Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.CN(C)C=O>[C:2]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:9]2)[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cccc(Br)c2)c(F)c1
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: CN(C)C=O
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cccc(-c3ccccc3)c2)c(F)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 966 %

Procedure:
5-(3-Bromo-phenyl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (500.0 mg, 0.10 mmol) prepared in Step 2 of Preparation 5, phenylboronic acid (201.0 mg, 1.65 mmol), Pd(PPh3)4 (64.0 mg, cat.) and a 2N sodium carbonate solution (3.3 mL) were added to N,N-dimethylformamide (5.0 mL). The reaction mixture was stirred at 80° C. for 18 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/60) to give 437.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:31][C:32]([OH:34])=[O:33])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26](=[O:29])[N:25]([CH3:30])[CH:24]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH3:39]O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:31][C:32]([O:34][CH3:39])=[O:33])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26](=[O:29])[N:25]([CH3:30])[CH:24]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CC(=O)O)(c2ccc(F)cc2)OC1=O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(=O)n(C)c3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
To a solution of 2-((S)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)acetic acid (290 mg, 0.625 mol) in MeOH (20 mL) was added SOCl2 (2 mL) at 0° C., and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated to give the residue, which was purified by preparative TLC to give methyl 2-((S)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)acetate (130 mg, 43.5%). 1H NMR (CDCl3): δ=1.52 (d, 3H), 2.36-2.55 (m, 3H), 2.67-2.71 (m, 2H), 2.90-3.04 (m, 3H), 3.68 (s, 3H), 3.71 (s, 3H), 5.66 (m, 2H), 6.66 (d, 1H), 6.90 (d, 2H), 7.03 (t, 2H), 7.13-7.15 (d, 2H), 7.23-7.29 (m, 2H), 7.42 (m, 1H), 7.56 (m, 1H).
Reaction SMILES: [Cl:1][C:2]([Cl:7])(Cl)[C:3](Cl)=[O:4].[CH3:8][C:9]([CH3:13])=[CH:10][CH:11]=[CH2:12].P(Cl)(Cl)(Cl)=O>[Zn].CCOCC>[Cl:1][C:2]1([Cl:7])[CH:11]([CH:10]=[C:9]([CH3:13])[CH3:8])[CH2:12][C:3]1=[O:4]
Reactant: C=CC=C(C)C
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Zn]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: CC(C)=CC1CC(=O)C1(Cl)Cl

Procedure:
The first step of Example 1 was repeated employing as the reactants, 5.6 ml trichloroacetyl chloride (50 mmol), 5 g (60 mmol) 4-methyl-1,3-pentadiene, 4.6 ml (50 mmol) phosphoryl chloride, 5 g (78 mmol) zinc and 500 ml ether. The yield was 6.8 g. or 71% theoretical, boiling at 65°-67° C. at 0.2 torr.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:4](=[O:12])[C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[Br:23]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:23][C:7]1[N:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[C:4](=[O:12])[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)[C:2]=1[CH3:1]
Reactant: COC(=O)c1ncc(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(Br)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 18.5 °C

Procedure:
Methyl 5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (400 g, 1 eq) was dissolved in DMF (3 L) and stirred at 17-20° C. N-Bromosuccinimide (229.3 g, 1 eq) was dissolved in DMF (1 L), and added to the ester solution over 1 hour. Post-addition, the reaction was stirred at 17-20° C. for 10 hours. The reaction mixture was added to water (15 L) with stirring. The resulting slurry was stirred at 20-25° C. overnight. The title compound was collected by filtration. The cake was washed with water (1 L) and heptane (1 L) and then dried to constant weight at 40° C. to give 456 g (91%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([C:27]#[N:28])[CH:25]=3)[NH:20][N:19]=2)[CH:15]=[CH:16][CH:17]=1.N>O1CCCC1>[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([CH2:27][NH2:28])[CH:25]=3)[NH:20][N:19]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cc2[nH]nc(-c3cccc(F)c3)c2cc1C#N
Agent: N
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1cc2[nH]nc(-c3cccc(F)c3)c2cc1CN
Reaction time: 0.17 h
Yield: 212.8 %

Procedure:
A total of 71 mg of lithium aluminium hydride was suspended in 4.7 ml of tetrahydrofuran, 249 mg of aluminium chloride was added under ice-cooling, and the mixture was stirred for 10 minutes. To the reaction mixture was added 50 mg of 3-(3-fluoro-phenyl)-6-methoxy-1H-indazole-5-carbonitrile obtained in Production Example II-1-d, followed by stirring at room temperature for 3 hours. The reaction mixture was ice-cooled, 27% aqueous ammonia was added and the mixture was filtrated through Celite. The filtrate was evaporated, and the residue was purified and separated by silica gel column chromatography (NH silica gel) (ethyl acetate), to give 108 mg of the title compound.
Reaction SMILES: O[CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:17]([O:19][CH3:20])=[O:18])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C1(P([N:44]=[N+:45]=[N-:46])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:44]([CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:17]([O:19][CH3:20])=[O:18])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)=[N+:45]=[N-:46]
Reactant: COC(=O)C1(c2ccc(COc3cccc(C(O)c4ccccc4)c3)cc2)CC1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COC(=O)C1(c2ccc(COc3cccc(C(N=[N+]=[N-])c4ccccc4)c3)cc2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 62.5 %

Procedure:
To a stirred solution of methyl 1-(4-((3-(hydroxy(phenyl)methyl)phenoxy)-methyl)phenyl)cyclopropanecarboxylate (1.824 g, 4.695 mmol) in toluene (21.8 mL) under an atmosphere of nitrogen, was added diphenylphosphoryl azide (1.21 mL, 5.635 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.84 mL, 5.635 mmol). The reaction mixture was stirred at 100° C. for 3 hours and then allowed to cool to room temperature. The reaction was quenched by addition of saturated aqueous ammonium chloride solution and extracted with ethyl acetate (×3). The combined organic extracts were washed with brine and dried (magnesium sulfate), filtered, and concentrated under reduced pressure to afford a brown oil. The crude material was purified by silica gel chromatography eluting with 0-14% ethyl acetate in iso-hexane to afford the title compound as a colourless oil (1.214 g, 62%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([C:17]4[CH2:18][CH2:19][N:20]([CH:23]5[CH2:28][CH2:27][CH:26]([C:29]([O:31]CC)=[O:30])[CH2:25][CH2:24]5)[CH2:21][CH:22]=4)[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1.O.[OH-].[Li+]>O1CCCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([C:17]4[CH2:18][CH2:19][N:20]([CH:23]5[CH2:24][CH2:25][CH:26]([C:29]([OH:31])=[O:30])[CH2:27][CH2:28]5)[CH2:21][CH:22]=4)[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1
Reactant: CCOC(=O)C1CCC(N2CC=C(c3cc4c(-c5cc(F)ccc5OC)ncnc4[nH]3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1ncnc2[nH]c(C3=CCN(C4CCC(C(=O)O)CC4)CC3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 86A (266 mg, 0.556 mmol) in 4 mL of tetrahydrofuran/water (3:1) was added lithium hydroxide mono hydrate (46.7 mg, 1.112 mmol). The reaction was stirred at room temperature overnight. The volatiles were then removed, and the residue dissolved in 5 mL water and the pH was adjusted to pH ˜6-7 with 1 M hydrochloric acid. The solid was collected by filtration and dried under high vacuum overnight to give the title compound as a hydrochloride salt. 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H) 8.81 (s, 1H) 7.13-7.52 (m, 3H) 6.62 (s, 1H) 6.32 (s, 1H) 3.83 (s, 3H) 3.32 (d, J=21.06 Hz, 2H) 2.67-2.86 (m, 2H) 2.56 (s, 1H) 2.41 (s, 1H) 2.10-2.27 (m, 1H) 1.83-2.08 (m, 3H) 1.24-1.76 (m, 6H). MS (ESI+) m/z 451.1 (M+H)+.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17].CC(C(O)=O)C1C=CC(CC2C(=O)CCC2)=CC=1.[OH-].[K+].[OH-].[Na+]>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4].O>[C:1]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)CCCCCCO
Agent: [Ti+4]
Agent: CC(C(=O)O)c1ccc(CC2CCCC2=O)cc1
Agent: CCCC[O-]
Solvent: O
Product: CC(C)CCCCCCOC(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A 4 liter distillation flask with top-mounted water separator and reflux condenser and also with a sampling port and thermometer was charged with 976 g of benzoic acid (8 mol), 1728 g of isononanol from Oxeno Olefinchemie GmbH (12 mol) and 0.59 g of butyl titanate (0.06% by weight based on the amount of acid) and this initial charge was heated at boiling under a nitrogen atmosphere. The water of reaction produced during the esterification was taken off at regular intervals. When the acid number fell below 0.1 mg KOH/g (after about 3 hours) the mixture was first cooled to below 60° C. and a 20 cm packed column was mounted. Thereafter the pressure was reduced to 2 mbar and first of all the excess alcohol was removed by distillation (temperature at the top of the column about 120° C.). Thereafter the batch was cooled to 80° C. and transferred to a 4 liter reaction flask with dip tube, top-mounted dropping funnel and column, and attached to a Claisen bridge. It was then neutralized with 5% strength by weight aqueous sodium hydroxide solution (5-fold excess of alkali) and stirred for 30 minutes more. Subsequently it was heated to 190° C. under reduced pressure (about 10 mbar). Then 8% by weight of fully demineralized water, based on the amount of crude ester employed, was added dropwise at constant temperature through the dropping funnel. Care was taken during this procedure to ensure that the overhead temperature did not climb above 120° C. Following the addition of water the heating was shut off and the mixture was cooled under reduced pressure. The ester was filtered off at room temperature on a suction filter with filter paper and filter aid. Gas chromatography indicated a purity for the ester of 99.7%.
Reaction SMILES: C(C1C=CC(N2CC[C@H](N[C@@H](C3C4C(=CC=CC=4)C=CC=3)C)C2)=CC=1)(=O)C.C([N:35]1[CH2:39][CH2:38][C@H:37]([NH:40][C@@H:41]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH3:50])[CH:44]=2)[CH3:42])[CH2:36]1)C1C=CC=CC=1.[ClH:51]>CO.O1CCOCC1.[OH-].[Pd+2].[OH-]>[ClH:51].[ClH:51].[CH3:50][O:49][C:45]1[CH:44]=[C:43]([C@H:41]([NH:40][C@H:37]2[CH2:38][CH2:39][NH:35][CH2:36]2)[CH3:42])[CH:48]=[CH:47][CH:46]=1
Reactant: COc1cccc([C@@H](C)N[C@H]2CCN(Cc3ccccc3)C2)c1
Agent: [Pd+2]
Agent: CC(=O)c1ccc(N2CC[C@H](N[C@H](C)c3cccc4ccccc34)C2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cccc([C@@H](C)N[C@H]2CCNC2)c1
Reaction time: 72 h

Procedure:
To a solution of 8.0 g of (R)-1-benzyl-3-pyrrolidinol and 16.5 ml of diisopropylethylamine dissolved in 400 ml of methylene chloride was added dropwise a solution of 13.4 g of anhydrous trifluoromethanesulfonic acid in 50 ml of a methylene chloride at −20° C. or lower. The reaction mixture was stirred for 15 minutes while maintaining it to −20° C., then, a solution of 9.88 g of (R)-1-(3-methoxyphenyl)ethylamine in 100 ml of methylene chloride was added dropwise to the mixture at −20° C. or lower, and the reaction mixture was stirred at room temperature for 16 hours. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol=1:0→50:1) and NH silica gel column chromatography (hexane:ethyl acetate=25:1→10:1) to obtain 3.98 g of (S)-(1-benzylpyrrolidin-3-yl)-[(R)-1-(3-methoxyphenyl)ethyl]amine. MS•APCI (m/z): 311 [M+H]+ (2) To a solution of 3.67 g of (S)-(1-benzylpyrrolidin-3-yl)-[(R)-1-(3-methoxyphenyl)ethyl]amine dissolved in 100 ml of methanol were added 830 mg of palladium hydroxide and 8.85 ml of a solution of 4M hydrochloric acid in dioxane, and the mixture was shaked under hydrogen atmosphere at 3 atm at room temperature for 3 days. Palladium hydroxide was removed, and the solvent was evaporated. To the residue was added methanol, and the resulting precipitates were collected by filtration, washed with methanol and dried to obtain 1.14 g of (S)-3-[(R)-1-(3-methoxyphenyl)-ethylamino]pyrrolidine dihydrochloride (the following Reference example Table, Reference example 1.001).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:11].C1C(=O)N([Cl:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Cl:19][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:11]
Reactant: Nc1ccc2ccccc2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Nc1ccc2ccccc2c1Cl
Temperature: 49 °C
Reaction time: 1.5 h
Yield: 96.2 %

Procedure:
To a CCl4 (600 mL) solution of 2-naphthylamine (10 g) at 49° C. was added NCS (9.51 g, 1.02 eq) in portions. The mixture was stirred at 49° C. for 1.5 h then concentrated to dryness to give 1-chloro-2-naphthylamine (11.94 g, 96%) as a dark solid. MS Found: (M+H)+=178.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[F:23][C:24]1([F:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[F:23][C:24]1([F:30])[CH2:29][CH2:28][N:27]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:19])[CH2:26][CH2:25]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: FC1(F)CCNCC1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCC(F)(F)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 4,4-difluoropiperidine (1.2 equiv) to give 203 (M+1 417.0)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([Cl:12])=[CH:5]2.O1CCOCC1.C(N(CC)C(C)C)(C)C.[CH2:28]([SH:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:28]([S:35][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([Cl:12])=[CH:5]2)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Clc1cc2cc(Br)ccc2cn1
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Clc1cc2cc(SCc3ccccc3)ccc2cn1
Temperature: 80 °C
Yield: 89.1 %

Procedure:
A pressure vessel was charged with 6-bromo-3-chloroisoquinoline (1.3307 g, 5.49 mmol), Xantphos (0.159 g, 0.274 mmol), and Pd2(dba)3 (0.126 g, 0.137 mmol). The vessel was flushed with Ar (g), then 1,4-dioxane (10.97 ml), N,N-diisopropylethylamine (1.917 ml, 10.97 mmol), and benzyl mercaptan (0.682 ml, 5.76 mmol) were added in sequence. The vessel was sealed and heated in an 80° C. heating bath for 16 h. The mixture was cooled, diluted with EtOAc, and filtered through diatomaceous earth. The filtrate was concentrated, and the residue was purified by chromatography on silica gel (25-g silica gel loading column, 0 to 30% EtOAC/Heptane) to give 6-(benzylthio)-3-chloroisoquinoline (1.398 g, 4.89 mmol, 89% yield) as a light-yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=8.94 (s, 1H), 7.81 (d, J=8.6 Hz, 1H), 7.55 (d, J=0.2 Hz, 1H), 7.50-7.39 (m, 4H), 7.38-7.28 (m, 3H), 4.30 (s, 2H); m/z (ESI) 286.2 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:15]2[NH:14][C:13](=S)[CH2:12][N:11]=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:25]([NH:29][NH2:30])(=O)[CH2:26][CH3:27]>C(O)C>[C:1]([NH:4][C:5]1[C:15]2[N:14]3[C:25]([CH2:26][CH3:27])=[N:29][N:30]=[C:13]3[CH2:12][N:11]=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCC(=O)NN
Reactant: CC(=O)Nc1cccc2c1NC(=S)CN=C2c1ccc(C#N)cc1
Solvent: CCO
Product: CCc1nnc2n1-c1c(NC(C)=O)cccc1C(c1ccc(C#N)cc1)=NC2
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 9-acetylamino-1,3-dihydro-5-(p-cyanophenyl)-2H-1,4-benzodiazepine-2-thione is heated in ethanol with propionic acid hydrazide and the resulting product heated to 250° C. to give 10-(acetylamino)-1-ethyl-6-(p-cyanophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15].[CH2:17]([CH:21]1[CH2:27][CH:26]2[NH:28][CH:23]([CH2:24][CH2:25]2)[CH2:22]1)[CH2:18][CH2:19][CH3:20]>CC#N>[CH2:17]([CH:21]1[CH2:22][CH:23]2[N:28]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:8][CH2:7][C:6]3=[O:15])[CH:26]([CH2:25][CH2:24]2)[CH2:27]1)[CH2:18][CH2:19][CH3:20]
Reactant: C[C@H](CI)CN1C(=O)CCc2ccccc21
Reactant: CCCCC1CC2CCC(C1)N2
Solvent: CC#N
Product: CCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)CCc2ccccc21
Reaction time: 20 h
Yield: 30.5 %

Procedure:
A 4 mL vial was charged with (S)-1-(3-iodo-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (122LH18) (0.185 g, 0.56 mmol) and 3-butyl-8-azabicyclo[3.2.1]octane (0.100 g, 0.60 mmol) in MeCN (0.5 mL) and shaken at 40° for 20 h. The reaction mixture was quenched with water, basified with ammonium hydroxide, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; n-heptane/EtOAc 4:1) to give the title compound (107LH54) (0.063 g, 30%). 1H NMR (CD3OD) δ 7.29-7.19 (m, 3H), 7.03-6.99 (m, 1H), 4.03-4.00 (m, 2H), 3.14-3.13 (m, 1H), 3.07-3.05 (m, 1H), 2.90-2.86 (m, 2H), 2.62-2.57 (m, 2H), 2.28-2.19 (m, 2H), 1.97-1.82 (m, 3), 1.58-1.42 (m, 5H), 1.34-1.15 (m, 8H), 0.90-0.87 (m, 6H); 13C NMR (CD3OD) δ 173.1, 140.3, 129.1, 128.4, 128.3, 124.3, 117.2, 62.2, 61.2, 58.2, 46.5, 39.0, 38.0, 32.9, 32.1, 30.3, 29.1, 27.8, 27.3, 26.3, 24.0, 17.1, 14.5.
Reaction SMILES: [CH3:1][C:2]1[CH2:11][S:10][C@@H:5]2[C@H:6]([NH2:9])[C:7](=[O:8])[N:4]2[C:3]=1[C:12]([OH:14])=[O:13].[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)C=C[C:16]=1[OH:25].[OH-].[NH4+]>O>[CH3:11][C:2]1([CH3:1])[S:10][C@@H:5]2[C@H:6]([NH:9][C:16]([CH2:15][C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:25])[C:7](=[O:8])[N:4]2[C@H:3]1[C:12]([OH:14])=[O:13]
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Oc1ccc2ccccc2c1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Temperature: 25 °C

Procedure:
The pH value of a mixture (slurry) of D-PGA.1/2H2SO4 (74.7 g, 0.375 mol), 7-ADCA (21.4 g, 0.10 mol), and 2-naphthol (10.8 g, 0.075 mol, particle size <100 μm) in approximately 300 ml of water was adjusted to 6.7 by addition of 4M ammonium hydroxide. Water was added to 400 ml followed by immobilized E. coli Penicillin G acylase prepared as described above (50 g on dry basis suspended in water to a total of 100 ml), and the mixture was stirred at 25° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[H-].[Na+].[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:23][C:20]2[CH:21]=[CH:22][C:17]([C:16]([O:15][CH3:14])=[O:25])=[CH:18][CH:19]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CNc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
To 4-chloro-2-nitroaniline (10 mmol, 1.73 g) in DMF (10 mL) was added NaH (11 mmol, 440 mg of 60% suspension in mineral oil). After 30 min the reaction vessel was placed in a water bath and methyl-4-(bromomethyl)benzoate (11 mmol, 2.52 g) was added (exothermic). The reaction mixture was allowed to stand at ambient temperature for 16 h, then poured into saturated NaHCO3, affording an orange precipitate which was filtered, washed with water and dried in vacuo. Purification by flash chromatography on silica eluting with 15% EtOAc in hexanes provided the product as an orange solid. LC-MS (ESI, Method C) 3.79 min, m/z 321.1 (M+1).
Reaction SMILES: [Cl:1][C:2](Cl)([P:9]([O:17][CH:18]([CH3:20])[CH3:19])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])[C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].C([Li])CCC.Cl>CCOCC.CCCCCC>[Cl:1][CH:2]([P:9]([O:17][CH:18]([CH3:20])[CH3:19])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])[C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)OC(=O)C(Cl)(Cl)P(=O)(OC(C)C)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)OC(=O)C(Cl)P(=O)(OC(C)C)c1ccccc1
Yield: 78 %

Procedure:
To a solution of 7.1 g of 1-methylethyl 2.2-dichloro-2[(1-methylethoxy)phenylphosphinyl]acetate in 150 ml of ether was added 14 ml of a solution of 1.6 M n-butyl lithium in hexane at -70° over 15 minutes. The solution was then allowed to warm to -10° before adding 60 ml of 0.5 M aqueous HCl solution at -10° to 0°. The phases were separated and the organic phase washed with water then 5% NaHCO3 solution. The solution was then dried and stripped to give 5.0 g of 1-methylethyl 2-chloro-2[(1-methylethoxy)phenylphosphinyl]acetate as a light yellow oil ND25 1.5057.