Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([S:9](Cl)(=[O:11])=[O:10])=[CH:8][C:4]=2[CH:3]=1.[NH3:15]>C1COCC1>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([S:9]([NH2:15])(=[O:11])=[O:10])=[CH:8][C:4]=2[CH:3]=1
Reactant: N
Reactant: O=S(=O)(Cl)c1cc2cc(Cl)ccc2s1
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc2cc(Cl)ccc2s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5-chloro-benzo[b]thiophene-2-sulfonyl chloride (Komoriya, Satoshi; Haginoya, Noriyasu, Bioorganic & Medicinal Chemistry (2005), 13(12), 3927-3954; 0.57 g, 2.1 mmol) in THF (8.0 mL) was added ammonia gas until saturation at ca. 10° C., then the flask was stoppered, and the reaction mixture was stirred at rt for 4 h. The reaction mixture was then quenched with water; the organic solvent was slowly evaporated under vacuum. The precipitate formed was filtered off, washed with water and dried over P2O5 under high vacuum to obtain the desired compound (0.52 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH2:18][CH:17]([C:19]([OH:21])=O)[CH2:16]3)[CH:9]=2)[N:3]=1.[C:22]1([NH2:29])[C:23]([NH2:28])=[CH:24][CH:25]=[CH:26][CH:27]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:29][C:19]([CH:17]1[CH2:16][N:15]([C:10]2[CH:9]=[C:8]([N:4]3[C:5]([CH3:7])=[N:6][C:2]([CH3:1])=[N:3]3)[N:13]=[C:12]([CH3:14])[N:11]=2)[CH2:18]1)=[O:21]
Reactant: Cc1nc(N2CC(C(=O)O)C2)cc(-n2nc(C)nc2C)n1
Reactant: Nc1ccccc1N
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CC(C(=O)Nc3ccccc3N)C2)cc(-n2nc(C)nc2C)n1
Temperature: 50 °C

Procedure:
Compound 107-2 (584 mg, 2.03 mmol), benzene-1,2-diamine (263 mg, 2.43 mmol), HOBt (465 mg, 3.04 mmol), EDC (582 mg, 3.04 mmol) and DIEA (1.77 mL, 10.1 mmol) were combined in degassed DMF (10 mL) and heated at 50° C. for 18 h. The mixture was cooled to room temperature, poured into sodium bicarbonate (200 mL, aqueous saturated) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc (containing 10% MeOH)/hexanes), providing 107-3 as a pale green solid. MS: m/z=379.3 (M+H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=3)[N:6]=2)[CH2:2]1.C(N(CC)CC)C.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[C:32]1[C:33]([C:42]2[CH:49]=[CH:48][C:45]([CH:46]=O)=[CH:44][CH:43]=2)=[N:34][C:35]2[N:36]([N:38]=[C:39]([CH3:41])[N:40]=2)[CH:37]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN1C(=O)CCC1.C(O)(=O)C>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[C:32]1[C:33]([C:42]2[CH:43]=[CH:44][C:45]([CH2:46][N:1]3[CH2:4][CH:3]([C:5]4[N:6]=[C:7]([C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=5)[NH:8][N:9]=4)[CH2:2]3)=[CH:48][CH:49]=2)=[N:34][C:35]2[N:36]([N:38]=[C:39]([CH3:41])[N:40]=2)[CH:37]=1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccc(F)cc3F)cn2n1
Reactant: Cc1cccc(-c2n[nH]c(C3CNC3)n2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2nc(C3CN(Cc4ccc(-c5nc6nc(C)nn6cc5-c5ccc(F)cc5F)cc4)C3)n[nH]2)n1
Reaction time: 1 h

Procedure:
164.5 mg 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-6-methylpyridine×2HCl (60% pure) are dissolved in 4.8 mL NMP. After addition of 0.2 mL triethylamine the reaction mixture is stirred for one hour. 200 mg (0.57 mmol) 4-[6-(2,4-Difluorophenyl)-2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-benzaldehyde and 0.06 mL acetic acid are added. The reaction mixture is stirred overnight at room temperature. 207.4 mg (0.98 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature for another night. The reaction mixture is poured on saturated NaHCO3/ice water. The precipitate is filtered off, washed with water and dried. After chromatography of the precipitate on silica gel (dichloromethane/methanol) 92.2 mg (27.9%) of the desired product are obtained.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([N:12]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([O:41]C)=[C:37]([Br:43])[CH:36]=2)=[CH:31][CH:30]=1)[C:13]([C:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][C:16]=1[CH2:24][CH2:25][CH2:26][CH3:27])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)=O.CC(C)=O.O>C(Cl)Cl>[CH2:5]([N:12]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[C:37]([Br:43])[CH:36]=2)=[CH:33][CH:34]=1)[C:13]([C:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][C:16]=1[CH2:24][CH2:25][CH2:26][CH3:27])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCCCc1oc2ccccc2c1C(=O)N(Cc1ccccc1)Cc1ccc(-c2ccc(OC)c(Br)c2)cc1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCCCc1oc2ccccc2c1C(=O)N(Cc1ccccc1)Cc1ccc(-c2ccc(O)c(Br)c2)cc1
Reaction time: 3 h
Yield: 75.5 %

Procedure:
Boron tribromide (22.0 mL of a 1 M solution in methylene chloride; 22.0 mmol) was added under nitrogen dropwise over 30 minutes to a solution N-benzyl-N-[(3′-bromo-4′-methoxy-1,1′-biphenyl-4-yl)methyl]-2-butyl-1-benzofuran-3-carboxamide (4.2 g, 7.22 mmol), of prepared in the previous step, in 150 mL of methylene chloride at dry ice-acetone temperature. After the addition the dry ice-acetone bath was replaced with an ice bath and the stirring continued for 3 h. At ice bath temperature water (100 mL) was added dropwise. The aqueous layer was separated and extracted two times with methylene chloride. The extracts were combined, extracted with saturated NaCl, dried (MgSO4) and the solvent removed under reduced pressure to give N-benzyl-N-[(3′-bromo-4′-hydroxy-1,1′-biphenyl-4-yl)methyl]-2-butyl-1-benzofuran-3-carboxamide (3.1 g, 72%) as an off-white solid, MS (ESI) m/z 568 [M+H]+. Elemental Analysis for C33H30BrNO3: Calc'd: C, 69.72; H, 5.32; N, 2.46; Found: C, 68.69; H, 5.42; N, 2.28.
Reaction SMILES: [CH:1]1([C:4](Cl)=O)[CH2:3][CH2:2]1.[NH2:7][C:8]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11].N1C=CC=CC=1.[NH2:24][NH2:25]>O1CCCC1.C(OCC)(=O)C>[NH2:24][N:25]1[C:10](=[O:11])[C:9]2[C:8](=[CH:16][C:15]([F:17])=[CH:14][CH:13]=2)[N:7]=[C:4]1[CH:1]1[CH2:2][CH2:3]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: NN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Nn1c(C2CC2)nc2cc(F)ccc2c1=O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Cyclopropanecarbonyl chloride (3.59 mL, 39.2 mmol) was added to a solution of 2-amino-4-fluorobenzoic acid (Aldrich) (2.0 g, 12.9 mmol) and pyridine (5.38 mL, 66.5 mmol) in tetrahydrofuran (15 mL). The mixture was stirred at 70° C. overnight. The mixture was cooled at 0° C., hydrazine (4.86 mL, 155 mmol) was added and the reaction was stirred at about room temperature for 30 minutes, then at about 75° C. for 24 hours. The reaction mixture was cooled to about 22° C., diluted with ethyl acetate, washed with aq. NaHCO3, dried with magnesium sulfate, filtered, and concentrated. The residue was suspended in toluene and concentrated. The process was repeated to obtain the crude title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][C@H:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[CH:21]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]CC=1.C(OCC)(=O)C>C1(=O)CCCCC1.[C].[Pd]>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:21]=2)[CH2:4][C@H:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: C1=CCCCCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNc2ccccc2NC1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O=C1CCCCC1
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccccc2)c2ccccc2NC1=O
Temperature: 145 °C
Reaction time: 2.5 h
Yield: 50.2 %

Procedure:
To a solution of 5 g of (R)-(+)-2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine in 25 ml of cyclohexanone were added 5.96 g of cyclooctene and 0.5 g of 10% palladium carbon. The mixture was stirred at the internal temperature of 145° C. for 2.5 hours. After the reaction mixture was cooled to room temperature, 20 ml of ethyl acetate was added. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was crystallized by adding thereto diisopropyl ether and n-hexane and the resulting crystals were collected by filtration, whereby 3.2 g of the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[C:3]=1[F:11].C[Si](C)(C)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16](F)[C:15]=1F.BrBr.O1C[CH2:29][CH2:28][CH2:27]1>Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:27]([C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[C:3]=2[F:11])=[CH:16][CH:15]=1)[CH2:28][CH3:29]
Reactant: C[Si](C)(C)c1cccc(F)c1F
Reactant: N#Cc1ccc(Br)c(F)c1F
Reactant: C1CCOC1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: BrBr
Product: CCCc1ccc(-c2ccc(C#N)c(F)c2F)cc1
Reaction time: 0.5 h

Procedure:
0.1 mol of chlorotriisopropyl orthotitanate in 20 ml of tetrahydrofuran is added at 5° C. to a mixture of 1-bromomagnesium-4-propylbenzene (prepared from 0.1 mol of 4-propyl-bromobenzene and 0.1 mol of magnesium) and 90 ml of tetrahydrofuran and the mixture is stirred at 5° to 20° C. for 30 minutes. A mixture of 1.3 g of bis-(triphenylphosphine)-nickel(II) chloride and 0.1 mol of 4-bromo-2,3-difluorobenzonitrile (prepared from 1-trimethylsilyl-2,3-difluorobenzene by conversion into the nitrile analogously to Example 1a) 1c) and subsequent bromination with bromine with removal by distillation of the resulting trimethylsilyl bromide) is added to this mixture. Stirring for 24 hours at room temperature and customary working up gives 4-propyl-2',3'-difluoro-4'-cyanobiphenyl.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH:11]([CH3:18])[CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:20](Cl)(=[O:22])[CH3:21].[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl>[C:20]([C:15]1[S:14][C:13]([CH2:12][CH:11]([O:10][S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=2)(=[O:9])=[O:8])[CH3:18])=[CH:17][CH:16]=1)(=[O:22])[CH3:21]
Reactant: Cc1ccc(S(=O)(=O)OC(C)Cc2cccs2)cc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(CC(C)OS(=O)(=O)c2ccc(C)cc2)s1

Procedure:
2-(p-Toluenesulphonyloxy)-propylthiophene was reacted with acetyl chloride and aluminium trichloride in methylene chloride to give 5-acetyl-2-(p-toluenesulphonyloxy)-propylthiophene. With sodium azide in DMSO there was obtained therefrom 5-(3-azidopropyl)-2-thienyl methyl ketone. Oxidation with sodium hypobromite gave 5-(3-azidopropyl)-2-thiophenecarboxylic acid, m.p. 71°-72°. Reaction of this acid with thionyl chloride and subsequent treatment with conc. ammonia yielded 5-(3-azidopropyl)-2-thiophenecarboxamide, m.p. 85°-87°. There was obtained therefrom after treatment with triphenylphosphine and hydrolysis 5-(3-aminopropyl)-2-thiophenecarboxamide, m.p. 143.5°-144° (from water).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]>[Pd]>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)CCCCCCC=Cc1cccs1
Agent: [Pd]
Product: O=C(O)CCCCCCCCc1cccs1
Yield: 87.4 %

Procedure:
This compound was synthesized from 9-(2-thienyl)-8-nonenoic acid (1.19 g, 5 mmol) by a hydrogenation reaction using Pd/C (120 mg). Crystallization afforded the product (1.05 g, 88%) as white crystals (mp 32°-33° C.); IR: 3400-2500, 1715, 705 cm-1 ; 1 H-NMR: 1.35 (m, 12H), 2.35 (t, 2H), 2.85 (t, 2H), 6.95 (m, 3H), 10.35 (bs, 1H). Anal. Calcd. for C13H20SO2 : C, 64.96, H, 8.39%; Found: C, 64.81, H, 8.43%.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(#N)C>[Br-:7].[CH2:8]([N+:4]1[CH:5]=[CH:6][N:2]([CH3:1])[CH:3]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCCCCCCCCCCBr
Reactant: Cn1ccnc1
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCCCCCCC[n+]1ccn(C)c1
Product: [Br-]
Temperature: 85 °C

Procedure:
About 2 g (0.025 mol) of 1-methylimidazole and 10.7 g (0.026 mol) of 1-bromodocosane were dissolved into 20 mL of acetonitrile. The mixture was refluxed at 85° C. for 24 hours, and subsequently cooled down to room temperature. The resulting samples (cake like) were filtered and washed with ethyl ether three times. The final product: 1-docosanyl-3-methylimidazolium bromide was obtained as a white powder after being dried in a vacuum oven. The yield of this procedure was 81.4% with a melting point (Mp): 82.9° C. The spectra of 1H NMR (CDCl3 as the solvent, δ, ppm) were: 10.713 (N—CH—N, s, 1H), 7.274 (N—CH—CH, s, 1H), 7.218 (N—CH—CH, s, 1H), 4.310 (N—CH2, t, 2H), 4.130 (N—CH3, s, 3H), 1.918 (N—CH2—CH2, m, 2H), 1.248 (N—CH2—CH2—(CH2)19, m, 38H), 0.874 (CH3, t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:7]=C([CH:11]=[CH:12][CH:13]=1)C#N)=[O:5].Cl.[C:21]([OH:24])(=[O:23])[CH3:22]>>[OH:1][C:2]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:7]=[C:22]([CH:11]=[CH:12][CH:13]=1)[C:21]([OH:24])=[O:23])=[O:5]
Reactant: COc1ccc(C(=O)c2cccc(C#N)c2)c(O)c1
Reactant: CC(=O)O
Agent: Cl
Product: COc1ccc(C(=O)c2cccc(C(=O)O)c2)c(O)c1

Procedure:
A solution of, 3-(2-hydroxy-4-methoxybenzoyl)benzonitrile (from the synthesis of Example 26; 2.75 g) in a mixture of concentrated hydrochloric acid (30 g) and acetic acid (30 g) is heated under reflux for 4 hours. The precipitate which forms is collected by filtration and recrystallized from ethanol to yield 3-(2-hydroxy-4-methoxybenzoyl)benzoic acid (1.5 g), m.p. 229°-236° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[CH:4][CH:3]=1.Cl[CH2:13][C:14]([CH2:16]Cl)=O.[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]=[N+:37]=[N-:38])=[CH:29][CH:28]=2)[C:22]([C:39]#[N:40])=[C:21]([SH:41])[N:20]=1.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][N:36]=[N+:37]=[N-:38])=[CH:31][CH:32]=2)[C:22]([C:39]#[N:40])=[C:21]([S:41][CH2:16][C:14]2[N:11]=[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[S:10][CH:13]=2)[N:20]=1
Reactant: NC(=S)Nc1ccc(F)cc1
Reactant: O=C(CCl)CCl
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc(OCCN=[N+]=[N-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c(N)nc(SCc2csc(Nc3ccc(F)cc3)n2)c(C#N)c1-c1ccc(OCCN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 74 mg (0.44 mmol) of 4-fluorophenylthiourea and 55 mg (0.44 mmol) of 1,3-dichloroacetone in 5 ml of ethanol is stirred at +85° C. for 60 min. After removal of the solvent on a rotary evaporator, the residue is taken up in 5 ml of DMF, 105 mg (0.31 mmol) of the compound from Example 38A and 78 mg (0.93 mmol) of sodium bicarbonate are added and the mixture is then stirred at RT for 20 h. The mixture is then added to 15 ml of saturated sodium bicarbonate solution. The mixture is extracted with ethyl acetate (three times, 15 ml each) and the combined organic phases are dried over magnesium sulphate. After removal of the solvent on a rotary evaporator, the crude product is purified chromatographically on silica gel 60 (mobile phase gradient dichloromethane/ethanol 200:1→20:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:19])[C:9](=[CH:15][N:16]([CH3:18])C)[C:10]([O:12][CH2:13][CH3:14])=[O:11].[Cl:20][C:21]1[CH:22]=C([CH:25]=[CH:26][C:27]=1[F:28])N>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:19])[C:9](=[CH:15][NH:16][C:18]1[CH:25]=[CH:26][C:27]([F:28])=[C:21]([Cl:20])[CH:22]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1Cl
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(F)c(Cl)c1)C(=O)c1ccccc1Cl
Temperature: 25 °C
Yield: 63 %

Procedure:
A solution of ethyl 2-chloro-α-[(dimethylamino)methylene]-β-oxo-benzenepropanoate (50 mg, 0.177 mmol) in 1 mL of EtOH was treated with neat 3-chloro-4-fluoroaniline (25.8 mg, 0.177 mmol). After stirring at rt until complete by TLC, the reaction was concentrated in vacuo. The residue was subjected to flash chromatography (1:1 EtOAc/hexanes), affording 42.6 mg (63%) of the product as a white solid, mp 96-102° C. 1H NMR (400 MHz, CDCl3 9:1 ratio of alkene isomers, major isomer NMR given) δ12.66 (d, 1H, J=12.8 Hz), 8.50 (d, 1H, J=13.2 Hz), 7.37-7.16 (m, 7H), 4.01 (q, 2H, J=7.1 Hz), 0.93 (t, 2H, J=7.1 Hz).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[C:6]([NH:11][NH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1)([O-])=O.O>C(O)(C)C>[ClH:1].[NH2:2][C:5]1[C:6]([NH:11][NH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)NNc1ncccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CCOC(=O)NNc1ncccc1N

Procedure:
The ethyl 3-(3-nitro-2-pyridyl)carbazate hydrochloride 34 g (0.13 mole) was slurried in 300 ml of isopropanol and treated with 4.4 g of 5% pd/C (50% H2O) in 40 ml of isopropanol. The reaction mixture was subjected to hydrogenation at 50 psig. A 24 psig drop at 27°0 was observed (theory 30 No. at 27°), and the mixture was cooled overnight. The crystalline product was collected along with the catalyst. The product was taken up in 300 ml of hot methanol, the catalyst filtered, and the product precipitated from the filtrate, m.p. 217°-219° dec. Yield: 11 g (37%).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]([OH:29])=O)[CH:13]=[CH:14][C:15]=1[O:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:32])=O>C1C=CC=CC=1>[C:1]([O:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]([Cl:32])=[O:29])[CH:13]=[CH:14][C:15]=1[O:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCc1ccc(OC(=O)c2ccccc2)c(OC(=O)c2ccccc2)c1
Solvent: c1ccccc1
Product: O=C(Cl)CCc1ccc(OC(=O)c2ccccc2)c(OC(=O)c2ccccc2)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
6 g of 3-(3,4-dibenzoyloxyphenyl)propionic acid was dissolved in 20 ml of benzene, and 2 g of thionyl chloride was added thereto. After stirring at 60° C. for 2 hours, the solvent was distilled off in order to obtain crude 3-(3,4-dibenzoyloxyphenyl)propionic acid chloride. To 50 ml of chloroform was added 2.8 g of morpholine, and the above-mentioned acid chloride was then slowly added dropwise thereto under cooling. After stirring at room temperature for 2 hours, the reaction solution was washed with a saturated saline solution and then dried over Glauber's salt, and the solvent was then distilled off under reduced pressure. The resultant residue was purified through a silica gel column chromatography. On eluting with ethyl acetate, 6.7 g of N-[3-(3,4-dibenzoyloxyphenyl)propionyl]morpholine was obtained.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]OS(C)(=O)=O)=[CH:16][CH:15]=1.[I-].[Na+].[CH:29]1([C:35]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:37]2[N:41]=[CH:40][N:39]([CH2:42][CH:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)[N:38]=2)[OH:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(N(C(C)C)CC)(C)C>C(#N)C.O>[CH:49]1([C@@:35]([OH:36])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:37]2[N:41]=[CH:40][N:39]([CH2:42][CH:43]3[CH2:48][CH2:47][N:46]([CH2:21][CH2:20][C:17]4[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][N:3]5[C:4](=[O:11])[C:5]6[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=6)[C:2]5=[O:1])=[CH:19][CH:18]=4)[CH2:45][CH2:44]3)[N:38]=2)[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: CS(=O)(=O)OCCc1ccc(CCN2C(=O)c3ccccc3C2=O)cc1
Reactant: OC(c1ccccc1)(c1ncn(CC2CCNCC2)n1)C1CCCCC1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCc1ccc(CCN2CCC(Cn3cnc([C@](O)(c4ccccc4)C4CCCCC4)n3)CC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 68 %

Procedure:
Methanesulfonic acid 2-{4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-phenyl}-ethyl ester (Preparation 35, 20.00 g, 53.56 mmol) was dissolved in acetonitrile (80 mL) and stirred at room temperature. Sodium iodide (16.06 g, 107.12 mmol) was added portionwise and the resulting slurry heated to 80° C. for 18 h. The reaction mixture was cooled to 50° C. and further acetonitrile (80 mL) was added. To this mixture was added cyclohexyl-phenyl-(1-piperidin-4-ylmethyl-1H-[1,2,4]triazol-3-yl)-methanol (Preparation 4, 15.87 g, 53.56 mmol) and diisopropylethylamine (9.79 mL, 56.24 mmol) and heating was continued for 6 hours, then allowed to cool to room temperature. Water (160 mL) was added and the resulting slurry stirred overnight at room temperature. The solid was collected by filtration and washed with acetonitrile (5×20 mL), then dried in vacuo at 45° C. for 8 hours to yield the title compound as a brown solid in 68% yield, 20.9 g,
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)(Cl)Cl>[Cl:24][CH2:25][C:26]([NH:10][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:2]([OH:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:27]
Reactant: O=C(Cl)CCl
Reactant: NC(c1ccccc1)C(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CCl)NC(c1ccccc1)C(O)c1ccccc1
Yield: 76.8 %

Procedure:
To a stirred solution of 2-hydroxy-1,2-diphenylethylamine (95.5 g, 0.39 m) (obtained by catalytic reduction of benzoin oxime) and triethylamine (43.3 g, 0.429 m) in chloroform (1 liter) maintained under nitrogen was added dropwise chloroacetylchloride (46.2 g, 0.41 m) and the mixture heated to reflux for 1 hour. After cooling, the mixture was washed with 10% HCl (1 liter) and water and the organic phase dried over MgSO4. The solvent was evaporated to a solid residue which was recrystallized from methanol to give 91.0 g of N-chloroacetyl-2-hydroxy-1,2-diphenylethylamine, m.p. 166°-169°.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=[O:6].O.[NH2:13][NH2:14].O>C(O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:13][NH2:14])=[O:6]
Reactant: NN
Reactant: COC(=O)c1cccc(I)c1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cccc(I)c1
Temperature: 25 °C

Procedure:
To Methyl 3-iodobenzoate (25.0 g, 95.41 mmol) in ethanol (120.0 ml) was added hydrazine hydrate (50.0 ml). The reaction mixture was reflux for 18 hours. Heating was stopped and then water (300.0 ml) was added. After cooling down to room temperature, white solid was appeared. The white product solid was collected by filtration. The product was washed with water and dried under vacuum. Final white pure product was obtained in 23.0 g (92.0%). 1H NMR (400 MHz, DMSO-d6, δ): 9.85 (s, br, 1H, NH), 8.14 (t, J=1.6 Hz, 1H), 7.85 (m, 1H), 7.82 (m, 1H), 7.25 (t, J=8.0 Hz, 1H), 4.50 (s, 2H, NH2). 13C NMR (100 MHz, CDCl3) δ: 168.54, 155.38, 129.54, 126.72, 125.57, 34.90, 31.07.