Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]([F:31])([F:30])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]1[S:20][C:19]2[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=2[C:17]=1[C:25]([O:27]CC)=[O:26])(=[O:14])=[O:13]>O1CCOCC1.O>[F:30][C:5]([F:4])([F:31])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]1[S:20][C:19]2[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=2[C:17]=1[C:25]([OH:27])=[O:26])(=[O:14])=[O:13]
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2C(F)(F)F)sc2c1CCCC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1c(NS(=O)(=O)c2ccccc2C(F)(F)F)sc2c1CCCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.3 %

Procedure:
Lithium hydroxide monohydrate (0.188 g) was added to a solution of ethyl 2-(2-trifluoromethylbenzenesulphonylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (Intermediate 27, 0.194 g) in dioxane (1 ml) and water (1 ml) and the mixture was stirred at room temperature for 16 hours. The mixture was then warmed to 60° C. for 1 hour and finally heated in the microwave at 160° C. for 15 minutes. After cooling to room temperature the volatile components were removed under reduced pressure. The residual solution was acidified with aqueous hydrochloric acid (1M) and directly purified by preparative HPLC(C18), eluting with a mixture of methanol and water containing 0.1% formic acid and a gradient of 40-95% to give 2-(2-trifluoromethylbenzenesulphonylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.015 g) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1.[Cl-].[NH4+]>C1COCC1>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:1]2[CH:5]=[CH:4][CH:3]=[C:2]2[CH:6]=[O:7])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc[nH]1
Reactant: COc1ccc(CCl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2cccc2C=O)cc1
Yield: 65.5 %

Procedure:
To pyrrole-2-carboxaldehyde (1.0 g, 10.5 mmol) in THF (60 mL) was added KO'Bu (1.2 g, 10.5 mmol), Et4N+T (100 mg) and 4-methoxybenzyl chloride (1.4 mL, 10.5 mmol). After 1 day saturated aqueous ammonium chloride was added and the mixture was extracted with EtOAc. The organic extract was dried over Na2SO4 and concentrated. Column chromatography (EtOAc/hexanes, 1:9) provided 1.48 g (65%) of 1-(4-methoxybenzyl)-1H-pyrrole-2-carbaldehyde as an oil.
Reaction SMILES: [H-].[Li+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([NH:8][C:9]2[S:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)=[CH:6][CH:5]=1.[CH3:22][O:23][CH2:24][CH2:25]Br>CN(C=O)C>[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([N:8]=[C:9]2[N:14]([CH2:25][CH2:24][O:23][CH3:22])[C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[N:19][C:11]=3[S:10]2)=[CH:6][CH:5]=1
Reactant: O=c1nc(Nc2ccc(Cl)cc2)sc2ncccc12
Reactant: COCCBr
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COCCn1c(=Nc2ccc(Cl)cc2)sc2ncccc2c1=O
Reaction time: 0.07 h
Yield: 26.8 %

Procedure:
In an atmosphere of argon, a mixture of 26 mg (3.3 mmol) of lithium hydride and 5 ml of DMF was put in a 100 ml flask. To the flask was then connected a dropping funnel which contained 800 mg (2.8 mmol) of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one and 10 ml of DMF. The solution of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one was then added dropwise to the aforementioned mixture with stirring in 4 minutes. The mixture was further stirred for 50 minutes. To the mixture was then added a mixture of 576 mg of 2-bromoethyl methyl ether and 2 ml of DMF. The mixture was then stirred for 21 hours. After the termination of reaction, the mixture was concentrated under reduced pressure. The resulting residue was then extracted with water and ethyl acetate. The resulting organic phase was separated, washed with water and saturated brine, and then dried over sodium sulfate. The drying agent was then removed by filtration. The filtrate was then concentrated under reduced pressure. The resulting residue was then purified through silica gel column chromatography (eluant: 1/2 mixture of ethyl acetate and normal hexane). As a result, 261 mg of 2-[(4-chlorophenyl)imino]-2,3-dihydro-3-(2-methoxyethyl)-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a low polarity substance, and 79 mg of 2-[N-(4-chlorophenyl)-N-(2-methoxyethyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a high polarity substance.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH3:16])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7]=2[CH:23]=1>CN(C)C=O.CN(CN(C)C)C.C(Cl)(=O)C>[F:25][C:2]([F:24])([F:1])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][CH2:11][N:12]([CH3:13])[CH3:6])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7]=2[CH:23]=1
Reactant: Cc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1)=NC2
Agent: CN(C)CN(C)C
Solvent: CC(=O)Cl
Solvent: CN(C)C=O
Product: CN(C)CCc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 1, a solution of 8-trifluoromethyl-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dimethylformamide, N,N,N',N'-tetramethyldiaminomethane and acetyl chloride (in 0.1 molar excess compared to the N,N,N', N'-tetramethyldiaminomethane) are reacted together to give 8-trifluoromethyl-1-[2-(dimethylamino)ethyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH:1]1([N:7]([CH3:19])[C:8](=[O:18])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Ni]>[NH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:8]([N:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:19])=[O:18]
Reactant: CN(C(=O)c1ccccc1[N+](=O)[O-])C1CCCCC1
Agent: [Ni]
Solvent: CO
Product: CN(C(=O)c1ccccc1N)C1CCCCC1
Yield: 95.8 %

Procedure:
A solution of the crude N-cyclohexyl-N-methyl-2-nitrobenzamide (1.05 g, 4 mmol) and a catalytic amount of Raney-Ni® in methanol (25 ml) was stirred overnight under hydrogen at room temperature. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting crude was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO4) and the solvents removed under reduced pressure to give (0.89 g, 96%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:25])[C@@:9]1([CH3:24])[CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.[OH-].[Pd+2].[OH-]>[CH3:25][N:8]([C@@:9]1([CH3:24])[CH2:13][CH2:12][NH:11][CH2:10]1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@@]1(C)CCN(C(=O)OCc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN(C(=O)OC(C)(C)C)[C@@]1(C)CCNC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Benzyl (3S)-3-[(tert-butoxycarbonyl)(methyl)amino]-3-methylpyrrolidine-1-carboxylate (I-347) (367 mg, 1.05 mmol) was dissolved in 1,4-dioxane (10 ml), then palladium hydroxide catalyst (37 mg) was added, followed by stirring under hydrogen atmosphere at room temperature for 5 hours. The reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the entitled compound. This was used in the next reaction as such.
Reaction SMILES: [NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:9](O)=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([N:24](CC)CC)C.C(Cl)(=O)C(C)(C)C>O1CCCC1>[NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:9]([NH2:24])=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(N[C@H](C(=O)O)c1ccccc1)OCc1ccccc1
Reactant: CCN(CC)CC
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)[C@@H](NC(=O)OCc1ccccc1)c1ccccc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 68.5 %

Procedure:
27.6 g (97 mmoles) of Z-L-Phg-OH are dissolved in 300 ml of dry tetrahydrofuran, and 13.55 ml (97 mmoles) of triethylamine are added to the solution. The mixture is cooled to -10° C., and 12.1 ml (97 mmoles) of pivaloyl chloride are introduced. The suspension of the mixed anhydride is stirred for 10 minutes at -10° C., thereafter cooling is stopped and ammonia is bubbled through the suspension for one hour. Next day the reaction mixture is evaporated, and the residue is processed as described for the D enantiomer. 18.90 g (68.7%) of Z-L-Phg-NH2 are obtained; m.p.: 172°-173° C., Rf4 =0.75, [α]D =+80.7° (c=1.0, in dimethyl formamide).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([OH:16])[CH:12]=2)[CH:7]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH3:28])[CH:21]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][OH:39]>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([O:16][CH2:36][CH2:37][CH2:38][OH:39])[CH:12]=2)[CH:7]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH3:28])[CH:21]=1)=[O:5])[CH3:2]
Reactant: OCCCBr
Reactant: CCOC(=O)N1C=Cc2cc(O)c(OC)cc2C1Cc1cccc(OCC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1C=Cc2cc(OCCCO)c(OC)cc2C1Cc1cccc(OCC)c1
Temperature: 85 °C
Yield: 31 %

Procedure:
To a stirred solution of 6-hydroxy-7-methoxy-1-(3-ethoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (737 mg, 1.92 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (2.6 g, 19.2 mmol) and 3-bromo-1-propanol (0.868 m]L, 9.62 mmol) at room temperature. The reaction mixture was heated 85° C. for 2 hrs. The solvent was evaporated and the residue was purified on a flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) to afford product 6-(3-hydroxy-propoxy)-7-methoxy-1-(3-ethoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester as a colorless oil (260 mg, 31% yield).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[C:6]2[C:17](=[CH:18][CH:19]=1)[C:9]1[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=1[CH2:7]2)[CH3:2].C(O[C:24](=[O:26])[CH3:25])(=O)C>O>[C:24]([N:3]([C:4]1[CH:5]=[C:6]2[C:17](=[CH:18][CH:19]=1)[C:9]1[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=1[CH2:7]2)[CH2:1][CH3:2])(=[O:26])[CH3:25]
Reactant: CCNc1ccc2c(c1)Cc1c-2[nH]c2ccccc12
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CCN(C(C)=O)c1ccc2c(c1)Cc1c-2[nH]c2ccccc12
Reaction time: 1 h
Yield: 90 %

Procedure:
5,10-Dihydro-2-(N-Ethylamino)indeno[1,2-b]indole (0.47 g, 1,90 mM) and acetic anhydride (4 cm3) were heated to 90°-95° C. for 4 hours. Water (30 cm3) was added to the cold solution and the mixture was stirred vigorously for 1 hour. The solid product which formed was then collected and washed with a few drops of cold ethanol to afford the title compound 0.5 g, 90% as a colourless solid, M.p. 232° C. 1H NMR (CDCl3) δ: 1.16 (3H, t, J=7.0 Hz), 1.90 (3H, s), 3.73 (2H, s), 3.81 (2H, q, J=7.0 Hz), 7.05-7.20 (4H, m), 7.46 (1H, d, J=7.5 Hz), 7.57 (1H, d, J=8.0 Hz), 7.63 (1H, d, J=7.0 Hz, 10.36 (1H, s)).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:19][C:20]1[CH:33]=[CH:32][C:23]2[S:24][C:25]([S:28](Cl)(=[O:30])=[O:29])=[C:26]([CH3:27])[C:22]=2[CH:21]=1>>[Cl:19][C:20]1[CH:33]=[CH:32][C:23]2[S:24][C:25]([S:28]([NH:1][C:2]3[CH:3]=[C:4]([CH:8]4[CH2:9][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11]4)[CH:5]=[CH:6][CH:7]=3)(=[O:29])=[O:30])=[C:26]([CH3:27])[C:22]=2[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2cccc(N)c2)C1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Product: Cc1c(S(=O)(=O)Nc2cccc(C3CN(C(=O)OC(C)(C)C)C3)c2)sc2ccc(Cl)cc12
Yield: 71 %

Procedure:
Following the same procedure as described in Example 1.7, tert-butyl 3-(3-aminophenyl)azetidine-1-carboxylate (100 mg, 0.40 mmol) was coupled with 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (118 mg, 0.42 mmol) to give tert-butyl 3-(3-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonamido)phenyl)azetidine-1-carboxylate (140 mg, 71%).
Reaction SMILES: CS(C)=O.[OH-].[K+].[C:7]1([C:13]2[NH:17][CH:16]=[N:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:18]I>O>[CH3:18][N:15]1[CH:14]=[C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:17]=[CH:16]1
Reactant: c1ccc(-c2cnc[nH]2)cc1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cn1cnc(-c2ccccc2)c1
Reaction time: 0.08 h
Yield: 77.9 %

Procedure:
Add 20 mL dimethyl sulfoxide (35 mL; 492.74 mmoles) to powdered potassium hydroxide (20.81 mmoles; 1.17 g). Add 5-phenyl-1H-imidazole (13.87 mmoles; 2.00 g) at room temperature and solid quickly dissolves giving an orange solution. After stirring 5 min add methyl iodide (15.26 mmoles; 950.36 μL) in one portion. Stir 4h at room temp. Dilute with water and extract with ethyl acetate (2×), then wash the organics with saturated aq. sodium chloride/water (2×) solution, dry over MgSO4, filter, evaporate to give 1.71 g yellow solid. Purify the crude by using ISCO chromatography over a biotage 40M column eluting with a gradient of 0.5% MeOH/DCM to 5% MeOH/DCM at a flow rate of 40 mL/min. Dry product fractions to give 1.43 g (65% yield) off-white solid. (7% of undesired regioisomer) MS (ES): (m/z)=159.0 [M+H].
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]([CH2:15][CH:16]=[CH2:17])[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:15]([CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH2:9][NH2:8])[CH:16]=[CH2:17]
Reactant: C=CCC(CNC(=O)OC(C)(C)C)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCC(CN)C(=O)OC
Reaction time: 3 h
Yield: 121.5 %

Procedure:
Dissolve N-(t-butyloxycarbonyl)-2-(2-propenyl)-β-alanine, methyl ester(5.6 g, 23.0 mmol) in methylene chloride (25 mL) and treat with trifluoroacetic acid (15 mL). Stir for three hours and remove the volatiles in vacuo. Treat the residue with water, make basic with sodium hydroxide (1.0 g, 25 mmol) and extract with ethyl acetate. Separate the organic phase and dry (Na2SO4). Evaporate to give 4.0 g of the title compound as an oil in ethyl acetate.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:33](=[O:34])[N:5]2[C:6]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[S:18])=[C:7]([CH2:10][CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[CH2:8][S:9][C@H:4]12.[C:35]([NH:54][C:55]1[S:56][CH:57]=[C:58](/[C:60](=[N:64]/[O:65][CH3:66])/[C:61](O)=[O:62])[N:59]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:35]([NH:54][C:55]1[S:56][CH:57]=[C:58](/[C:60](=[N:64]/[O:65][CH3:66])/[C:61]([NH:2][CH:3]2[C:33](=[O:34])[N:5]3[C:6]([C:17]([O:19][CH:20]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[S:18])=[C:7]([CH2:10][CH:11]4[CH2:16][CH2:15][CH2:14][CH2:13][O:12]4)[CH2:8][S:9][C@H:4]23)=[O:62])[N:59]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(CC3CCCCO3)CS[C@H]12
Reactant: CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(CC3CCCCO3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 68.5 %

Procedure:
Diphenylmethyl 7-amino-3-(tetrahydropyran-2-yl)methylthio-3-cephem-4-carboxylate hydrochloride (300 mg) was reacted with (Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetic acid (267 mg), followed by purifying the reaction product in accordance with the procedure of Example 1(d), affording the titled compound (360 mg; 78%).
Reaction SMILES: S(Cl)([Cl:3])=O.[N+:5]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)([O-:7])=[O:6]>CCOCC.CN(C=O)C>[N+:5]([O:8][CH2:9][CH2:10][CH2:11][C:12]([Cl:3])=[O:14])([O-:7])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCO[N+](=O)[O-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(Cl)CCCO[N+](=O)[O-]

Procedure:
Thionyl chloride (0.6 ml, 7.7 mmol) was slowly added, under stirring and under argon, to a solution of 4-(Nitrooxy)butanoic acid (1.00 g, 6.7 mmol) in anhydrous Et2O (25 ml) kept 0° C. A few drops of DMF (4-5 drops) were also added under stirring to the reaction mixture and the reaction temperature was allowed to rise to r.t. (ca. 20° C.). The reaction mixture was stirred at room temperature and under argon for 5 hours. The reaction mixture was concentrated in vacuo to provide crude 4-(nitrooxy)butanoyl chloride.
Reaction SMILES: [F:1][C@@H:2]([CH3:11])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.C(O)(=O)C>CO.[Pd]>[F:1][C@@H:2]([CH3:11])[CH2:3][O:4][CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1
Reactant: C[C@H](F)COc1ccncc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@H](F)COC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
2.2 g of 4-{[(2S)-2-fluoropropyl]oxy}pyridine was added to a solution of 22 mL of acetic acid in 22 mL of methanol, and 500 mg of 10% palladium on carbon (wet type) was added thereto under an argon atmosphere. The mixture was stirred at room temperature overnight under a hydrogen atmosphere of 3 atm. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (chloroform/methanol) to obtain 988 mg of 4-{[(2S)-2-fluoropropyl]oxy}piperidine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@@H:10]([C@@H:20]([OH:22])[CH3:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][N:27]=1>CN(C=O)C>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C@@H:10]([C@@H:20]([O:22][C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][N:27]=2)[CH3:21])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: C[C@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](Oc1ccc(C#N)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
To a stirred solution of 250 mg (0.79 mmol) of (S)-1-[(3R,4S)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethanol in DMF (10 mL) was added NaH (57 mg, 1.18 mmol). The reaction mixture was stirred at RT for 30 minutes, and then at 50° C. for 20 minutes. A solution of 6-chloro-nicotinonitrile (132 mg, 0.95 mmol) in DMF (2 mL) was added dropwise and stirring was continued 3 hours at 50° C. The reaction mixture was concentrated under vacuo. Extraction with EtOAc/H2O, followed by column chromatography (SiO2, EtOAc/H, 1:3) yielded 265 mg (80%) of the title compound as a colorless oil. ES-MS m/e: 418.3 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8](/[N:10]=[CH:11]/[N:12]([CH3:14])[CH3:13])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1.[I-].[Na+]>CN(C)C=O>[C:1]([C:5]1[CH:9]=[C:8](/[N:10]=[CH:11]/[N:12]([CH3:14])[CH3:13])[N:7]([CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)/C=N/c1cc(C(C)(C)C)n[nH]1
Reactant: BrCC1CCCCO1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)/C=N/c1cc(C(C)(C)C)nn1CC1CCCCO1
Temperature: 65 °C
Reaction time: 16 h
Yield: 53.9 %

Procedure:
To a solution of Example 63A (1.0 g, 5.2 mmol) in N,N-dimethylformamide (10 mL) were added sodium hydride (0.52 g, 12.9 mmol, 60% in mineral oil, Aldrich), 2-(bromomethyl)tetrahydro-2H-pyran (0.8 mL, 6.2 mmol) and sodium iodide (0.23 g, 1.5 mmol). After stirring at 65° C. for 16 h, the reaction mixture was cooled and quenched with saturated NaHCO3 (10 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-10% methanol in dichloromethane) to provide 0.82 g (55%) of the title compound. 1H NMR (501 MHz, chloroform-d) δ ppm 1.22-1.33 (m, 1H), 1.27 (s, 9H), 1.34-1.49 (m, 3H), 1.51-1.62 (m, 1H), 1.72-1.83 (m, 1H), 2.87 (s, 3H), 2.95 (s, 3H), 3.36-3.49 (m, 1H), 3.73-3.83 (m, 1H), 3.95 (dd, J=11.3, 3.0 Hz, 1H), 4.02 (dd, J=13.4, 7.7 Hz, 1H), 4.17 (dd, J=13.4, 5.8 Hz, 1H), 5.55 (s, 1H), 8.00 (s, 1H). MS (ESI+) m/z 293 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][C:6]1([CH2:21][CH2:22][CH3:23])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[Cl:20])C.[OH-].[Na+]>CCO>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]([Cl:20])=[C:13]2[C:18]=1[C:10]1[CH2:9][CH2:8][O:7][C:6]([CH2:21][CH2:22][CH3:23])([CH2:5][C:4]([OH:24])=[O:3])[C:11]=1[NH:12]2
Reactant: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(Cl)ccc(Cl)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCC1(CC(=O)O)OCCc2c1[nH]c1c(Cl)ccc(Cl)c21
Temperature: 50 °C
Reaction time: 6 h
Yield: 65.8 %

Procedure:
To a solution of 5,8 dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester (1.2 g, 3.24 mmol) in EtOH (35 mL) was added 1 N NaOH (7 mL). The reaction mixture was stirred at 50° C. for 6 hours. The most of EtOH/NaOH was removed under reduced pressure and the resulting mixture was purified on HPLC to yield a white solid 0.730 g (66%). 1H NMR (CDCl3): 300 MHz δ 9.12 (bs, 1H), 7.03 (d, J=8.26 Hz, 1H), 6.96 (d, J=8.26 Hz, 1H), 4.04 (m, 2H), 3.14(m, 2H), 3.06(m, 2H), 2.03 (m, 2H), 1.42 (m, 1H), 1.21(m, 1H), 0.89 (t, J=7.34 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:32])[C:7]=1[C:8]#[C:9][C@H:10]1[O:15][CH2:14][C@@H:13]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[N:12]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:11]1>[Pt](=O)=O>[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:32])[C:7]=1[CH2:8][CH2:9][C@H:10]1[O:15][CH2:14][C@@H:13]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[N:12]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C#Cc2c(N)cncc2F)OC[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: O=[Pt]=O
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cncc2F)OC[C@H]1CO[Si](C)(C)C(C)(C)C
Reaction time: 24 h
Yield: 68.6 %

Procedure:
Platinum(IV) oxide (0.536 g, 2.36 mmol) was suspended in nitrogen degassed trifluororoethanol. tert-Butyl (2R,5S)-2-[(3-amino-5-fluoropyridin-4-yl)ethynyl]-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)morpholine-4-carboxylate (2.20 g, 4.72 mmol) (68% pure) was dissolved in nitrogen degassed trifluorethanol (94 mL) and added to the suspension of platinum oxide. The reaction was shaken on the Parr at 50 psi hydrogen for 24 hr. The reaction was degassed with nitrogen, filtered through celite and the solvent removed in vacuo. Purification on silica gel (330 g) eluting with a gradient of 0-100% EtOAc/hexanes afforded the title compound (1.52 g, 3.24 mmol, 69% yield) as a white solid, MS (ESI): m/z=470.51 (MH+); 100% pure by LCMS