Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:54][CH2:55]S(Cl)(=O)=O>ClCCl.O>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]([O:9][CH2:55][Cl:54])=[O:8])[CH:3]=1
Reactant: O=C(O)c1cccnc1
Reactant: O=S(=O)(Cl)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: O=C(OCCl)c1cccnc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 25.5 %

Procedure:
A mixture of nicotinic acid (200 mg, 1.6 mmol), sodium bicarbonate (540 mg, 6.4 mmol), and tetrabutylammonium sulfate (54 mg, 0.16 mmol) was dissolved in a mixture of 4 ml of dichloromethane and 4 ml of water, and cooled to 0° C. To this stirred mixture was added chloromethylchlorosulfone (165 μl, 1.6 mmol) in 1 ml of dichloromethane, and the mixture was allowed to warm to room temperature, stirring overnight. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to a yellow oil, which was dissolved in dichloromethane and filtered through a silica plug. Removal of the solvent under reduced pressure provided chloromethyl pyridine-3-carboxylate (70 mg).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[C:23]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=3)[C:22]([CH3:34])=[C:21](Br)[CH:20]=2)[O:7][C@@H:6]1[CH2:36][O:37][C:38](=[O:40])[CH3:39])(=[O:3])[CH3:2].[CH3:41][O:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.F[B-](F)(F)F.C1([PH+](C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:20]=[C:21]([C:46]3[CH:47]=[CH:48][C:43]([O:42][CH3:41])=[CH:44][CH:45]=3)[C:22]([CH3:34])=[C:23]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=3)[CH:24]=2)[O:7][C@@H:6]1[CH2:36][O:37][C:38](=[O:40])[CH3:39])(=[O:3])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc(Br)c2C)cc1
Agent: [Pd+2]
Agent: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc(-c3ccc(OC)cc3)c2C)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-bromo-5-(4-ethylbenzyl)-4-methylphenyl)-tetrahydro-2H-pyran-3,4,5-triyl triacetate (131) (WO2008/101939, Example V) (500 mg, 0.807 mmole) in toluene (6 mL) and water (3 mL) were added 4-methoxyphenylboronic acid (147 mg, 0.969 mmole), Pd(OAc)2 (18.1 mg, 0.0807 mmole), tricyclohexylphosphonium tetrafluoroborate (59.4 mg, 0.161 mmole), and K3PO4 (685 mg, 3.23 mmole). The mixture was stirred at 100° C. overnight. After cooling to ambient temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography to yield the title compound (484 mg, 0.748 mmole, 93%) as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([F:16])[CH:14]=2)[N:9]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:8]=1[CH2:26]Br)=[O:6].[C:28]([CH2:30][NH:31][S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])#[N:29].Cl>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([F:16])[CH:14]=2)[N:9]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:8]=1[CH2:26][N:31]([CH2:30][C:28]#[N:29])[S:32]([C:35]1[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=1)(=[O:34])=[O:33])=[O:6]
Reactant: COC(=O)c1c(CBr)n(S(=O)(=O)c2ccccc2)c2ncc(F)cc12
Reactant: Cc1ccc(S(=O)(=O)NCC#N)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(CN(CC#N)S(=O)(=O)c2ccc(C)cc2)n(S(=O)(=O)c2ccccc2)c2ncc(F)cc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.3 %

Procedure:
Sodium hydride (1.6 g, 60% dispersion in mineral oil, 40.5 mmol) was added portionwise to a cooled (0° C.) solution of 1-benzenesulfonyl-5-fluoro-2-bromomethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (15.8 g, 36.9 mmol) and N-cyanomethyl-4-methyl-benzenesulfonamide (8.5 g, 40.5 mmol) in DMF (150 mL). The reaction mixture was stirred at 0° C. for 15 minutes, then allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture was poured into a cooled, stirred solution of 2M hydrochloric acid (400 mL). The resultant precipitate was collected by filtration (slow) and the cake washed with water, followed by methanol and then diethyl ether. The resulting cake was dried to afford the title compound as a grey solid (16.7 g, 82%). 1H NMR (400 MHz, DMSO-d6): 8.49 (dd, J=2.8, 1.2 Hz, 1H), 8.24-8.24 (m, 2H), 8.14 (dd, J=8.8, 2.8 Hz, 1H), 7.75-7.74 (m, 1H), 7.70-7.68 (m, 2H), 7.62-7.62 (m, 2H), 7.39-7.35 (m, 2H), 5.36 (s, 2H), 4.42 (s, 2H), 3.88 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: O[CH2:2][C@H:3]([CH3:24])[CH2:4][O:5][C:6]1[C:7](=[O:23])[O:8][C:9]([CH3:22])([CH3:21])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1.CCN(CC)CC.CS(Cl)(=O)=O.C([O-])(O)=O.[Na+].S([O-])(=O)(=O)C.[F-:47].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.C1COCC1>[F:47][CH2:2][C@H:3]([CH3:24])[CH2:4][O:5][C:6]1[C:7](=[O:23])[O:8][C:9]([CH3:22])([CH3:21])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: C[C@@H](CO)COC1=C(c2ccc(S(C)(=O)=O)cc2)C(C)(C)OC1=O
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](CF)COC1=C(c2ccc(S(C)(=O)=O)cc2)C(C)(C)OC1=O
Reaction time: 1 h

Procedure:
To the alcohol of Example 8 Step 3 (800 mg, 2.25 mmol) in CH2Cl2 (10 mL) at -20∞C. were added Et3N (943 mL, 6.05 mmol) and MsCl (348 mL, 4.51 mmol). After a period of 1 h at 0∞C., saturated NaHCO3 was added. The organic phase was separated, dried over Na2SO4, filtered and evaporated. To the crude mesylate in THF (10.0 mL) was added a 1M THF solution of tetrabutylammonium fluoride (6.77 mL, 6.77 mmol). After a period of 2 h at 50∞C., the reaction mixture was partitioned between 25% NH4OAc and EtOAc. The organic phase was separated, dried over Na2SO4, filtered and evaporated. The title compound (370 mg) was purified by flash chromatography.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH2:25].C(N(C(C)C)CC)(C)C.C(OC(O)C)C.C(=O)([O-])[O-].[K+].[K+]>O.CCCCCC>[Br:20][C:21]1[CH:22]=[C:23]([CH2:24][NH:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:26]=[CH:27][CH:28]=1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Reactant: NCc1cccc(Br)c1
Agent: CCOC(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2ncc(C#N)c(NCc3cccc(Br)c3)c2cc1OCC
Yield: 68.5 %

Procedure:
A stirred mixture of 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile (0.69 g, 2.5 mmol), 3-bromobenzylamine (0.78 g, 3.5 mmol), diisopropylethyl amine (1.05 ml, 6.0 mmol), and 7.5 ml of ethoxyethanol was refluxed for 4 h, cooled, and stirred with a mixture of hexane and water containing 0.4 g of potassium carbonate for 3 h. The resulting solid was filtered, washed with water, and dried. Recrystallization from acetone-hexane gave 0.73 g of off-white solid, mp 156-159° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]([CH3:14])[CH3:13])[CH:6]=[C:5]2[CH3:15].[Li]CCCC.CN([CH:24]=[O:25])C>>[CH3:13][N:12]([CH3:14])[C:7]1[CH:6]=[C:5]([CH3:15])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:24]=[O:25])[CH:3]=2)[N:8]=1
Reactant: Cc1cc(N(C)C)nc2ccc(Br)cc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: Cc1cc(N(C)C)nc2ccc(C=O)cc12

Procedure:
To a stirred solution of 0.30 g (0.00113 moles) of 6-bromo-2-dimethylamino-4-methylquinoline in 30 ml of dry (freshly distilled from over LiAlH4) THF under N2 at -78° C., 1.45 ml (0.00226 moles) of 1.56M n-BuLi was added dropwise over a 5 minute period. 0.23 ml (0.00297 moles) of dry DMF (freshly distilled from over CaH2) was added to the reaction mixture in one portion. The dry ice/acetone bath was removed 12 minutes after the addition of DMF and the solution allowed to warm to -40°. The reaction mixture was poured onto 17 ml of 1N HCl in ice (22 minutes after addition of DMF) and extracted with 30 ml ether. The aqueous solution was made alkaline to pH 12 and extracted with three 20 ml portions of CH2Cl2. The yellow-orange coloured extract was washed with H2O and then dried over MgSO4 . The solvent was removed under vacuum, and the residue dried in a vacuum oven, wt 0.23 g (95.8%), m.p. 96°-99° C. The product was recrystallised three times (EtOH/H2O). The TLC of the recrystallised product showed several spots, with the predominant component having an Rf 0.38 in 2:1 hexane/EtOAc and being fluorescent under long hot UV. The product was dissolved in 2:1 hexane/EtOAc and placed on silica flash column. Fractions were collected; those containing the Rf 0.38 product were combined, and the solvent removed in vacuo. The residue was recrystallised from absolute ethanol; weight 0.04 g, (17%) m.p. 116.0°-117.8° C. Anal. Calcd. for C13H14N2O: C, 72.87; H, 6.59; N, 13.07. Found: C, 72.74; H, 6.64; N, 13.05.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:24][CH:23]=2)(=[O:21])=[O:20])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccccc3)CC2)cc1

Procedure:
1-Benzyl-4-(4butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-benzyl-4-(4butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (5.1 g, 11.1 mmol) dissolved in THF:methanol 3:1 and 10N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.66 g (56%); off white solid; mp 210° C.; MS: 432 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[N:17][C:16]([CH2:19][O:20]S(C)(=O)=O)=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:31]=[C:30]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:29]=[CH:28][C:27]=1O>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[N:17][C:16]([CH2:19][O:20][C:27]3[CH:28]=[CH:29][C:30]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:31][C:26]=3[F:25])=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)c1ccc(O)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc(COS(C)(=O)=O)n2)CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(n2cnc(COc3ccc(S(C)(=O)=O)cc3F)n2)CC1

Procedure:
A mixture of 4-(3-methanesulfonyloxymethyl-[1,2,4]triazol-1-yl) -piperidine-1-carboxylic acid tert-butyl ester (Intermediate 1, 0.222 g, 0.641 mmol), 2-Fluoro-4-methanesulfonyl-phenol (0.122 g, 0.641 mmol) and CsCO3 (0.250 g, 0.769 mmol) in acetonitrile (10 mL) was heated under reflux for 4 hours. After cooling, the solution was filtered through a pad of celite and the solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel with Hexanes and EtOAc to afford the desired product. 1H NMR (CDCl3): δ 8.15 (1H, s), 7.62 (2H, m), 7.37 (1H, m), 5.25 (2H, s), 4.25 (3H, m), 3.05 (3H, s), 2.85 (2H, m), 2.18 (2H, m), 1.97 (2H, m), 1.43 (9H, s).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH:13]([OH:26])[CH2:14][O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][CH:20]=[N:21]3)[CH2:7]1)=[O:5])C.O.CO.[OH-].[Li+:31]>O1CCCC1>[OH:26][CH:13]([CH2:14][O:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2)[CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([O-:5])=[O:3])[CH2:7]1.[Li+:31]
Reactant: CCOC(=O)[C@@H]1CCCN(CC(O)COc2cccc3ncccc23)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])[C@@H]1CCCN(CC(O)COc2cccc3ncccc23)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(R)-1-[2-Hydroxy-3-(quinolin-5-yloxy)-propyl]-piperidine-3-carboxylic acid ethyl ester (44) (0.739 g; 2.06 mmol) is dissolved in 20 mL of a 2:2:1 mixture of tetrahydrofuran:water:methanol. Lithium hydroxide (52 mg; 2.17 mmol) is added and the mixture stirred at ambient temperature. After 16 hours, the mixture is concentrated in vacuo at 40° C. Further drying on the vacuum pump affords the desired product (45) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[C:8]([O:14][CH2:15][C:16]([N:18]2[CH2:23][C@H:22]([CH3:24])[N:21]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:20][C@H:19]2[CH3:33])=[O:17])=[N:9][CH:10]=[C:11]([Cl:13])[CH:12]=1)C.O.[OH-].[Li+].Cl.P([O-])([O-])([O-])=O>O1CCCC1.CO.O>[Cl:13][C:11]1[CH:12]=[C:7]([CH2:6][CH2:5][C:4]([OH:34])=[O:3])[C:8]([O:14][CH2:15][C:16]([N:18]2[CH2:23][C@H:22]([CH3:24])[N:21]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:20][C@H:19]2[CH3:33])=[O:17])=[N:9][CH:10]=1
Reactant: CCOC(=O)CCc1cc(Cl)cnc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ncc(Cl)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.4 %

Procedure:
To a solution of 3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-propionic acid ethyl ester (0.081 g, 0.17 mmol) in tetrahydrofuran (2 mL), methanol (2 mL) and water (1 mL) was added lithium hydroxide monohydrate (0.013 g, 0.32 mmol). The reaction mixture was stirred at ambient temperature for 3 hours, neutralized with 0.2M hydrochloric acid and phosphate buffer (pH=7), and extracted with ethy acetate. The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification with via HPLC gave the title compound (0.020 g, LRMS: 464.4).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6].[CH3:25][O:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1>>[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18]([C:32]4[C:27]([O:26][CH3:25])=[N:28][CH:29]=[CH:30][CH:31]=4)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6]
Reactant: COc1ncccc1B(O)O
Reactant: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: COc1ncccc1-c1ccc2c(c1)-c1nc(C(=O)N(CCO)C(C)C)sc1CCO2
Yield: 7.2 %

Procedure:
Following the procedure for 277, 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide (52.2 mg, 0.127 mmol) and 2-methoxypyridin-3-ylboronic acid (23.3 mg, 0.152 mmol) were reacted to give 299 (4.0 mg, 7% yield, M+1 440.1).
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:23]2[C:31]3[C:26](=[C:27]([CH2:32][S:33][CH3:34])[CH:28]=[CH:29][CH:30]=3)[N:25]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:24]=2)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]([F:42])[CH:11]=1.CI>O1CCCC1.ClCCl>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:23]2[C:31]3[C:26](=[C:27]([CH2:32][S:33][CH3:34])[CH:28]=[CH:29][CH:30]=3)[N:25]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:24]=2)[CH:17]([CH3:1])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]([F:42])[CH:11]=1
Reactant: CCOC(=O)CC(c1ccc(Cl)cc1F)c1cn(C(=O)OC(C)(C)C)c2c(CSC)cccc12
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: ClCCl
Product: CCOC(=O)C(C)C(c1ccc(Cl)cc1F)c1cn(C(=O)OC(C)(C)C)c2c(CSC)cccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.55 ml (7.10 mmol) of a 2N solution of lithium diisopropylamide in tetrahydrofuran were introduced into 40 ml of absolute tetrahydrofuran at −78° C., a solution of 3.00 g (5.93 mmol) of the compound from Example 35A in 20 ml of tetrahydrofuran was added, and the mixture was stirred for 1 h. 1.01 g (7.11 mmol) of methyl iodide were added at −78° C., and the reaction mixture was warmed to RT. It was then diluted with dichloromethane, the phases were separated, and the organic phase was washed with 1N hydrochloric acid, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 2.45 g (80% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[C:8]=2[CH:21]=1)([O-])=O>C(O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[C:8]=2[CH:21]=1
Reactant: CCCN(CCC)C(=O)c1csc2ccc([N+](=O)[O-])cc12
Agent: [Fe]
Solvent: CCO
Product: CCCN(CCC)C(=O)c1csc2ccc(N)cc12

Procedure:
80 g of 5-nitro-N,N-dipropyl-3-benzothiophencarboxamide were reduced with Fe-powder in 90% ethanol as in Example 11. Yield of title compound: 75 g as a semicrystalline product. 1H NMR(CDCl3): 7.0 ppm(d,1H); 6.5 ppm(d,1H); 6.3 ppm(s,1H); 4.4 ppm(dd,1H); 3.0-3.9 ppm(m,8H); 1.4-1.9 ppm(m,4H); 0.9 ppm(d.t.,6H).
Reaction SMILES: [NH2:1][C:2]1[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].N1C=CC=CC=1.[Cl:20][CH2:21][C:22](Cl)=O>ClC(Cl)C.C(Cl)(Cl)Cl>[Cl:20][CH2:21][C:22]1[NH:13][C:12]2[CH:11]=[CH:10][CH:9]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]=2[N:1]=1
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)c1cccc(N)c1N
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cccc2[nH]c(CCl)nc12
Reaction time: 8 h
Yield: 47.7 %

Procedure:
To a solution of ethyl 2,3-diaminobenzoate (4.72 g) and pyridine (2.49 g) in dichloroethane (50 ml) was added chloroacetyl chloride (3.11 g) in chloroform (10 ml) at −70° C. and the reaction mixture was stood overnight. After the reaction mixture was concentrated in vacuo, the residue was diluted with ethnaol (50 ml). To the solution was added p-toluenesulfonic acid (249 mg) and the reaction mixture was refluxed for 2 hours. After the reaction mixture was concentrated in vacuo, the reside was diluted with ethyl acetate and satureated sodium hydrogen carbonate aqueous solution. The organic layer was separated and washed with brine. The solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give ethyl 2-chloromethyl-1H-benzimidazole-4-carboxylate (2.98 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[O:12]=[C:13]1[C:18]2=[CH:19][NH:20][C:21]([CH:22]=O)=[C:17]2[CH2:16][CH2:15][O:14]1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[CH:22][C:21]3[NH:20][CH:19]=[C:18]4[C:13](=[O:12])[O:14][CH2:15][CH2:16][C:17]=34)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: O=C1Cc2ccc(F)cc2N1
Product: O=C1Nc2cc(F)ccc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
6-Fluoro-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:6][CH2:5]1.[F:18][C:19]1[CH:20]=[C:21]2[C@:28]3([C:32](=[O:33])[NH:31][C:30](=[O:34])[NH:29]3)[CH2:27][C@@H:26]([C:35](Cl)=[O:36])[O:25][C:22]2=[CH:23][CH:24]=1>>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:7]1[CH2:6][CH2:5][N:4]([CH2:3][CH2:2][NH:1][C:35]([C@@H:26]2[CH2:27][C@@:28]3([C:32](=[O:33])[NH:31][C:30](=[O:34])[NH:29]3)[C:21]3[C:22](=[CH:23][CH:24]=[C:19]([F:18])[CH:20]=3)[O:25]2)=[O:36])[CH2:9][CH2:8]1
Reactant: COc1ccccc1N1CCN(CCN)CC1
Reactant: O=C1NC(=O)[C@@]2(C[C@@H](C(=O)Cl)Oc3ccc(F)cc32)N1
Product: COc1ccccc1N1CCN(CCNC(=O)[C@@H]2C[C@]3(NC(=O)NC3=O)c3cc(F)ccc3O2)CC1

Procedure:
This compound was prepared by the similar procedure as in the case of Example 8, excepting that 4-(2-aminoethyl)-1-(2-methoxyphenyl)pyperazine and (2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbonyl chloride (Reference Example 1) were employed.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]1([CH2:19][O:20][P:21]([CH2:36][C:37]([OH:39])=O)([CH:23]([NH:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH3:24])=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(#N)C.[NH:43]1[CH2:57][CH2:56][CH2:55][C@H:44]1[C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46]>C(OCC)(=O)C>[C:13]1([CH2:19][O:20][P:21]([CH2:36][C:37]([N:43]2[CH2:57][CH2:56][CH2:55][C@H:44]2[C:45]([O:47][CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)=[O:46])=[O:39])([CH:23]([NH:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH3:24])=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(NC(=O)OCc1ccccc1)P(=O)(CC(=O)O)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(NC(=O)OCc1ccccc1)P(=O)(CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Reaction time: 1 h

Procedure:
1,1'-Carbonyldiimidazole (1 g. 0.066 mole) is added to a chilled (0°) solution of the product from part (c) (2.5 g., 0.063 mole) in 40 ml. of acetonitrile. The mixture is stirred for one hour at 0°. A solution of L-proline, benzyl ester (1.3 g., 0.066 mole) in 20 ml. of acetonitrile is added. The mixture is stirred at ambient temperature for 16 hours. The solvent is removed in vacuo. The residue is dissolved in dichloromethane (125 ml.), washed with 5% potassium bisulfate, saturated sodium bicarbonate solution, brine, and dried (MgSO4). The solution is concentrated in vacuo to give an oil residue of 3.3 g. Tlc, silica gel, ethyl acetate shows a major spot at Rf 0.10. A portion (2.2 g.) is chromatographed on silica gel, eluting with ethyl acetate to give 1.7 g. of (±)-1-[(phenylmethoxy)[1-[[(phenylmethoxy)carbonyl]amino]ethyl]phosphinyl]acetyl]-L-proline, phenylmethyl ester.