Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li:5])CCC.[CH2:6]([C:10]1[CH2:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9]>CCCCCC.O1CCCC1>[CH2:6]([C:10]1([Li:5])[CH:14]=[CH:13][CH:12]=[CH:11]1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCC1=CC=CC1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: [Li]C1(CCCC)C=CC=C1
Reaction time: 1 h
Yield: 70 %

Procedure:
The solution of 36.7 ml (0.09 mol) n-butyl lithium in 2.5 M hexane solution was slowly dropped into the solution of 11.0 g (0.09 mol) of n-butyl cyclopentadiene in 100 ml of tetrahydrofuran (THF) while being cooled with ice bath and stirred. After completion of dropping, the stirring was continued for 1 hours to yield a white clouding solution of n-butyl cyclopentadienyl lithium.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:28][C:29]([F:41])([F:40])[C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:39][S:36]([C:33]3[CH:32]=[CH:31][C:30]([C:29]([F:28])([F:40])[F:41])=[CH:35][CH:34]=3)(=[O:37])=[O:38])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1)c1ccccc1

Procedure:
Prepared by coupling of 1a and 4-(trifluoromethyl)benzenesulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method B described hereinabove. Yield (18%); 1H NMR (d6-DMSO) δ 12.46 (br s, 1H), 8.11 (d, J=8.5 Hz, 2H), 7.99 (d, J=8.5 Hz, 2H), 7.40-7.07 (m, 13H), 6.84 (d, J=8.1 Hz, 2H), 6.40 (d, J=15.7 Hz, 1H), 2.35 (q, J=7.3 Hz, 2H), 0.81 (t, J=7.3 Hz, 3H); APcI m/z: 562 (M+H+)
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][C:9](=[O:21])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[F:20])[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].[F:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30]O)=[CH:27][CH:26]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:21])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:30][CH2:29][C:28]3[CH:32]=[CH:33][C:25]([F:24])=[CH:26][CH:27]=3)=[CH:15][C:14]=2[F:20])[O:11][CH3:12])=[CH:22][CH:23]=1)#[N:2]
Reactant: OCCc1ccc(F)cc1
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(O)cc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(OCCc2ccc(F)cc2)cc1F

Procedure:
In analogy to example 22.1, (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-4-hydroxy-phenyl)-2-methoxy-acetamide (example 70.4) was reacted with 4-fluorophenethyl alcohol, diethyl azodicarboxylate and triphenyl-phosphine in THF to give (RS)-N-(4-cyano-benzyl)-2-{2-fluoro-4-[2-(4-fluoro-phenyl)-ethoxy]-phenyl}-2-methoxy-acetamide. Colorless oil. MS 437.3 ([M+H]+)
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH2:6][CH:7]1[O:21][C:10]2=[C:11]3[C:16](=[C:17]([CH3:19])[CH:18]=[C:9]2[CH2:8]1)[NH:15][C:14](=[O:20])[CH:13]=[CH:12]3)#[N:2].[CH3:24][NH2:25]>C(O)C.CN(C)C=O>[C:1]([N:3]=[C:4]([NH:25][CH3:24])[NH:5][CH2:6][CH:7]1[O:21][C:10]2=[C:11]3[C:16](=[C:17]([CH3:19])[CH:18]=[C:9]2[CH2:8]1)[NH:15][C:14](=[O:20])[CH:13]=[CH:12]3)#[N:2]
Reactant: CSC(=NC#N)NCC1Cc2cc(C)c3[nH]c(=O)ccc3c2O1
Reactant: CN
Solvent: CCO
Solvent: CN(C)C=O
Product: CNC(=NC#N)NCC1Cc2cc(C)c3[nH]c(=O)ccc3c2O1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
The compound obtained in Example 212 (0.66 g, 2.01 mmol) was dissolved in a mixture of ethanol (30 ml) and dimethylformamide (50 ml). To the obtained solution, 30% methylamine in ethanol (25 ml) was added and stirred at 80° C. for 1.5 hours. The solvent was distilled off under reduced pressure, and the residue was washed with ethanol. 0.626 g (assayed quantitatively) of the title compound was obtained as a pale yellow solid. The solid was recrystallized from chloroform--methanol--ether, to obtain the title compound as colorless needles (mp. 262°-265° C. (dec.)).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:3]=1[NH:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10]>CO.[C].[Pd]>[F:1][C:2]1[C:3]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10])=[C:11]([CH:12]=[CH:13][CH:14]=1)[NH2:15]
Reactant: COCCCCNc1c(F)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COCCCCNc1c(N)cccc1F
Reaction time: 3.5 h
Yield: 98.3 %

Procedure:
2-Fluoro-N-(4-methoxybutyl)-6-nitroaniline (3.54 g) was dissolved in methanol (50 ml), palladium-carbon (5%, 140 mg) was added, and the mixture was stirred for 3.5 hr under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the object product (3.05 g).
Reaction SMILES: [C:1]1([N:7]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:8]2[CH:20]=[CH:19][C:18]3[C:17]4[C:12](=[CH:13][C:14](Br)=[CH:15][CH:16]=4)[C:11]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:10]=3[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH:70]([C:72]1[CH:77]=[CH:76][N:75]=[CH:74][CH:73]=1)=[CH2:71]>C(N(CC)CC)C>[C:1]1([N:7]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:8]2[CH:20]=[CH:19][C:18]3[C:17]4[C:12](=[CH:13][C:14]([CH:71]=[CH:70][C:72]5[CH:77]=[CH:76][N:75]=[CH:74][CH:73]=5)=[CH:15][CH:16]=4)[C:11]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:10]=3[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=Cc1ccncc1
Reactant: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(Br)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(C=Cc3ccncc3)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Yield: 59.45 %

Procedure:
N,N-diphenyl-7-bromo-9,9-di-n-decyl-9H-fluorene-2-amine (8.08 9,11.66 mmol), tri-o-tolylphosphine (1.42 g, 4.67 mmol), triethylamine (30 ml, degassed with nitrogen for 15 minutes), 4-vinylpyridine (2.52 ml, 23.32 mmol) and palladium(Il) acetate (0.13 g, 0.58 mmol) were added to a single-necked round bottom flask equipped with a magnetic stirrer and reflux condenser. The solution was heated at reflux by means of an oil bath under nitrogen for 16 hours. The solvent was removed under reduced pressure and the residue dissolved in methylene chloride. The organic layer was washed 3 times with water, dried over anhydrous MgSO4, filtered and concentrated. The product was purified by column chromatography using silica gel and 85:15 hexane:ethyl acetate to afford a yellow oil in 59.45% yield. The oil, upon standing for several days, gradually solidified to give a waxy solid (mp 88.4° C.-89.3° C.). Mass Spec. m/z 716 (M+), 576, (M-C10H20), 358 (M++). Elemental Analysis: Calculated for C52H64N2 : C, 87.10; H, 9.00; N, 3.90. Found: C, 87.17; H, 9.45; N, 3.35.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:4]1(=[O:6])[N:12]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCCC(=O)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(O)CCCN1C(=O)c2ccccc2C1=O

Procedure:
To a mixture of phthalic anhydride (14.8 g, 100 mmole) and 4-aminobutyric acid (10.3 g, 100 mmole) in 150 mL of dry toluene was added triethylamine (1.3 mL, 9.3 mmole). The reaction mixture was heated to reflux in a flask equipped with a Dean Stark trap and condensor. After refluxing for 2.5 hours, the reaction solution was cooled in an ice bath which resulted in the formation of a white precipitate. The solid was isolated by filtration and washed with 5% HCl (3×80 mL) followed by cold water (2×70 mL). 4-Phthalimidobutyric acid was obtained as a white powder (16.8 g, 72%). m.p.: 118-118.6° C.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[C:14](F)[CH:13]=[CH:12][C:11]=3[N+:17]([O-:19])=[O:18])[CH:5]=2)[CH2:3][CH2:2]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[C:14]([NH:29][C@H:27]([C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)[CH3:28])[CH:13]=[CH:12][C:11]=3[N+:17]([O-:19])=[O:18])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)cc1Nc1cc(C2CC2)[nH]n1
Reactant: C[C@H](N)c1ccc(F)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ccc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)c1)c1ccc(F)cc1
Temperature: 230 °C
Yield: 96.7 %

Procedure:
A mixture of 5-cyclopropyl-N-(5-fluoro-2-nitrophenyl)-1H-pyrazol-3-amine (Method 82; 0.27 g, 1.03 mmol), (S)-1-(4-fluoro-phenyl)-ethylamine (0.72 g, 5.15 mmol), and DIEA (0.27 ml, 1.54 mmol) in n-BuOH (5 ml) was heated in a sealed tube at 230° C. for 23 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane:EtOAc=1:2) to give the title compound as a yellow solid (0.38 g, 97%). NMR (400 MHz) 12.25 (s, 1H), 10.14 (s, 1H), 7.87 (d, J=9.6 Hz, 1H), 7.76 (d, J=6.4 Hz, 1H), 7.36 (m, 2H), 7.15 (m, 2H), 6.68 (s, 1H), 6.22 (d, J=8.4 Hz, 1H), 5.60 (br, 1H), 4.57 (m, 1H), 1.87 (m, 1H), 1.44 (d, J=6.8 Hz, 3H), 0.98 (m, 2H), 0.70 (m 2H). MS: Calcd.: 381; Found: [M+H]+ 382.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[F:17][C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>O1CCCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[C:7]([C:8]2[N:12]([S:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=3)(=[O:26])=[O:25])[CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: O=Cc1c[nH]c(-c2cccnc2Cl)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc(-c2cccnc2Cl)n(S(=O)(=O)c2cccc(F)c2)c1
Reaction time: 0.25 h
Yield: 95.2 %

Procedure:
To a solution of 5-(2-chloropyridin-3-yl)-1H-pyrrole-3-carbaldehyde (250 mg) in tetrahydrofuran (25 mL) was added sodium hydride (60% in oil, 73 mg) at room temperature and the mixture was stirred for 15 min. 3-Fluorobenzenesulfonyl chloride (310 mg) was added to the reaction mixture, and the mixture was further stirred for 30 min. The reaction mixture was diluted with saturated brine, and extracted with ethyl acetate. The extract 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=1:1) to give the title compound as a colorless oil (yield 420 mg, 95%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@@H:4]([NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([OH:20])[CH:7]=1.[N:33]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1.C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C@H:4]([NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C:3]([O:2][CH3:1])=[O:32])=[CH:7][C:8]=1[O:20][C:38]([N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:39])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(O)c1)NC(=O)OCc1ccccc1
Reactant: O=C(Cl)N1CCCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OC(=O)N2CCCC2)c1)NC(=O)OCc1ccccc1
Temperature: 40 °C
Reaction time: 48 h

Procedure:
(S)-2-Benzyloxycarbonylamino-3-(4-benzyloxy-3-hydroxy-phenyl)-propionic acid methyl ester (434 mg) was dissolved in dichloromethane (7 ml) and a solution of 1-pyrrolidinylcarbonyl chloride (200 mg) in dichloromethane (2 ml) was added. Triethylamine (0.22 ml) was added dropwise followed by a catalytic amount of DMAP. The mixture was stirred and heated at 40° C. overnight. The reaction was monitored by HPLC/MS and further portions of 1-pyrrolidinylcarbonyl chloride (400 mg) and triethylamine (0.4 ml) were added and heating continued at 55 C for 48 hours. The reaction mixture was diluted with dichloromethane and washed with dil HCl, with aq sodium bicarbonate and with brine. Drying (MgSO4) and evaporation gave the crude product. Silca gel chromatography, eluting with mixtures of ethyl acetate-hexane gave pyrrolidine-1-carboxylic acid 2-benzyloxy-5-((S)-2-benzyloxycarbonylamino-2-methoxycarbonyl-ethyl)-phenyl ester as a colourless gum, 364 mg; Rf 0.3 (ethyl acetate-hexane 1:1); HPLC/MS retention time 7.31 min, m/z 533 (MH+).
Reaction SMILES: [F:1][C:2]1(B(O)O)[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[OH:19]O.O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:4]([OH:19])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: OO
Reactant: CCCCCCOC1C=C(F)C=CC1(F)B(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCOc1c(F)ccc(F)c1O
Reaction time: 0.75 h
Yield: 87 %

Procedure:
White crystals of 1,4-difluoro-2-hexyloxybenzene-1-boronic acid (48 g) were dissolved in warm toluene (150 ml) and hydrogen peroxide (43 ml, 30%) was added drop-wise. Heating was continued for 45 min at 100° C. Once the solution had cooled to room temperature water was added (50 ml) and the layers were separated. The toluene layer was washed with ferrous ammonium sulphate (10%, 2×50 ml) and water (2×50 ml). The combined organic extracts were dried with magnesium sulphate, filtered and the solvent was removed to yield crude 3,6-difluoro,2-hexyloxyphenol as a pale yellow oil (31.67 g, 100%). The crude product was dissolved in toluene (150 ml), extracted with sodium hydroxide solution (10%w/v in methanol, 3×50 ml). The purple, aqueous extract, containing the phenoxide anion of the product, was then re-acidified with concentrated HCl until all of the colour had been displaced (pH˜4). The phenol was then extracted with dichloromethane (3×100 ml), washed with water (3×50 ml), dried with magnesium sulphate and filtered. Removal of the solvent in vacuo yielded the required product as an orange/brown oil (27.2 g, 87%). Kugelrohr distillation was performed under reduced pressure (2 mbar), the colourless distillate collected when the oven temp was 100° C. was found to contain only 4 (26.5 g, 82%), (Found: C, 62.65; H, 6.9. C12H16O2F2 requires C, 62.6; H, 6.9; O, 13.91; F, 16.52%); vmax(film)/cm−1 3524 and 2932 (C—H aliph), 2300 (C═C); δH(300 MHz; CDCl3) 0.90 (3H, t, 3J(H,H)=7 Hz, —CH3), 1.32 (4H, m, 2×—CH2—), 1.34 (2H, septet, 3J(H,H)=7 Hz, —CH2CH2CH2O—Ar), 1.76 (2H, quintet, 3J(H,H)=7 Hz, —CH2CH2CH2O—Ar), 4.17 (2H, t, 3J(H,H)=7 Hz, —CH2CH2O—Ar), 5.70 (1H, s, —OH, removed with D2O), 6.58 (1H, ddd, 3J(H,F)=13.3, 3J(H,H)=7.4, 4J(H,F)=4.5 Hz, C3H), 6.74 (1H, ddd, 3J(H,F)=18.3, 3J(H,H) 7.4, 4J(H,F)=4.6 Hz, C4H); δC(75 MHz 1H{BB}, INEPT; CDCl3) 14.31 (CH3), 22.91 (CH2), 25.78 (CH2), 30.34 (CH2), 31.87 (CH2), 74.90 (CH2), 106.65 (CH, dd, 2J(C,F)=15.1, 3J(C,F)=8.4 Hz, C4), 110.75 (CH, dd, 2J(C,F)=15.1, 3J(C,F)=8.4 Hz, C5), 135.67 (C, dd, 2J(C,F)=15.1, 3J(C,F)=8.4 Hz, C1), 138.42 (C, dd, 2J(C,F)=15.1, 3J(C,F)=8.4 Hz, C2), 147.65 (C, dd, 1J(C,F)=239, 4J(C,F)=2.6 Hz, C6), 151.7 (C, dd, 1J(C,F)=248, 4J(C,F)=2.6 Hz, C3); m/z 230 (M+, 10%), 146 (M+-alkoxy chain, 100%), 43 (50%).
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=1[C:12]#[C:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[NH4+].[Cl-]>[Zn]>[NH2:24][C:22]1[CH:21]=[CH:20][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=2[C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[C:2]([F:1])[CH:23]=1
Reactant: Nc1nccc(Oc2ccc([N+](=O)[O-])cc2F)c1C#Cc1ccccn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Product: Nc1ccc(Oc2ccnc(N)c2C#Cc2ccccn2)c(F)c1
Yield: 78 %

Procedure:
The title compound was prepared from the reduction of 4-(2-fluoro-4-nitrophenoxy)-3-(2-(pyridin-2-yl)ethynyl)pyridin-2-amine (35 mg, 0.10 mmol) using zinc dust (65 mg, 1.0 mmol) and NH4Cl (53 mg, 1.0 mmol) in the same manner as Step C of Example 11. This gave the title compound (25 mg, 78%) as brown oil. MS (ESI+): m/z 321.25 (M+H)+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:6]=1[C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[N:14]=1)=[O:8])(=[O:3])[CH3:2].[Br:24]N1C(=O)CCC1=O>C(#N)C>[C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:6]=1[C:7]([NH:9][C:10]1[S:11][C:12]([Br:24])=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[N:14]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1ccc(Br)cc1C(=O)Nc1nc(C(C)(C)C)cs1
Solvent: CC#N
Product: CC(=O)Oc1ccc(Br)cc1C(=O)Nc1nc(C(C)(C)C)c(Br)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]thiazol-2-yl}benzamide (compound of Example 181(2); 0.20 g, 0.50 mmol) was dissolved in acetonitrile (10 mL). N-Bromosuccinimide (97.9 mg, 0.55 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give the title compound as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](Cl)=[O:6].C(N(CC)CC)C.[NH2:19][C:20]1[CH:42]=[CH:41][C:23]([C:24]([N:26]2[CH2:32][C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[CH2:29][C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[CH:37]1[C:28]2[CH2:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[CH2:32][N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:5](=[O:6])[C:4]4[CH:3]=[C:2]([Cl:1])[CH:10]=[C:9]([Cl:11])[CH:8]=4)=[CH:42][CH:41]=3)=[O:25])[C:27]=2[CH:40]=[CH:39][CH:38]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
A mixture of 301.6 mg of 3,5-dichlorobenzoyl chloride and 145 mg of triethylamine is stirred in 2 ml of methylene chloride while 314 mg of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine in 5 ml of methylene chloride is added. The reaction mixture is stirred at room temperature for 2 hours and 100 mg of 3,5-dichlorobenzoyl chloride added. The reactants are heated at reflux for 36 hours. The cooled reaction mixture layer washed with 1N HCl, water, 1N NaOH, water and brine. The organic layer is dried with Na2SO4 and passed through a short pad of hydrous magnesium silicate and hexane added to the filtrate at the boil to give 242 mg of the desired product as a crystalline solid, m.p. 263°-265° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[N:20])[CH:17]=4)[NH:12][N:11]=3)[CH:8]=[CH:9][C:2]1=2.[OH:21]O.[OH-].[Na+].Cl>O.C(O)C>[O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH2:20])=[O:21])[CH:17]=4)[NH:12][N:11]=3)[CH:8]=[CH:9][C:2]1=2
Reactant: N#Cc1ccc2[nH]nc(-c3ccc4c(c3)CCO4)c2c1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC(=O)c1ccc2[nH]nc(-c3ccc4c(c3)CCO4)c2c1
Temperature: 45 °C
Yield: 53 %

Procedure:
A mixture of 3-(2,3-dihydrobenzo[b]furan-5-yl)-1H-indazole-5-carbonitrile (0.50 g, 1.9 mmol), 95% ethanol (6 mL), aqueous 30% hydrogen peroxide (3 mL), and 6.0 N aqueous sodium hydroxide (1 mL) was heated at 45° C. for 3 h. The reaction mixture was diluted with water (40 mL) and acidified to pH 6 with 3 N hydrochloric acid. The solid was filtered and dried in a vacuum oven to give product (0.080 g, 53% yield): 1H NMR (DMSO-d6) δ 13.22 (s, 1H), 8.54 (s, 1H), 8.12 (s, 1H), 7.90 (d, 2H), 7.76 (d, 1H), 7.55 (d, 1H), 7.32 (s, 1H), 6.91 (d, 1H), 4.59 (t, 2H), 3.28 (t, 2H); ES-MS (m/z) 280 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]2)=[N:5][N:6]=1.[CH3:18][CH2:19][CH2:20][C:21](=O)[CH2:22][C:23](=O)[CH2:24][CH2:25][CH3:26]>C(O)(=O)C>[CH2:20]([C:21]1[CH:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:6]2[N:5]=[C:4]([N:7]3[CH2:8][CH2:9][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:12]3)[N:3]=[C:2]2[N:1]=1)[CH2:19][CH3:18]
Reactant: CCOC(=O)N1CCN(c2nnc(N)[nH]2)CC1
Reactant: CCCC(=O)CC(=O)CCC
Solvent: CC(=O)O
Product: CCCc1cc(CCC)n2nc(N3CCN(C(=O)OCC)CC3)nc2n1
Yield: 93.9 %

Procedure:
A mixture of 4.48 g (0.02 moles) of 4-(5-amino-4H-1,2,4-triazol-3-yl)-1-piperazinecarboxylic acid, ethyl ester, 3.12 g (0.02 moles) of 4,6-nonanedione and 50 ml of glacial acetic acid was refluxed for 12 hours. The resulting solution was evaporated to dryness in vacuo. The residue was partitioned and treated as described in Example 12 and gave 6.77 g of the desired product as colorless crystals, mp 130°-132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=1)=[O:16]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:20]2[CH:21]=[CH:22][C:17]([C:15](=[O:16])[CH2:14][CH3:13])=[CH:18][CH:19]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(O)c1ccc(Cl)cc1
Reactant: CCC(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCC(=O)c1ccc(OC(C)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
26.5 g of 1-(4-chlorophenyl)-ethanol are added dropwise to 7.9 g of sodium hydride (55% in oil) in 250 ml of dimethylacetamide and the mixture is stirred at room temperature for 30 minutes. 25.7 g of 4-fluoropropiophenone are then added dropwise; the mixture is heated to 100° C. and stirred for 90 minutes. After cooling, the reaction mixture is concentrated in vacua; the residue is taken up in ethyl acetate, washed twice with water and once with saturated sodium chloride solution and dried over sodium sulfate. The solvent is evaporated off in vacuo and the residue is purified by recrystallisation from hexane to yield the title compound having a melting point 70-71° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]=[C:6]=[O:7])=[O:4].C1(C)C=CC=CC=1.[C:15]([CH:17]1[CH2:19][NH:18]1)#[N:16].C>C(OCC)(=O)C>[Cl:1][CH2:2][C:3]([NH:5][C:6]([N:18]1[CH2:19][CH:17]1[C:15]#[N:16])=[O:7])=[O:4]
Reactant: N#CC1CN1
Reactant: O=C=NC(=O)CCl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#CC1CN1C(=O)NC(=O)CCl

Procedure:
A solution of 36 g. chloroacetyl isocyanate in 100 ml. toluene is added dropwise, while stirring and cooling, at a temperature of 20° to 30° C. to 20.4 g. 2-cyanoaziridine dissolved in 200 ml. toluene. The resulting suspension is further stirred for 1 hour at ambient temperature, then filtered with suction. The solid material obtained is washed with toluene and triturated with diethyl ether to give 62 g. of crude product. This is introduced into about 2.5 to 3 liters ethyl acetate at a temperature of 60° C., boiled for a short time and the clear solution treated with active charcoal. After filtration, the clear and still hot filtrate is evaporated in a vacuum and the evaporation residue is triturated with anhydrous diethyl ether and dried for 1 hour at 70° C. There are obtained 39.3 g. of product with a melting point of 152°-155° C. After further purification by stirring for 5 minutes with 200 ml. ethyl acetate at 60° C. and trituration of the crystals obtained with diethyl ether, there are obtained, after drying in a vacuum at 70° C. 28.9 g. 1-(N-chloroacetyl-carbamoyl)-2-cyanoaziridine; m.p. 152°-155° C.