Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:9]([N:11](C)[C@H:12]([CH2:21][O:22][C:23](=[O:35])[NH:24][C:25]1[N:26]=[CH:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=O)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[C:25]([NH:24][C:23]([O:22][CH2:21][C@@H:12]([NH:11][CH3:9])[CH2:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])=[O:35])[N:26]=1
Reactant: [H][H]
Reactant: CN(C(=O)OCc1ccccc1)[C@H](COC(=O)Nc1cc2ccccc2cn1)CC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CN[C@H](COC(=O)Nc1cc2ccccc2cn1)CC(=O)OC(C)(C)C
Yield: 99.1 %

Procedure:
To a solution of (S)-tert-butyl 3-((benzyloxycarbonyl)(methyl)amino)-4-(isoquinolin-3-ylcarbamoyloxy)butanoate (1.8 g, 3.65 mmol) and MeOH (5 mL) was added 10% Pd—C (500 mg). The resulting mixture was stirred under 12 psi of hydrogen for 1 h. The mixture was filtered and concentrated, and the remaining residue was dried in vacuo to give (S)-tert-butyl 4-(isoquinolin-3-ylcarbamoyloxy)-3-(methylamino)butanoate (1.3 g), which was used without further purification. LRMS (M+H+) m/z 360.1
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=[CH:17][C:18]([O:20]C)=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[OH-].[Na+].CO>[C:1]1([C:7]2[C:15]([CH:16]=[CH:17][C:18]([OH:20])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C=Cc1c(-c2ccccc2)nn2ccccc12
Yield: 68.9 %

Procedure:
A mixture of methyl 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylate (trans isomer) (4.05 g) in 1N sodium hydroxide solution (58.3 ml) and methanol (80 ml) was refluxed for 1 hour and evaporated in vacuo. The residue was dissolved in water and washed with chloroform. The aqueous layer was acidified with 1N hydrochloric acid. The resulting precipitates were filtered and recrystallized from isopropyl alcohol to give crystals of 3-(2-phenylpyrazolo[1,5-a]-pyridin-3-yl)acrylic acid (2.65 g).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][C:6]([NH2:8])=[O:7])[CH3:2].[CH3:9][N:10]([CH3:15])[CH2:11][CH2:12][CH2:13]N.N>>[CH3:9][N:10]([CH3:15])[CH2:11][CH2:12][CH2:13][NH:8][C:6](=[O:7])[CH2:5][CH2:4][O:3][CH2:1][CH3:2]
Reactant: CCOCCC(N)=O
Reactant: CN(C)CCCN
Agent: N
Product: CCOCCC(=O)NCCCN(C)C

Procedure:
117.2 g of (1.0 mole) of 3-ethoxypropionamide are heated with 107.3 g (1.05 mole) of 3-dimethylaminopropylamine for 6 hours in a temperature range of 145°-170° C. until the evolution of ammonia is complete. In the subsequent distillation in a high vacuum 184 g (0.91 mole=91% of the theoretical yield) of colorless liquid are obtained having a Bp0.1 of 114°-118° C.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(#N)C>O>[N:13]1([C:2]2[N:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1ccc(N2CCOCC2)nc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Ethyl 6-chloronicotinate (5.0 g) and morpholine (10 ml) were mixed and then heated to 100° C. In less than 5 minutes at this temperature, a thick paste formed. Acetonitrile (15 ml) was added and heating was continued overnight at 90° C. The mixture was cooled, diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo to give ethyl 6-morpholin-4-ylpyridine-3-carboxylate as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:18]=[C:19]=[S:20])=[C:16]([CH3:17])[C:11]=2[N:10]=[C:9]1[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([NH2:25])[CH2:23][NH2:24]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:24][CH2:23][CH2:22][NH2:25])=[S:20])=[C:16]([CH3:17])[C:11]=2[N:10]=[C:9]1[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(N=C=S)ccc2c1nc(C)n2C(=O)OC(C)(C)C
Reactant: NCCN
Solvent: ClCCl
Product: Cc1c(NC(=S)NCCN)ccc2c1nc(C)n2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-t-butoxycarbonyl-2,4-dimethyl-5-isothiocyanatobenzimidazole (1.15 g, 3.8 mmol) in methylene chloride (100 mL) is added dropwise over 15 minutes to 1,2-ethylenediamine (1.26 mL, 18.9 mmol) in solution in methylene chloride (200 mL). The mixture is stirred for 2 hours at room temperature. The mixture is rotary evaporated and the residue is triturated with ether (150 mL) for 1 hour at room temperature. The solid is filtered and dried in vacuo to afford N-(1-t-butoxycarbonyl-2,4-dimethyl-5-benzimidazolyl)-N′-2-aminoethylthiourea as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:17]([CH:21]=2)[C:18](O)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:17]([CH:21]=2)[C:18]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccccc3)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.5 %

Procedure:
5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-phenylbenzoic acid (40 mg, 0.1020 mmol), 4-dimethylaminopyridine (6.2 mg, 0.0508 mmol) and morpholine (18 mg, 0.2068 mmol) were dissolved in methylene chloride (5 ml), then WSC-HCl (59 mg, 0.3077 mmol) was added thereto and the mixture was stirred at room temperature for 16 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (hexane:ethyl acetate=1:1) to give the title compound (13 mg, 0.0281 mmol, 28%).
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[O:29]([C:36]1[N:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([NH:1][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][CH:43]=[N:44][C:36]=3[O:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: O=C(Cl)c1cccnc1Oc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3cccnc3Oc3ccccc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 2-phenoxynicotinoyl chloride: ESMS m/e: 577.3 (M+H)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([Cl:32])[C:27]=2[Br:33])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][N:43]=1)[C:38](Cl)=[O:39]>O1CCCC1>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([CH2:24][N:25]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([Cl:32])[C:27]=2[Br:33])[C:38]([C:37]2[CH:41]=[CH:42][N:43]=[C:35]([Cl:34])[CH:36]=2)=[O:39])[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC=C(CNc2ccnc(Cl)c2Br)CC1
Reactant: O=C(Cl)c1ccnc(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(CN(C(=O)c2ccnc(Cl)c2)c2ccnc(Cl)c2Br)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88.3 %

Procedure:
Lithium bis(trimethylsilyl)amide (1M solution in THF, 3 ml) was added dropwise to a stirred solution of 4-[(3-Bromo-2-chloro-pyridin-4-ylamino)-methyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.53 g) in tetrahydrofuran (20 ml) at −78° C. under N2. The yellow solution was warmed to 0° C. and then 2-chloroisonicotinoyl chloride (50% solution in toluene, 0.95 g) was added. The solution was stirred at 0° C. for 10 min., quenched by addition of aqueous ammonium chloride, extracted with EtOAc, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2 then CH2Cl2/EtOAc 8:2 cyclohexane:ethyl acetate 8:2) to afford 4-{[(3-bromo -2-chloro-pyridin-4-yl)-(2-chloro-pyridine-4-carbonyl)-amino]-methyl }-3,6-dihydro-2H -pyridine-1-carboxylic acid tert-butyl ester (0.63 g), which was identified by its mass and 1H NMR spectra. MS (ES+) 443/445 (MH+—BOC), 484/486 (MH+-isoprene).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][N:21]=[N+]=[N-])=[N+:2]=[N-:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>Cl.CCOCC>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH2:21])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCOCCOCCOCCOCCOCCN=[N+]=[N-]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: [N-]=[N+]=NCCOCCOCCOCCOCCOCCN
Reaction time: 24 h
Yield: 95.7 %

Procedure:
To a vigorously stirred suspension of 1,17-diazido-3,6,9,12,15-pentaoxaheptadecane (25 g, 75 mmol) in 5% HCl (200 mL) was added a solution of triphenylphosphine (19.2 g, 73 mmol) in ether (150 mL) over 3 hrs at room temperature. The reaction mixture was stirred for additional 24 hrs. The phases were separated and the aqueous phase was extracted with dichloromethane (3×40 mL). The aqueous phase was cooled in an ice/water bath and the pH was adjusted to 12 by addition of solid potassium hydroxide. The aqueous phase was concentrated and the product was taken up in dichloromethane (150 mL). The organic phase was dried (Na2SO4) and concentrated giving a yellow oil 22 g (95%). The product was identified by electrospray mass spectrometry (ESI-MS) (MH+ calculated: 307.19. found 307.4). The crude oil was used in the next step without further purification.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[N:8]=[C:9]([F:31])[N:10]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1)(=[O:3])[CH3:2].C(Cl)(=O)C1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>>[F:31][C:9]1[N:10]([C:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[C:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[C:2]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[N:8]=1
Reactant: CC(=O)NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: O=C(Cl)c1ccncc1
Product: O=C(NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1)c1ccncc1

Procedure:
Use of the same technique as for the starting material of Example 29, but replacing acetyl chloride with isonicotinoyl chloride gave 2-fluoro-4-(2-isonicotinoylaminoethyl)-1-triphenylmethylimidazole, having the following n.m.r. spectrum in CDCl3 : 2.7 (t, 2H); 3.71 (q, 2H); 6.35 (s, 1H); 7.0-7.5 (m, 15H); 7.65 (q, 2H); 8.72 (q, 2H).
Reaction SMILES: [C@@H:1]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH2:19][C:20]3[S:21][C:22]([C:25]4[CH:30]=[CH:29][C:28]([CH:31]=[O:32])=[CH:27][CH:26]=4)=[CH:23][CH:24]=3)[CH:13]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[BH4-].[Na+]>C(O)C.O1CCCC1>[C@@H:1]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH2:19][C:20]3[S:21][C:22]([C:25]4[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][CH:26]=4)=[CH:23][CH:24]=3)[CH:13]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: O=Cc1ccc(-c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)s2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)s2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
1-(β-D-Glucopyranosyl)-4-chloro-3-(5-(4-formylphenyl)-2-thienylmethyl)benzene (84 mg) obtained in Example 249 was dissolved in a mixture of ethanol (2 ml)-tetrahydrofuran (2 ml) and added thereto was sodium borohydride (7 mg). The mixture was stirred at room temperature for 1 hour. The mixture was quenched by 2N hydrochloric acid aqueous solution (3 drops) at 0° C., and the solvents were evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to give the desired 1-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-hydroxymethylphenyl)-2-thienylmethyl)benzene (82 mg) as colorless foam. APCI-Mass m/Z 494/496 (M+NH4).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH2:11][C:12](=O)[CH3:13])[CH:5]=1.Cl.[Br:17][C:18]1[CH:19]=[C:20]([NH:24]N)[CH:21]=[CH:22][CH:23]=1>CC(O)(C)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:21]3[C:20](=[CH:19][C:18]([Br:17])=[CH:23][CH:22]=3)[NH:24][C:12]=2[CH3:13])[CH:5]=1
Reactant: NNc1cccc(Br)c1
Reactant: COC(=O)c1cccc(SCC(C)=O)c1
Agent: Cl
Solvent: CC(C)(C)O
Product: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Br)ccc23)c1

Procedure:
3-(2-Oxo-propylsulfanyl)-benzoic acid methyl ester (3.65 g, 16.29 mmol) and 3-bromophenylhydrazine hydrochloride (4.01 g, 17.92 mmol) were mixed together in t-BuOH (100 mL) and heated to reflux for 1 hour. After cooling the reaction was concentrated then submitted to standard workup procedure and the crude mixture was purified by silica gel chromatography (0-30% EtOAc in hexanes) to afford a separable 5:4 mixture of regioisomers wherein the title compound was the major product.
Reaction SMILES: C([O:8][N:9]([CH3:37])[C:10]([C@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[S:18]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=3)[NH:29][CH:28]=2)[CH2:23][CH2:22]1)(=[O:20])=[O:19])=[O:11])C1C=CC=CC=1>C(O)C.O1CCCC1.[Pd]>[OH:8][N:9]([CH3:37])[C:10]([C@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[S:18]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=3)[NH:29][CH:28]=2)[CH2:23][CH2:22]1)(=[O:20])=[O:19])=[O:11]
Reactant: CN(OCc1ccccc1)C(=O)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(O)C(=O)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Reaction time: 1.17 h
Yield: 83 %

Procedure:
A suspension of 10% Pd/C (0.20 g) and N-benzyloxy-N-methyl-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide (0.40 g, 0.75 mmol) [prepared as described in Step 4 above] in 80% ethanol/tetrahydrofuran (6 ml) was stirred under a hydrogen atmosphere (1 atm) for 70 min. The reaction was degassed with nitrogen, filtered through Celite and the filtrate was concentrated in vacuo. The residue was chromatographed (PTLC, SiO2, 10% methanol/methylene chloride) to give N-hydroxy-N-methyl-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide (83%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH2:6][C@H:7]1[O:11][C:10](=[O:12])[N:9]([C@H:13]([CH3:16])[CH2:14][OH:15])[CH2:8]1.O[C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH2:6][C@H:7]1[O:11][C:10](=[O:12])[N:9]([C@H:13]([CH3:16])[CH2:14][O:15][C:21]2[CH:53]=[CH:52][C:24]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]3=[O:51])=[CH:23][CH:22]=2)[CH2:8]1
Reactant: C[C@H](CO)N1C[C@@H](COc2cccc(Cl)c2)OC1=O
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: C[C@H](COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)N1C[C@@H](COc2cccc(Cl)c2)OC1=O
Yield: 76.4 %

Procedure:
A procedure similar to that described in Preparation 6 was repeated, except that 0.52 g of 2(R)-[5(S)-(3-chlorophenoxymethyl)-2-oxooxazolidin-3-yl]propanol (prepared as described in Preparation 28), 1.01 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.44 g of tributylphosphine, 0.55 g of azodicarbonyldipiperidine and 30 ml of anhydrous benzene were used, to give 1.02 g of the title compound having an Rf value of 0.26 (on silica gel thin layer chromatography, using a 1:1 by volume mixture of ethyl acetate and hexane as the developing solvent) and having [α]D =+35.9° (methanol, c=1.000).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](I)[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[N:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[Na+].[Na+].O>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[C:8]([C:22]2[N:18]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[N:19]=[CH:20][CH:21]=2)[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: N#Cc1c(F)cc(I)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(F)cc(-c2ccnn2C2CCCCO2)cc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
To a solution of 2-chloro-6-fluoro-4-iodobenzonitrile (5.75 g, 20.4 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.39 g, 26.6 mmol) in THF (60 ml) was added bis(triphenylphosphine)-palladium(II) chloride (0.717 g, 1.02 mmol), sodium carbonate (5.20 g, 49.0 mmol) and water (20 ml). Reaction mixture was heated at 60° C. for 2 h, concentrated to ¼ of the volume, diluted with water (40 ml) and stirred at RT for 1 h. Thus resulting solid was filtered and suspended in EtOH (30 ml). Suspension was stirred at −10° C. for 1 h, precipitate was filtered and washed with EtOH to yield 2.90 g (46%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.49-1.72 (m, 3H), 1.78-2.03 (m, 2H), 2.29-2.44 (m, 1H), 3.56-3.68 (m, 1H), 3.93-4.03 (m, 1H), 5.36 (dd, 1H), 6.78 (d, 1H), 7.66 (d, 1H), 7.73 (dd, 1H), 7.81 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([N+:15]([O-])=O)[C:3]=1[NH2:18]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([NH2:15])[C:3]=1[NH2:18]
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2F)CC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: CN1CCN(c2ccc(N)c(N)c2F)CC1

Procedure:
A reaction tube was charged with suspension of 1 (330 mg, 1.15 mmol) and Lindlar catalyst (245 mg, 10 mol %) in methanol (5 mL), sealed, and placed on a Parr shaker. The reaction was pressurized with H2 (60 psi) and maintained for 1 h. The reaction was filtered through Celite and the remaining solids were washed with MeOH. The combined organics were concentrated to give 2 as a brown semi-solid which was taken on without further purification.
Reaction SMILES: Cl.[F:2][C:3]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([F:19])[C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(N(CC)CC)C.[CH3:27][N:28]=[C:29]=[O:30]>C1C=CC=CC=1>[CH3:27][NH:28][C:29]([N:9]1[CH2:10][CH2:11][CH:6]([O:5][C:4]2[C:12]([F:19])=[C:13]([F:18])[C:14]([F:17])=[C:15]([F:16])[C:3]=2[F:2])[CH2:7][CH2:8]1)=[O:30]
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Reactant: CN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CNC(=O)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
To a stirring solution of 5.3 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine hydrochloride in 100 ml of benzene was added 2.37 ml of triethylamine followed by 1.00 ml of methyl isocyanate. The reaction mixture was stirred at ambient temperature for three hours and then evaporated to a semi-solid. The semi-solid was purified by means of high pressure liquid chromatography (silica gel; elution with 50% ethyl acetate/dichloromethane) to afford 5.14 g (93.3%) of 1-[(N-methylamino)carbonyl]-4-(2,3,4,5,6-pentafluorophenoxy)piperidine, m.p. 107°-110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(OC([N:36]1[CH2:41][CH2:40][N:39]([C:42](=[O:45])[CH2:43]Cl)[CH2:38][CH2:37]1)=O)(C)(C)C>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:43][C:42](=[O:45])[N:39]2[CH2:40][CH2:41][NH:36][CH2:37][CH2:38]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: O=C1OC2(CCN(C(=O)c3cn(CC(=O)N4CCNCC4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure V as described hereinabove, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (the preparation of which have been described in example 19) with commercially available 4-(2-Chloro-acetyl)-piperazine-1-carboxylic acid tert-butyl ester as electrophile, the title compound was obtained as a white solid after removal of the Boc protecting group under standard conditions (TFA/dichloromethane, room temperature).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][C:10]2[CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[CH3:16][NH2:17]>C(Cl)Cl>[CH3:16][NH:17][S:12]([C:8]1[CH:7]=[CH:6][C:5]2[CH2:4][CH2:3][C:2](=[O:1])[CH2:11][C:10]=2[CH:9]=1)(=[O:14])=[O:13]
Reactant: CN
Reactant: O=C1CCc2ccc(S(=O)(=O)Cl)cc2C1
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc2c(c1)CC(=O)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a solution of 7-oxo-5,6,7,8-tetrahydro-naphthalene-2-sulfonyl chloride (see Preparative Example 3, 1.14 g, 4.7 mmol) in CH2Cl2 (10 mL) at 15° C. (using a water bath) was added MeNH2 (2M in THF, 7 mL, 14 mmol, 3 eq) dropwise. After stirring at room temperature for 30 minutes, the mixture was diluted with CH2Cl2 (30 mL), washed with H2O (20 mL), dried (Na2SO4), and concentrated. The residue was chromatographed on silica by eluting with 20% EtOAc/hexanes to give 0.45 g (40%) of 7-oxo-5,6,7,8-tetrahydro-naphthalene-2-sulfonic acid methylamide as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.70 (d, 1H, J=8.1 Hz), 7.63 (s, 1H), 7.40 (d, 1H, J=8.1 Hz), 4.66 (q, 1H, J=5.4 Hz), 3.64 (s, 2H), 3.14 (t, 2H, J=6.6 Hz), 3.65 (d, 3H, J=5.4 Hz), 2.57 (t, 2H, J=6.6 Hz).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[C:28](O)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:35])[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)c1ccccc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccccc1

Procedure:
The title compound, white solid (100 mg, 92%), MS (ISP) m/z=435.3 [(M+H)+], mp 207.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and benzoic acid.