Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][C:17](=[O:19])[N:16]([CH3:20])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N+:21]([C:24]1[O:28][C:27]([CH:29]=O)=[CH:26][CH:25]=1)([O-:23])=[O:22]>CC(O)=O.CO>[CH3:20][N:16]1[N:15]=[C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:5]3[CH:4]=[CH:3][C:2](/[N:1]=[CH:29]/[C:27]4[O:28][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=4)=[CH:7][CH:6]=3)[CH2:13][CH2:12]2)[O:18][C:17]1=[O:19]
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: Cn1nc(C2CCN(c3ccc(N)cc3)CC2)oc1=O
Solvent: CC(=O)O
Solvent: CO
Product: Cn1nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3)CC2)oc1=O
Yield: 86 %

Procedure:
5-[1-(4-Aminophenyl)-4-piperidyl]-3-methyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7b, 0.27 g, 1 mmol) on reacting with 5-nitro2-furaldehyde in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 10 h and the obtained solid is filtered, washed with water and recrystallized in ethanol to obtain product 3-methyl-5-[1-(4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9b, 341 mg, 86%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]3[C:30](O)=[O:31])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:33][OH:34]>>[OH:34][NH:33][C:30]([C@@H:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:24]1[NH:23][S:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([CH3:1])[CH:11]=2)=[CH:19][CH:18]=1)(=[O:22])=[O:21])=[O:31]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CCCC[C@H]3C(=O)O)cc2)c2ccccc2n1
Reactant: NO
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CCCC[C@H]3C(=O)NO)cc2)c2ccccc2n1
Yield: 46 %

Procedure:
According to the procedure of Example 10, Step 2, the reaction of 113.6 mg (0.5 mmol) of cis-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohexanecarboxylic acid with hydroxylamine provided 53.7 mg of the title compound in 46% yield. MS: 470.1 (M+H)+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([OH:17])[CH:12]3[O:11][CH2:10]2)[C:5]([CH3:18])=[CH:4][N:3]=1.[CH3:19][N:20]1[CH:24]=[C:23]([NH2:25])[CH:22]=[N:21]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:18][C:5]1[C:6]([NH:8][CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([OH:17])[CH:12]3[O:11][CH2:10]2)=[N:7][C:2]([NH:25][C:23]2[CH:22]=[N:21][N:20]([CH3:19])[CH:24]=2)=[N:3][CH:4]=1
Reactant: Cn1cc(N)cn1
Reactant: Cc1cnc(Cl)nc1NC1COC2C(O)COC12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1COC2C(O)COC12
Temperature: 150 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a suspension of 6-((2-chloro-5-methylpyrimidin-4-yl)amino)hexahydrofuro[3,2-b]furan-3-ol (54 mg, 0.20 mmol) in n-BuOH (1 mL) was added 1-methyl-1H-pyrazol-4-amine (32 mg, 0.24 mmol) and DIPEA (78 mg, 0.60 mmol). Then the mixture was stirred under nitrogen atmosphere at 150° C. overnight and concentrated in vacuo. To the residue was added water (20 mL), and extracted with DCM (20 mL×3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give crude oil. Then it was purified by silica gel column chromatography (DCM/MeOH (v/v)=20/1) to give the title compound as an off-white solid (46 mg, 70%).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:8]([NH:9][CH2:10][CH3:11])=[CH:7][N:6]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:5]=1.C(N(CC)CC)C.[C:25]([O:28][CH:29]([CH3:33])[C:30](Cl)=[O:31])(=[O:27])[CH3:26]>C(Cl)Cl>[C:25]([O:28][CH:29]([CH3:33])[C:30]([N:9]([C:8]1[C:4]([Cl:3])=[N:5][N:6]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=1)[CH2:10][CH3:11])=[O:31])(=[O:27])[CH3:26]
Reactant: CCNc1cn(-c2cccnc2)nc1Cl
Reactant: CC(=O)OC(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(C(=O)C(C)OC(C)=O)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine dihydrochloride (3.00 g, 10.2 mmol) in CH2Cl2 (20 mL) cooled in an ice bath were added triethylamine (5.7 mL, 40.6 mmol) followed by dropwise addition 1-chloro-1-oxopropan-2-yl acetate (1.3 mL, 10.2 mmol). The reaction mixture was stirred overnight warming to room temperature. The reaction mixture was then diluted with CH2Cl2 and washed with water. The phases were separated, and the organics were dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with 0%-70% acetone/hexanes to afford the title compound C12 as a tan taffy-like solid (3.2 g, 93%): 1H NMR (400 MHz, CDCl3) δ 8.99 (d, J=2.5 Hz, 1H), 8.62 (dd, J=4.8, 1.3 Hz, 1H), 8.18 (s, 1H), 8.04 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.46 (ddd, J=8.4, 4.8, 0.5 Hz, 1H), 5.01 (d, J=6.5 Hz, 1H), 3.54 (m, 2H), 2.09 (s, 3H), 1.39 (d, J=6.8 Hz, 3H), 1.17 (t, J=7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.01, 148.62, 140.57, 140.24, 135.63, 127.56, 126.33, 124.06, 122.58, 67.49, 43.74, 20.61, 16.80, 12.57 (one carbon signal not located); ESIMS m/z 336.4 ([M+H]+), 335.0 ([M−H]−).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=O.CC[O:17][CH2:18]C.[N:20]1C=CC=CC=1>CCO>[CH3:18][O:17][N:20]=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[C:2]([OH:1])[CH:3]=1
Reactant: c1ccncc1
Reactant: CCOCC
Reactant: COCCOc1ccc(C=O)cc1O
Solvent: CCO
Product: COCCOc1ccc(C=NOC)cc1O
Temperature: 25 °C
Yield: 81 %

Procedure:
An amount of 3-hydroxy-4-(2-methoxyethoxy)benzaldehyde (1.24 g, 6.32 mmol) in 20 mL of EtOH and 10 mL of pyridine is added methoxy]amine hydrochloride (1.06 g, 12.64 mmol). The reaction mixture is stirred at room temperature over weekend. Solvent is removed under vacuum to give colorless oil which is added ether, washed twice with saturated NaHCO3 solution, once with brine, dried over Mg2SO4, filtered and evaporated to give colorless oil. Leaving this oil overnight at room temperature gave 1.15 g (81.0% yield) of colorless solid: mp: 63-64° C.; MS (ESI) m/z 226.1 (M+H)+1
Reaction SMILES: [CH3:1][C@@H:2]1[O:8][C:7](=[O:9])[CH2:6][C@@H:5]2[C@H:3]1[O:4]2.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[O:9]=[CH:7][CH2:6][C@H:5]1[O:4][C@H:3]1[C@H:2]([CH3:1])[OH:8]
Reactant: C[C@@H]1OC(=O)C[C@H]2O[C@@H]12
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: C[C@H](O)[C@@H]1O[C@@H]1CC=O
Reaction time: 2 h

Procedure:
To a solution of 2.58 g (20 mmol) of (1S,2S,6R)-2-methyl-3,7-dioxabicyclo[4.1.0]-heptan-4-one in 300 ml of anhydrous toluene cooled to -75° was added under argon 14 ml (24.5 mmol) of a 1.75 M solution of DIBAL-H in toluene. The reaction mixture was stirred at -75° for 2 hr and then quickly poured onto a slurry of 260 g of silica gel (Silica Gel 60 Merck) in toluene and allowed to filter. The slurry was washed with 3 L of methylene chloride-methanol (9:1). The combined filtrate and washings were evaporated to dryness under reduced pressure. The residual oil was distilled with a Kugelrohr distillation apparatus to afford 3,4-anhydro-2,6-dideoxy-L-ribo-hexose: bp 90° (oven temperature) (0.1 mm); [α]25D +25.16° (c 1.013, MeOH).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]3[N:27]=[C:28]([NH2:30])[N:29]=[C:25]3[CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.NC1C=CC=C(Br)N=1>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]3[N:27]=[C:28]([NH:30][CH:10]4[CH2:11][CH2:12][N:7]([C:5]5[S:4][N:3]=[C:2]([CH3:1])[N:6]=5)[CH2:8][CH2:9]4)[N:29]=[C:25]3[CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1
Reactant: Nc1nc2cccc(-c3ccc(F)cc3)n2n1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Agent: Nc1cccc(Br)n1
Product: Cc1nsc(N2CCC(Nc3nc4cccc(-c5ccc(F)cc5)n4n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 5-(4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine. The latter compound can be prepared in analogy to example 1 steps d-f) starting from 2-amino-6-bromo-pyridine. The title compound was obtained as a white solid.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:11]([O:13][C:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[O:22])=[O:15])[CH3:12].[Cl:23][C:24]1[CH:35]=[CH:34][C:27]([C:28](N(OC)C)=[O:29])=[CH:26][CH:25]=1>C1COCC1>[CH2:11]([O:13][C:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH:18]([C:28](=[O:29])[C:27]2[CH:34]=[CH:35][C:24]([Cl:23])=[CH:25][CH:26]=2)[C:17]1=[O:22])=[O:15])[CH3:12]
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: CON(C)C(=O)c1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CCCC(C(=O)c2ccc(Cl)cc2)C1=O
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a solution of LHMDS (21 mL, 2.1 mmol) in 50 mL of anhydrous THF under a nitrogen atmosphere at −78° C. was added 2-oxo-cyclohexanecarboxylic acid ethyl ester Compound 1a (1.80 g, 10.0 mmol) in 10 mL of anhydrous THF. The resultant homogeneous mixture was left to stir at −78° C. for 40 min followed by the drop wise addition of 4-chloro-N-methoxy-N-methyl-benzamide Compound 1b (2.0 g, 10 mmol) in 10 mL of anhydrous THF. The reaction mixture was allowed to stir for 18 hours and allowed to warm to ambient temperature. The reaction mixture was quenched with water (50 mL) and the organic layer was extracted with EtOAc (200 mL) and washed with brine, separated and dried with anhydrous Na2SO4, then filtered and concentrated in vacuo to yield 3-(4-chloro-benzoyl)-2-oxo-cyclohexanecarboxylic acid ethyl ester Compound 1c (1.7 g) as an oil, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH3:14].P(Cl)(Cl)(Cl)(Cl)[Cl:19]>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]([Cl:19])[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC(=O)Nc1ccccc1C(F)(F)F
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: CCCCC(Cl)=Nc1ccccc1C(F)(F)F
Yield: 102.5 %

Procedure:
Using the procedure of Step B of Example 6, 20 g of the product of Step A and 19 g of phosphorus pentachloride were reacted to form 22.05 g of N-(2-trifluoromethylphenyl)-pentanimidoyl chloride as an oil which was used as is for the next step.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]#[CH:14])(OC(C)(C)C)=O.[CH3:15][OH:16].[ClH:17].O>C(O)C>[ClH:17].[CH3:13][C:9]1[N:8]=[C:12]2[CH:14]=[C:13]([C@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)[O:16][C:15]2=[CH:11][CH:10]=1
Reactant: C#C[C@H]1CCCN1C(=O)OC(C)(C)C
Reactant: CO
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc2oc([C@H]3CCCN3)cc2n1

Procedure:
The title compound was prepared from 1-Boc-2(R)-ethynylpyrrolidine according to the procedures of Example 5 above: [α]D≤ +16.5° (c 1.0, MeOH); Anal. Calcd for C12H14N2O.2.0 HCl.0.2 H2O.0.2 ethanol: C, 51.39; H, 6.19; N, 9.67. Found: C, 51.63; H, 6.49; N, 9.33.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)C([N:11]1[CH2:16][C:15]2([CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[C:27]([CH2:29][CH2:30][OH:31])[CH:26]=[CH:25][C:24]=3[F:32])[CH2:18][CH2:17]2)[O:14][CH2:13][CH2:12]1)=O>O.C(#N)C>[O:14]1[C:15]2([CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[C:27]([CH2:29][CH2:30][OH:31])[CH:26]=[CH:25][C:24]=3[F:32])[CH2:18][CH2:17]2)[CH2:16][NH:11][CH2:12][CH2:13]1
Reactant: O=C(N1CCOC2(CCN(Cc3cc(CCO)ccc3F)CC2)C1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: OCCc1ccc(F)c(CN2CCC3(CC2)CNCCO3)c1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
A solution of sodium carbonate (1.4 g) in water (40 mL) was added to a solution of 2,2,2-trifluoro-1-(9-(2-fluoro-5-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethanone [Example 44, step b] (4.2 g) in acetonitrile (40 mL). The reaction mixture was stirred at 20° C. for 20 hours. The acetonitrile was removed under reduced pressure and the remaining aqueous solution was extracted with DCM (×9). The combined DCM extracts were dried, filtered and the solvent removed under reduced pressure to yield the subtitled compound. Yield 2.7 g.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH2:13][CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:10]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[N:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCCCCc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCCc1ccc(C=Nc2ccc(C#N)cc2)cc1

Procedure:
A mixture of 5.9 g. of p-aminobenzonitrile and 8.8 g. of p-n-pentylbenzaldehyde in 100 ml. of benzene is treated with 150 mg. of p-toluenesulfonic acid and reacted as described in Example 1. After evaporation, there remain 13.9 g. of a yellow oil which crystallizes with cooling. Purification is carried out by several recrystallizations from isopropanol as described in Example 1. The p-[(p-n-pentylbenzyliden)amino]benzonitrile which is obtained has a melting point of 45.6°-46.4°C. and a clearing point of 75.0°C. UV (ethanol): ε279 = 24400 (shoulder at 314 nm). The nuclear magnetic resonance, mass spectrum, infrared and microanalysis data confirm the structure.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH:20]([CH3:22])[CH3:21])[CH:12]=2)=[O:7])CCC.[NH2:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27]>>[OH:27][CH2:26][CH:25]([NH:24][C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH:20]([CH3:21])[CH3:22])[CH:12]=2)=[O:7])[CH2:28][OH:29]
Reactant: CCCCOC(=O)c1nc(Cl)c2cc(OC(C)C)ccc2c1O
Reactant: NC(CO)CO
Product: CC(C)Oc1ccc2c(O)c(C(=O)NC(CO)CO)nc(Cl)c2c1

Procedure:
Prepared from 1-chloro-4-hydroxy-7-isopropoxy-isoquinoline-3-carboxylic acid butyl ester and 2-amino-propane-1,3-diol analogously to Example C-1: MS-(−)-ion: 353.2.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([N:33]3[C:37](=[O:38])[CH2:36][N:35]([CH3:39])[C:34]3=[O:40])[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([N:33]3[C:37](=[O:38])[CH2:36][N:35]([CH3:39])[C:34]3=[O:40])[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccc(N3C(=O)CN(C)C3=O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2ccc(N3C(=O)CN(C)C3=O)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[(2-n-propyl-6-(1-methyl-imidazolidin-2,4-dion-3-yl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:8][C:6]1[CH:5]=[C:4]([CH3:9])[C:3]([O:10][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1cc(Br)cc(Cl)c1O
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(Cl)c1Oc1ccc([N+](=O)[O-])cn1
Temperature: 50 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a DMF (30 mL) solution of 2-chloro-4-bromo-6-methylphenol (4.90 g) were added 2-chloro-5-nitropyridine (3.58 g) and K2CO3 (3.12 g) at room temperature. After stirring at 50° C. for 3 hours, the solvent was removed under reduced pressure. To the residue was added water, and extracted with AcOEt. The organic layer was washed with water, saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 2-(4-bromo-2-chloro-6-methylphenoxy)-5-nitropyridine as a brown solid (7.59 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[C:20](=[O:26])[NH:21][CH:22]2[CH2:25][CH2:24][CH2:23]2)=[O:14])[N:8]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:7]=1)=[O:5])C.[OH-].[Na+]>C1COCC1.O>[CH:22]1([NH:21][C:20]([C@@H:16]2[CH2:17][CH2:18][CH2:19][N:15]2[C:13](=[O:14])[CH2:12][O:11][C:9]2[N:8]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=2)=[O:26])[CH2:23][CH2:24][CH2:25]1
Reactant: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reaction time: 4 h

Procedure:
To a solution of 3.2 g 5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester in 40 ml THF and 5 ml water were added 340 mg NaOH portionwise at 0° C. After 4 h the solution was neutralized with Amberlite IR-120 ion exchange resin, filtered and washed with methanol. The crude product obtained after evaporation of the solvents was used in the subsequent reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:14][CH2:15][CH:16]=O)[C:10](=[O:13])[CH:11]=[CH:12][C:6]2=[N:5][CH:4]=1.[NH2:18][CH:19]1[CH2:23][N:22]([C:24]2[CH:25]=[CH:26][C:27]3[O:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=3[CH:34]=2)[C:21](=[O:35])[CH2:20]1.C(O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:14][CH2:15][CH2:16][NH:18][CH:19]3[CH2:20][C:21](=[O:35])[N:22]([C:24]4[CH:25]=[CH:26][C:27]5[O:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=5[CH:34]=4)[CH2:23]3)[C:10](=[O:13])[CH:11]=[CH:12][C:6]2=[N:5][CH:4]=1
Reactant: NC1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Reactant: COc1cnc2ccc(=O)n(CCC=O)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cnc2ccc(=O)n(CCCNC3CC(=O)N(c4ccc5c(c4)NC(=O)CO5)C3)c2n1
Temperature: 25 °C
Reaction time: 13 h
Yield: 29.3 %

Procedure:
3-(3-Methoxy-6-oxopyrido[2,3-b]pyrazin-5(6H)-yl)propanal (292 mg, 1.25 mmol) and 6-(4-amino-2-oxopyrrolidin-1-yl)-2H-1,4-benzoxazin-3(4H)-one (Reference Example 6; 310 mg, 1.25 mmol) were dissolved in a mixed solvent (33 ml) of dichloromethane/N,N-dimethylformamide (10:1). Acetic acid (0.143 ml, 2.50 mmol) and anhydrous sodium sulfate (600 mg) were added to the solution and the mixture was stirred at room temperature for 13 hours. Sodium triacetoxyborohydride (531 mg, 2.50 mmol) was added to the reaction solution, the mixture was stirred for 4 hours and the solvent was removed under reduced pressure. A lower layer solvent of chloroform/methanol/water (7:3:1) was added to the residue, the resultant was alkalized by adding saturated sodium bicarbonate water under cooling on ice and extracted with a lower layer solvent of chloroform/methanol/water (7:3:1). After drying the extract with anhydrous sodium sulfate, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to yield 170 mg (29%) of the title compound in the form of a white solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7](Cl)=[N:8][CH:9]=1.[CH:11]([OH:14])([CH3:13])[CH3:12]>>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:14][CH:11]([CH3:13])[CH3:12])=[N:8][CH:9]=1
Reactant: CC(C)O
Reactant: Clc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Product: CC(C)Oc1ccc(Br)cn1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
60% NaH in oil (1.5:1, Sodium hydride:Mineral Oil, 5.20 g) was added in two portions to isopropyl alcohol (150 mL) at room temperature under N2. The mixture was stirred at 60° C. for 30 min. 5-bromo-2-chloropyridine (10.00 g, 51.96 mmol) was added in two portions and the mixture was stirred at reflux 4 h and then at 80° C. overnight. The solution was concentrated in vacuo. Water (50 mL) and EtOAc (50 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was removed in vacuo. The crude product was subjected to flash chromatography (silica, 0-50% EtOAc in heptanes) to give the title compound as a clear oil (8.74 g, 78%). 1H NMR (600 MHz, DMSO) δ 8.17 (s, 1H), 7.61 (dd, 1H), 6.59 (d, 1H), 5.23 (m, 1H), 1.33 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH3:24][N:25]([CH3:36])[C:26](=[O:35])[CH2:27][NH:28][C:29]1[CH2:33][S:32][C:31](=[O:34])[N:30]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:33]2/[C:29]([NH:28][CH2:27][C:26]([N:25]([CH3:36])[CH3:24])=[O:35])=[N:30][C:31](=[O:34])[S:32]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CN(C)C(=O)CNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CN(C)C(=O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 55.5 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (6.57 g) and N,N-dimethyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)glycinamide (4.68 g) in 2-propanol (60 mL) was added piperidinium acetate (2.81 g). The reaction mixture was stirred at 80° C. for 4 hr and concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane). The obtained solid was washed with diisopropyl ether and recrystallized from ethyl acetate/heptane to give the title compound (5.62 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][C:7](=O)[CH:6]=[C:5]2[CH3:14].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:19]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([Cl:19])[CH:6]=[C:5]2[CH3:14]
Reactant: Cc1cc(=O)[nH]c2c(C)cc(Br)cc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc(Cl)nc2c(C)cc(Br)cc12
Yield: 93 %

Procedure:
This quinolone (410 mg, 1.6 mmol) in POCl3 (5 mL) was refluxed for 2 h, then poured onto ice. The solution was neutralized to pH 7 by addition of NH4OH, and the resulting solid collected by filtration. Washing with water and drying in vacuo gave 6-bromo-2-chloro-4,8-dimethyl-quinoline (407 mg, 93%).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]#[N:9].[C:10]([N:18]=[C:19]=[S:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:8]([C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]=1[NH:1][C:19]([NH:18][C:10](=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[S:20])#[N:9]
Reactant: N#CC1=C(N)CCCC1
Reactant: O=C(N=C=S)c1ccccc1
Product: N#CC1=C(NC(=S)NC(=O)c2ccccc2)CCCC1

Procedure:
Prepared as in Example 1a from 2-aminocyclohex-1-enecarbonitrile (Example 10b) and benzoyl isothiocyanate as a white solid. MS 286 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10]O.[Br:12][C:13]1[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=1>>[Br:12][C:13]1[CH:14]=[CH:15][C:16](=[O:19])[N:17]([CH2:10][CH2:9][C:8]#[C:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:18]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16](=[O:19])[N:17]([C:10]#[C:9][CH2:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:18]=1
Reactant: OCCC#Cc1ccccn1
Reactant: O=c1ccc(Br)c[nH]1
Product: O=c1ccc(Br)cn1C#CCCc1ccccn1
Product: O=c1ccc(Br)cn1CCC#Cc1ccccn1
Yield: 46.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 109(D), from 4-(pyridin-2-yl)but-3-yn-1-ol (700 mg, 4.76 mmol, Example 3(A)) and 5-bromo-1H-pyridin-2-one (870 mg, 5.00 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 334 mg (1.10 mmol, 23%) of 5-bromo-1-(4-pyridin-2-yl-but-ynyl)-1H-pyridin-2-one.