Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:6]=1[S:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH3:4].[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[S:36](Cl)(=[O:38])=[O:37]>>[CH2:1]([C:5]1[N:10]=[C:9]([NH:11][S:36]([C:30]2[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:29]=2[Cl:28])(=[O:38])=[O:37])[CH:8]=[CH:7][C:6]=1[S:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:20])=[O:21])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: CCCCc1nc(N)ccc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Product: CCCCc1nc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ccc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1

Procedure:
Prepared from 6-butyl-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-pyridin-2-ylamine and 2,4-dichlorobenzenesulfonyl chloride using General Method 11 step 2 to give N-{6-butyl-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-pyridin-2-yl}-2,4-dichloro-benzenesulfonamide. 1HNMR CDCl3 8.10 (1H, d), 7.58 (2H, d), 7.47 (1H, s), 7.36 (1H, d), 7.07 (2H, d), 6.81 (1H, d), 2.97 (4H, m), 2.80 (2H, t), 1.15-1.65 (10H, m), 0.81 (3H, t). LCMS (Luna 2,): rt=8.11 minutes, 612 (M−H)−.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:27])[NH2:26].Cl[CH2:29][C:30](=O)[CH3:31].CN(C)C=O>O>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[N:4][N:3]1[C:25]1[S:27][CH:29]=[C:30]([CH3:31])[N:26]=1
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(N)=S)OCO3
Reactant: CC(=O)CCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1csc(N2N=C(c3ccc([N+](=O)[O-])cc3)c3cc4c(cc3CC2C)OCO4)n1
Temperature: 85 °C
Reaction time: 0.67 h
Yield: 82.5 %

Procedure:
A mixture of 0.76 g (1.98 mmol) of the starting material I, 1.10 g (11.88 mmol) of chloroacetone and 15 ml of dimethylformamide was stirred at 80-90° C. for 40 min. Then the reaction mixture was diluted with water, the precipitated crystals were filtered off, dried and purified by refluxing in ethanol to yield 0.69 g (82%) of the title compound; Mp.: 188-189° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:13][C@@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OCc2ccc(Cl)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(CO[C@@H]2CCNC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (R)-3-(4-chlorobenzyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.88 mmol) in dichloromethane cooled at 0° C. was treated with trifluoroacetic acid (20%) and warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organics were dried over sodium sulfate. The product was used without any further purification. ESI-MS m/z: 211 (M+1), UV retention time: 0.97 min.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[C@@H:21]([NH2:26])[CH2:22][CH2:23][CH:24]=[CH2:25].Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][C:12]=1[C@@H:21]([NH:26][C:28](=[O:29])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:22][CH2:23][CH:24]=[CH2:25]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CCC[C@H](N)c1cc(C(F)(F)F)ccc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC[C@H](NC(=O)OCc1ccccc1)c1cc(C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To DIPEA (7.48 mL, 42.8 mmol) and (1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]pent-4-en-1-amine (4.4 g, 14.3 mmol) in DCM (20 mL) was added benzyl chloroformate at 0° C. The reaction was stirred at room temperature for 2 hours and was quenched with water. The organic was washed with 10% aqueous KOH and the aqueous was back-extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, concentrated and then purified by column chromatography to yield benzyl {(1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]pent-4-en-1-yl}carbamate (5.8 g, 13.1 mmol). 1H NMR (500 MHz, CDCl3) δ7.72 (m, 1H), 7.58 (s, 1H), 7.39 (b, 5H), 7.1 (m, 1H), 5.83 (m, 1H), 5.3 (b, 1H), 5.15 (m, 3H), 2.22 (m, 1H), 2.18 (m, 1H), 1.95 (m, 1H), 1.78 (m, 1H).
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:16][CH2:17][C:18]#N>ClCCl>[C:1](=[N:14][CH2:18][C:17]#[N:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCN
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: N#CCN=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 157.5 %

Procedure:
A mixture of benzophenone imine (25 g, 0.138 mol, Aldrich) and aminoacetonitrile hydrochloride (25 g, 0.270 mol, Lancaster) in dichloromethane (1000 mL) was stirred in a 2 L Erlenmeyer flask under nitrogen at room temperature for 5 days. The reaction mixture was filtered to remove the precipitated ammonium chloride and the filtrate was evaporated to dryness in vacuo. The resulting residue was dissolved in ether (400 mL) washed with water (200 mL) and brine. After drying over magnesium sulfate the solution was evaporated to give (benzhydrylideneamino)-acetonitrile (47.89 g).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH:12]=[CH2:13].CC(C)([O-])C.[K+].C(OCC)(=O)C>C(O)(C)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:13][C:12]([C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][C:6]=2[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: C=CC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)C1=Cc2cc(Br)ccc2OC1
Temperature: 25 °C

Procedure:
To a solution of 5-bromosalicylaldehyde (10.0 g) and tert-butyl acrylate (17.5 ml) in tert-butanol (100 ml) was added potassium tert-butoxide (1.67 g) at room temperature, and the mixture was refluxed for 66 hours and cooled to room temperature. To the mixture was added ethyl acetate, and the mixture was washed with water, 1N sodium hydroxide and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:19) to give tert-butyl 6-bromo-2H-1-benzopyran-3-carboxylate (10.86 g) as pale yellow crystals.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[NH2:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:36][CH:37]=4)=[O:2])([CH2:9][CH2:8]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 10.9 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (120 mg) and 1,1-dimethylethyl 4-aminobenzoate (158 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-[4-(1,1-dimethylethyloxycarbonyl)phenyl]amino]carbonylbicyclo[2.2.2]oc t-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (20.1 mg).
Reaction SMILES: C([Si]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH:16]2[CH2:18][CH2:17]2)=[CH:11][C:10]=1[CH3:19])(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>C1COCC1>[CH:16]1([C:12]2[CH:11]=[C:10]([CH3:19])[C:9]([OH:8])=[C:14]([CH3:15])[CH:13]=2)[CH2:18][CH2:17]1
Reactant: Cc1cc(C2CC2)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(C2CC2)cc(C)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To a suspension of (4-bromo-2,6-dimethylphenoxy)tert-butyldimethylsilane (668 mg, 2.12 mmol) and tetrakis(triphenylphosphine)palladium (122 mg, 0.11 mmol) in THF (20 mL) was added cyclopropyl zinc chloride (28.0 mL, 11.2 mmol). The mixture was heated at 80° C. for 24 h and cooled to room temperature. The reaction was passed through a short pad of SiO2 to remove the catalyst and the solution was concentrated to oil. The resulting oil was diluted in EtOAc (100 mL), washed with brine (100 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=90:10) yielded 370 mg (63%) of tert-butyl(4-cyclopropyl-2,6-dimethylphenoxy)dimethylsilane. To tert-butyl(4-cyclopropyl-2,6-dimethylphenoxy)dimethylsilane (320 mg, 1.16 mmol) in THF (10 mL) was added a solution of tetrabutylammonium fluoride (5.0 mL, 1 M in THF, 5.0 mmol) and acetic acid (0.40 mL). The reaction was stirred at room temperature for 3 h and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=85:15) yielded 175 mg (93%) of 4-cyclopropyl-2,6-dimethylphenol as a light yellow oil.
Reaction SMILES: [CH2:1]=[C:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)[C:3](O)=[O:4].[NH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1>>[CH2:1]=[C:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)[C:3]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=1)=[O:4]
Reactant: C=C(C(=O)O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: COC(=O)c1ccc(N)cc1
Product: C=C(C(=O)Nc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
In a manner similar to Example 4(c), by reaction of 4.6 g (18 mmol) of α-methylene-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylacetic acid with 2.7 g (18 mmol) of methyl 4-aminobenzoate, 2.4 g (34%) of the expected ester are obtained in the form of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH:12]=O)=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1.[CH3:25][NH2:26].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH2:12][NH:26][CH3:25])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1
Reactant: O=Cc1cnc2ccc(Cl)nc2c1Nc1cccc(C(F)(F)F)c1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNCc1cnc2ccc(Cl)nc2c1Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6-chloro-4-((3-(trifluoromethyl)phenyl)amino)-1,5-naphthyridine-3-carbaldehyde (0.75 g, 2.13 mmol) was dissolved in ethanol (20 mL), added 1.2 mL of a solution of methylamine in ethanol (concentration 27%), stirred at room temperature for 4 h, and then added sodium borohydride (0.82 g, 21.7 mmol) to the system, continued stirring at room temperature for 18 h. The reaction was quenched with a saturated aqueous solution of sodium carbonate, concentrated under reduced pressure to remove ethanol, extracted with 80 mL of dichloromethane, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain 0.77 g of the titled compound.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[CH2:29][NH:28][CH:27]([CH3:35])[CH2:26]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:28]1[CH:27]([CH3:35])[CH2:26][C:25]2[C:30](=[CH:31][C:32]([O:33][CH3:34])=[C:23]([O:22][CH3:21])[CH:24]=2)[CH2:29]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1OC)CC(C)NC2
Reactant: O=C(CCCCCCCBr)NOCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CN(CCCCCCCC(=O)NOCc1ccccc1)C(C)C2

Procedure:
In a manner analogous to that of example 1(b), 8-bromo-octanoic acid benzyloxy-amide (example 1(a); 0.7 g, 2.1 mmol) was reacted with 6,7-dimethoxy-3-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.5 g, 2.1 mmol) in the presence of potassium carbonate (0.3 g, 2.2 mmol) and DMF as solvent to give 8-(6,7-dimethoxy-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-octanoic acid benzyloxyamide as an almost colorless wax (yield 0.35 g, 37%; purified by column chromatography using silica gel and ethyl acetate: methanol=95:5 as an eluent). MS (M+H+)=455.
Reaction SMILES: Cl[C:2]1[C:7]2=[N:8][O:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:22])[C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[N:10]1[O:9][N:8]=[C:7]2[C:2]([C:16]3[CH:17]=[CH:18][C:13]([N:12]([CH3:22])[CH3:11])=[CH:14][CH:15]=3)=[CH:3][CH:4]=[CH:5][C:6]=12
Reactant: Clc1cccc2nonc12
Reactant: CN(C)c1ccc(B(O)O)cc1
Product: CN(C)c1ccc(-c2cccc3nonc23)cc1

Procedure:
Starting from 4-chloro-benzo[1,2,5]oxadiazole and 4-(dimethylamino)phenylboronic acid. Orange powder. MS(ES+): 240 (M+1).
Reaction SMILES: [OH-:1].[K+].[CH2:3]([N:10]1[C:14]([CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:13][N:12]=[C:11]1[CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:33]([C:34]#[N:35])=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:24][CH2:23]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CC(O)(C)C>[CH2:3]([N:10]1[C:14]([CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:13][N:12]=[C:11]1[CH:22]1[CH2:23][CH2:24][N:25]([C:28]2[C:33]([C:34]([NH2:35])=[O:1])=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:26][CH2:27]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#Cc1cccnc1N1CCC(c2nnc(CN3CCOCC3)n2Cc2ccccc2)CC1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: NC(=O)c1cccnc1N1CCC(c2nnc(CN3CCOCC3)n2Cc2ccccc2)CC1
Temperature: 100 °C
Yield: 85.1 %

Procedure:
Powdered potassium hydroxide (95 mg, 1.68 mmol) was added to a solution of the carbonitrile of example 52 (250 mg, 0.56 mmol) in 2-Methyl-propan-2-ol (10 ml). The mixture was heated at 100° C. for 18 hr before evaporating under reduced pressure. The residue was purified by chromatography on silica gel using methanol and ammonium hydroxide in dichloromethane (5:0.5:95) as eluant to give the title compound (220 mg), as a white solid
Reaction SMILES: C[O:2][C:3](=O)[C:4](=[C:13]1[CH2:16][N:15]([CH:17]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:14]1)[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1>C(Cl)Cl.C1COCC1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:17]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[N:15]2[CH2:16][C:13](=[C:4]([C:5]3[CH:6]=[C:7]([F:12])[CH:8]=[C:9]([F:11])[CH:10]=3)[CH2:3][OH:2])[CH2:14]2)=[CH:26][CH:27]=1
Reactant: COC(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCC(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2.11 g (4.45 mmol) of methyl{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(3,5-difluorophenyl)acetate in 40 mL of hexanes and 40 mL of CH2Cl2 was added a solution of 26.7 mL (26.7 mmol) of DIAL-H (1M solution in THF), followed by stirring for 1 h at −78° C. The reaction mixture was warmed to rt for 1.5 h, quenched by addition of 8 g of sodium sulfate decahydrate, and stirred for 1 h at rt. The quenched reaction was filtered and the organic layer was concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound as a white solid. 1NMR (CDCl3) δ 3.99 (s, 2H), 4.03 (s, 21), 4.35 (s, 2H), 4.54 (s, 1H), 6.70-6.80 (m, 3H), 7.306-7.40 (m, 8H); Mass Spectrum: m/e=446 (M+1 35Cl, 35Cl) and 448 (M+1 35Cl, 37Cl).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3C(C)=NN=[C:10]3[CH2:9][N:8]=[C:7](C3C=CC=CC=3F)[C:6]=2[CH:23]=1>CN(C)C=O.C(Cl)(=O)C>[NH:11]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:23][C:6]=2[CH:7]=[N:8][CH:9]=[CH:10]1
Reactant: Cc1nnc2n1-c1ccc(F)cc1C(c1ccccc1F)=NC2
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: C1=CNc2ccccc2C=N1

Procedure:
In the manner given in Example 1, a solution of 8-fluoro-1-methyl-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dimethylformamide, N,N,N',N'-tetrapropyldiaminomethane and acetyl chloride (in 0.5 molar excess compared to the N,N,N',N'-tetrapropyldiaminomethane) are reacted together to give 8-fluoro-1[2-(dipropylamino)ethyl]-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4-benzodiazepine
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2([C:17]([O:19][CH3:20])=[O:18])[CH:10]([C:11](I)=[CH:12][CH2:13][CH:14]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)[CH3:29].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CO.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>[CH2:1]([N:8]1[CH2:16][C:15]2([C:17]([O:19][CH3:20])=[O:18])[CH:10]([C:11]([C:33]3[CH:34]=[CH:35][C:30]([CH2:28][CH3:29])=[CH:31][CH:32]=3)=[CH:12][CH2:13][CH:14]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1ccc(B(O)O)cc1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(I)=CCC2c1ccccc1
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: Cc1ccccc1
Solvent: CO
Product: CCc1ccc(C2=CCC(c3ccccc3)C3(C(=O)OC)CN(Cc4ccccc4)CC23)cc1
Yield: 72 %

Procedure:
By carrying out the reaction as in Stage C of Example 45, but from 1.35 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-iodo4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate in 20 cm3 of toluene, from 340 mg of tetrakis(triphenylphosphine)palladium, from 0.38 g of trimer anhydride of 4-ethylphenylboronic acid in 10 cm3 of methanol and from 15 cm3 of a 2N aqueous sodium carbonate solution at reflux for eighteen hours, 0.92 g (72%) of methyl (3aRS,4SR,7aRS)-2-benzyl-7-(4-ethylphenyl)-4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate was obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and of ethyl acetate (90/10 by volume), in the form of a viscous yellow oil, the characteristic of which was as follows:
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:19]=[CH:18][C:9]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][C:7]=1[F:20].O1CCCC1.Cl.C(=O)([O-])O.[Na+]>CO>[F:20][C:7]1[CH:8]=[C:9]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:18]=[CH:19][C:6]=1[CH:2]=[O:1]
Reactant: Fc1cc(COc2ccccn2)ccc1C1OCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=Cc1ccc(COc2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.3 %

Procedure:
To a solution of 2-(4-[1,3]dioxolan-2-yl-3-fluoro-benzyloxy)-pyridine (2.17 g, 7.88 mmol) described in Manufacturing Example 204-1-4 in methanol (10 mL) and tetrahydrofuran (10 mL) was added 5 N hydrochloric acid (8.43 mL, 8.43 mmol). This solution was stirred for 15 minutes at room temperature. This mixture was cooled to 0° C. and neutralized with a saturated sodium hydrogencarbonate aqueous solution, after which it was extracted with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (1.81 g). The title compound was used in the following reaction without any further purification.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.C(#N)C.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([N:2]2[N:3]=[N:4][CH:5]=[N:1]2)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(-n2ncnn2)cc1
Temperature: 110 °C

Procedure:
1H-tetrazole in acetonitrile solution (0.45M, 19 mL, 8.5 mmol) was combined with 4-fluoro-nitrobenzene (1 g, 7.09 mmol) in a 40 mL pressure tube, followed by addition of potassium carbonate. The tube was sealed and heated at 110° C. overnight (caution: build-up of pressure possible; use a safety shield). Pressure buildup was observed. The pressure was released carefully. The reaction was concentrated to dryness and diluted with water. The aqueous mixture was extracted 4 times with DCM. The combine organic layers were dried over sodium sulfate, filtered, concentrated and purified by column chromatography through a 40 gram biotage silica gel cartridge eluted with 5-20% ethyl acetate/hexanes (gradient) to give the product as white solid. LRMS talc: 191.0; obs: 192.3 (M+1).
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl>CN1CCCC1=O>[CH2:6]([NH:13][CH2:3][CH:2]([F:5])[F:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCc1ccccc1
Reactant: FC(F)CCl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: FC(F)CNCc1ccccc1
Yield: 92.7 %

Procedure:
An amount of 10 g (92 mmol) of 2,2-difluoro-1-chloroethane, 5 g (46 mmol) of benzylamine and 5.2 g (51 mmol) of triethylamine are heated in 20.6 g of N-methylpyrrolidone in an autoclave at an internal temperature of 120° C. for 6 hours. Subsequently, 100 g of 1N hydrochloric acid are added and the solvent is removed under vacuum. The residue is taken up in 30 ml of dichloromethane and adjusted to pH 8 with solid sodium hydrogencarbonate. The phases are subsequently separated and the aqueous phase is again extracted with 20 ml of dichloromethane. The organic phase is distilled. An amount of 7.3 g of N-benzyl-2,2-difluoroethanamine is obtained, which corresponds to a yield of 93%, based on benzylamine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][N:9]=2)=[C:4]([F:23])[CH:3]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[CH2:25]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][N:9]=2)=[C:4]([F:23])[CH:3]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)cc2F)nc1
Reactant: CCCCCCCCCCBr
Product: CCCCCCCCCCOc1ccc(-c2ccc(OCCCCCCCC)cn2)c(F)c1

Procedure:
2-(4-Hydroxy-2-fluorophenyl)-5-octyloxypyridine, which is alkylated with 1-bromodecane to produce 2-(4-n-decyloxy-2-fluorophenyl)-5-octyloxypyridine, is obtained analogously by reacting 4-benzyloxy-2-fluoroacetophenone with 2-octyloxytrimethinium perchlorate, ammonium acetate 5. and hydrogenating cleavage of the benzyl ether.