH:13][C:3]=1[C:4]([NH:21][CH3:20])=[O:6]
Reactant: CCCCCCOC(=O)c1cc(C#N)cc(C)c1N
Reactant: CN
Agent: C[O-]
Agent: [Na+]
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Yield: 81.1 %

Procedure:
The above-described method (Example 3) was repeated to stir hexyl 2-amino-5-cyano-3-methylbenzoate (1.40 g, 4.89 mmol) with methylamine (10.8 g, 139 mmol, 40% in methanol) and sodium methoxide (441 mg, 0.12 mmol, 30% in methanol) at room temperature for 18 hours. The entire reaction batch was vacuum distilled and stirred with diisopropyl ether. 2-Amino-5-cyano-N,3-dimethylbenzamide (0.75 g, 75.8% of theory, 93.6 area % LC) was obtained as a brown solid.
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]([F:27])([F:26])[O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[N:16][C:15]([C:18]3[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=3)=[N:14]2)=[CH:9][CH:8]=1>CCO.O>[N:2](=[CH:22]/[C:21]1[CH:24]=[CH:25][C:18]([C:15]2[N:16]=[CH:17][N:13]([C:10]3[CH:11]=[CH:12][C:7]([O:6][C:5]([F:27])([F:26])[F:4])=[CH:8][CH:9]=3)[N:14]=2)=[CH:19][CH:20]=1)\[NH2:3]
Reactant: NN
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: CCO
Solvent: O
Product: N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 0 °C

Procedure:
To a 250 milliliter (mL) round-bottomed flask containing hydrazine hydrate (64% aqueous (aq) solution; 7.27 mL, 15.0 millimoles (mmol)) in EtOH (100 mL) at 80° C. was added 4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-benzaldehyde (5.00 grams (g), 1.50 mmol) portionwise over 5 minutes (min). The solution was stirred at reflux for an additional 3 hours (h) before being diluted with water (H2O; 300 mL) and cooled to 0° C. The precipitated product was collected by vacuum filtration as a white solid (4.89 g, 93%): mp 222-226° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.22 (d, J=8.2 Hz, 2H), 7.84-7.79 (m, 3H), 7.66 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.2 Hz, 2H), 7.29 (s, 1H), 5.63 (br s, 2H); ESIMS m/z 348 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:4]([CH2:5][N:19]2[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cccc(C=O)c1N1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1cccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
A 100 mL round-bottom flask was charged with 3-methyl-2-(morpholin-4-yl)benzaldehyde (1.34 g, 6.51 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (1.00 g, 5.37 mmol, 0.82 equiv), 1,2-dichloromethane (30 mL). The mixture was stirred at room temperature for 0.5 hour. Sodium triacetoxyborohydride (3.42 g, 16.1 mmol, 2.48 equiv) was added. The resulting solution was stirred for 2 h at room temperature and diluted with 1,2-dichloromethane (30 mL). The resulting solution was washed with H2O (2×30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/3) to provide 0.800 g (34% yield) of tert-butyl 4-[[3-methyl-2-(morpholin-4-yl)phenyl]methyl]piperazine-1-carboxylate as light red oil. LCMS (ESI, m/z): 396 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH:26]([CH3:28])[O:25][CH:24]([CH3:29])[CH2:23]2)[C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:33][N:34]1[CH:38]=[N:37][CH:36]=[N:35]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]#[N:10])([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][CH:24]([CH3:29])[O:25][CH:26]([CH3:28])[CH2:27]2)[CH2:33][N:34]2[CH:38]=[N:37][CH:36]=[N:35]2)=[CH:4][CH:3]=1
Reactant: CC1CN(CCCCCCCCCCCC(C#N)c2ccc(Cl)cc2)CC(C)O1
Reactant: ClCn1cncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CN(CCCCCCCCCCCC(C#N)(Cn2cncn2)c2ccc(Cl)cc2)CC(C)O1

Procedure:
This compound (350 mg.) was prepared using the procedure described in Example 2b except using 500 mg. (1.25 mmoles) of 2-(4-chlorophenyl)-13-(2,6-dimethyl-4-morpholinyl)tridecanonitrile, 60 mg (1.35 mmoles) of sodium hydride, 150 mg. (1.25 mmoles) of 1-(chloromethyl)-1,2,4-triazole, and 15 ml. of DMF and was isolated as an amber oil.
Reaction SMILES: [C:1]1([S:7][C:8]2([O:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=3[N+:23]([O-])=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O.C(O)(=O)C.[Fe]>[C:1]1([S:7][C:8]2([O:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:20])([F:21])[F:22])=[CH:14][C:13]=3[NH2:23])[CH2:9][CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1OC1(Sc2ccccc2)CC1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(OC(F)(F)F)ccc1OC1(Sc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
Iron powder (13.5 g, 241 mmol) was added to a suspension of 2-(1-phenylthiocycloprop-1-yl)oxy-5-(trifluoromethoxy)nitrobenzene (Description 4, 11.27 g, 30.1 mmol) in water (300 mL) and acetic acid (75 mL) and the mixture was stirred at 80° C. overnight. The mixture was cooled and filtered through celite, washing with ether. The filtrate was extracted with ether, the combined organic fractions were washed with aqueous sodium hydroxide (1M), dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/Et2O (90:10 increasing to 80:20), to give the title compound as a yellow solid (8 g, 78%). 1H NMR (360 MHz, CDCl3) δ 7.48 (2H, m), 7.34-7.23 (3H, m), 7.15 (1H, d, J 8.74 Hz), 6.60-6.56 (2H, m), 3.78 (2H, br s), 1.49-1.46 (2H, m), and 1.39-1.35 (2H, m).
Reaction SMILES: [NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([C:10]3[NH:14][N:13]=[N:12][N:11]=3)[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.C(N(CC)CC)C.Cl[Si](C)(C)C.CO[CH:31](OC)[N:32]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>ClCCl>[N:32]1([CH:31]=[N:1][CH:2]2[C:15](=[O:16])[N:4]3[CH:5]([C:10]4[NH:11][N:12]=[N:13][N:14]=4)[C:6]([CH3:8])([CH3:9])[S:7][C@H:3]23)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Reactant: COC(OC)N1CCCCCC1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)S[C@@H]2C(N=CN3CCCCCC3)C(=O)N2C1c1nnn[nH]1
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a stirred solution of 1.2 g (5 mmoles) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, 1.0 g (10 mmole) of triethylamine and 30 ml of dichloromethane, cooled to 0° C., is added 0.54 g (5 mmole) of chlorotrimethylsilane. After 15 minutes, 0.86 (5 mmole) of 1-(dimethoxymethyl)hexahydroazepine (British Patent No. 1,293,590) is added, and stirring is continued for a further 1 hour. The volatile components are removed by evaporation in vacuo, and then the residue is extracted with 25 ml of acetone. The insoluble material is filtered off, and the acetone is evaporated in vacuo to a yellow foam, which changes to a white powder on trituration with ether. This affords 1.44 g (82% yield) of 6-([hexahydro-1-azepinyl]methyleneamino)-2,2-dimethyl-3-(5-tetrazolyl)penam. The infrared spectrum of the product (KBr disc) shows absorption bands at 1795 cm-1 (β-lactam), 1706 cm-1 and 1645 cm-1. The NMR spectrum (CDCl3) shows absorption bands at 8.00 ppm (singlet, 1H, N--CH=N), 5.90 and 5.60 ppm (two doublets, 2H, J = 4 Hz, C-5 and C-6 hydrogens), 5.40 ppm (singlet, 1H, C-3 hydrogen), 3.90-3.50 (multiplet, 4H, CH2 --N--CH2), 2.00-1.50 ppm (multiplet, 11H, C-2 methyl hydrogens and [CH2 ]4) and 1.20 ppm (singlet, 3H, C-2 methyl hydrogens). Examination of the product by thin-layer chromatography (0.2M NaOAc: acetone; 1:6) showed a single spot (Rf 0.23).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[CH3:41][O:42][C:43]1[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1>O1CCCC1.O>[Cl:3][C:4]1[C:9]([C:10]2[N:14]([S:49]([C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([O:42][CH3:41])[CH:44]=3)(=[O:51])=[O:50])[CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2Cl)c1
Reaction time: 0.75 h
Yield: 98.2 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added dropwise a solution of tert-butyl {[5-(2-chloropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (340 mg) in tetrahydrofuran (5 mL), 15-crown-5 (330 mg) and 3-methoxybenzenesulfonyl chloride (310 mg) under ice-cooling and the mixture was stirred for 45 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→2:1) to give the title compound as a pale-yellow oil (yield 501 mg, 98%).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]=[CH:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](I)[CH:20]=[CH2:21].O>CN(C=O)C>[Br:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]=[CH:7][C:8](=[O:10])[N:9]([CH2:21][CH:20]=[CH2:19])[C:4]=2[CH:3]=1
Reactant: O=c1cnc2ncc(Br)cc2[nH]1
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(=O)cnc2ncc(Br)cc21
Yield: 64.2 %

Procedure:
7-Bromopyrido[2,3-b]pyrazin-2(1H)-one (368 mg, 1.628 mmol) was suspended in dry DMF (10 ml) under argon at rt, and the stirred suspension was treated with K2CO3 (741 mg, 5.372 mmol) and allyl iodide (331 μL, 3.581 mmol). It was then stirred for 2 h before addition of water (100 ml). The mixture was then extracted with DCM (3×200 ml). The DCM extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give a brown solid which was purified by column chromatography on silica with a 0-10% MeOH in DCM gradient to give the desired product as a light brown solid (278 mg, 64%).