Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([C:13]([O-:15])=[O:14])=[N:9]2)=[CH:5][CH:4]=1.[K+].Cl>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([C:13]([OH:15])=[O:14])=[N:9]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(Cn2nnc(C(=O)[O-])n2)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: COc1ccc(Cn2nnc(C(=O)O)n2)cc1
Reaction time: 3 h
Yield: 56.9 %

Procedure:
Potassium 2-(4-methoxybenzyl)-2H-tetrazole-5-carboxylate (2.45 g) was dissolved in a minimum quantity of water and acidified to pH 1 by treatment with concentrated hydrochloric acid. The mixture was stirred for 3 hours, and then the solid was filtered off and washed with water to give 2-(4-methoxybenzyl)-2H-tetrazole-5-carboxylic acid (1.20 g), m.p. 146°-147° C. (with decomposition).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:7][C:6](=[O:8])[O:5][CH2:4]2)[CH2:2]1.CN(C)C(=O)C.[CH3:15][O-:16].[Na+].[Cl-].[NH4+]>CO.O>[CH3:15][O:16][C:6](=[O:8])[CH2:7][C:3]1([CH2:4][OH:5])[CH2:1][CH2:2]1
Reactant: C[O-]
Reactant: O=C1CC2(CC2)CO1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CO
Product: COC(=O)CC1(CO)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47 %

Procedure:
To a stirred solution of crude 5-oxa-spiro[2.4]heptan-6-one (2.24 g, ca. 20 mmol; prepared according to the method of EP 0 678 515 A1 (herein incorporated by reference in its entirety for all purposes): impurity is N,N-dimethyl acetamide) in anhydrous methanol (40 mL) in water bath, was added sodium methoxide (1.296 g, 24 mmol). After 15 min, ammonium chloride (2 g) was added and the mixture was stirred at room temperature for 30 min. The mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:1)) to afford 5.8 g (47%) of (1-hydroxymethyl-cyclopropyl)-acetic acid methyl ester as a colorless oil. 1H-NMR (200 MHz, CDCl3) δ 0.47-0.61 (4H, m), 2.44 (2H, s), 2.55 (1H, t, J=5.6 Hz), 3.48 (2H, d, J=5.6 Hz), 3.69 (3H, s).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:24])=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([CH2:20]Cl)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[NH2:25][C:26]([C:28]1([NH:41][CH3:42])[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)=[O:27].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:25][C:26]([C:28]1([N:41]([CH2:20][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][C:16]=2[O:22][CH3:23])[N:13]=[CH:12][N:11]=[C:10]3[NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[C:4]=2[F:24])[CH3:42])[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH2:32][CH2:33]1)=[O:27]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CCl
Reactant: CNC1(C(N)=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 78.8 %

Procedure:
N-(3-chloro-2-fluorophenyl)-6-(chloromethyl)-7-methoxyquinazolin-4-amine hydrochloride (0.30 g, 0.775 mmol) was added over a period of 40 minutes to a stirred solution of tert-butyl 4-(aminocarbonyl)-4-(methylamino)piperidine-1-carboxylate (0.498 g, 1.93 mmol) and DIPEA (0.50 g, 3.89 mmol) in DMF (1 ml) at 120° C. The reaction mixture was stirred for 1 hour, cooled, concentrated and purified by column chromatography on silica eluting with acetonitrile to afford tert-butyl 4-(aminocarbonyl)-4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-1-carboxylate (0.35 g, 79%) as a white foam; Mass Spectrum: (M+H)+ 573.
Reaction SMILES: [O-][N+:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[OH2:26].[OH-].[Na+]>C(OC(=O)C)(=O)C>[OH:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]2[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:6][C:5]3[CH:4]=[CH:3][NH:2][C:11](=[O:26])[C:10]=3[N:9]=2)=[CH:13][CH:14]=1
Reactant: [O-][n+]1ccc2cc(-c3ccccc3)c(-c3ccc(CO)cc3)nc2c1
Reactant: O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: O=c1[nH]ccc2cc(-c3ccccc3)c(-c3ccc(CO)cc3)nc12
Temperature: 130 °C

Procedure:
A suspension of [4-(7-oxido-3-phenyl-1,7-naphthyridin-2-yl)phenyl]methanol (144 mg, 0.44 mmol) in acetic anhydride (2 mL) was heated at 130° C. for two hours and then cooled to ˜100° C. Water was added and the stirred mixture was allowed to cool to room temperature. This solution was extracted with methylene chloride and the organic layer was washed with NaHCO3/Na2CO3 solutions, dried, filtered and the solvent evaporated. This residue was determined to be mainly the acylated product, 4-(7-oxo-3-phenyl-7,8-dihydro-1,7-naphthyridin-2-yl)benzyl acetate, by NMR. This material was dissolved in tetrahydrofuran (5 mL) and 5 N NaOH (0.5 mL, 2.5 mmol) was added. The mixture was heated at 60° C. for two hours. The cooled solution was extracted with methylene chloride. The organic layer was washed with aqueous NaHCO3 and then dried, filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel eluting with 0-5% methanol/ethyl acetate (sat'd with ammonia) to give the title compound. 1H-NMR (500 MHz, CDCl3): δ 10.60 (1H, br s), 7.93 (1H, s), 7.44 (2H, d, J=8 Hz), 7.28-7.34 (4H, m), 7.22-7.27 (4H, m), 6.59 (1H, d, J=7 Hz), 4.65 (2H, s). m/e (m+1): 329.2.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH3:39])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Cl:42].O>C(OC(OCC)C)C.C(OCC)C>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH2:39][Cl:42])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Reactant: OCl
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)OCC
Product: C=C(CCl)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Yield: 90 %

Procedure:
A 200 mg quantity of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-methyl-3-butenate was dissolved in 4.3 ml of diethoxyethane. The solution was cooled in an ice bath with stirring. Thereto was added dropwise over 3 minutes 1.73 ml of a 0.3M solution of HOCl in diethyl ether. Water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled off at reduced pressure. The resulting residue was separated and purified by silica gel column chromatography, giving 191 mg of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-chloromethyl-3-butenate in 90% yield.
Reaction SMILES: C([Li])(C)(C)C.I[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[Br:13][C:14]1[CH:15]=[C:16](/[C:20](/[C:28]2[C:29]([C:34]#[N:35])=[N:30][CH:31]=[CH:32][CH:33]=2)=[N:21]\S(C(C)(C)C)=O)[CH:17]=[CH:18][CH:19]=1>C1COCC1>[Br:13][C:14]1[CH:15]=[C:16]([C:20]2([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)[C:28]3[C:29](=[N:30][CH:31]=[CH:32][CH:33]=3)[C:34]([NH2:35])=[N:21]2)[CH:17]=[CH:18][CH:19]=1
Reactant: Ic1ccncc1
Reactant: CC(C)(C)S(=O)/N=C(\c1cccc(Br)c1)c1cccnc1C#N
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: NC1=NC(c2ccncc2)(c2cccc(Br)c2)c2cccnc21
Temperature: -100 °C
Reaction time: 0.08 h
Yield: 69 %

Procedure:
tert-Butyllithium (1.5 M solution in pentane, 2.15 mL) was diluted with anhydrous THF (10 mL) at −100° C. under an atmosphere of argon. To this was added dropwise a solution of 4-iodopyridine (330 mg, 1.773 mmol) in anhydrous THF (8 ml,), the mixture was stirred at −100° C. for 5 min and then a solution of N-[(1E)-(3-bromophenyl)(2-cyanopyridin-3-yl)methylene]-2-methylpropane-2-sulfinamide (Example 2, 629 mg, 1.612 mmol) in THF (10 mL) was added dropwise while maintaining the temperature at or below −100° C. The mixture was stirred for 1.5 h during which time it was allowed to warm up to −75° C. The reaction was quenched by the addition of water and the mixture was diluted with ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium hydrogen carbonate and brine, then dried over magnesium sulfate and evaporated. The residue was dissolved in methanol (10 mL) and treated with 2 M hydrochloric acid in diethyl ether overnight at room temperature. The solvents were evaporated and the residue was taken up with saturated aqueous hydrogen carbonate and dichloromethane. The phases were separated, the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated. Purification by column chromatography using a gradient of increasing concentration of 2 M methanolic ammonia in dichloromethane (from 0 to 5%) gave 406 mg (69% yield) of the title compound. 1H NMR (CDCl3) δ 8.67 (dd, 1H), 8.53 (m, 2H), 7.90 (dd, 1H), 7.41 (m, 3H), 7.23 (m, 3H), 7.18 (m, 1H); MS (ESI) m/z 365, 367 [M+1]+.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:23][OH:24])[C:13]2[C:8](=[CH:9][C:10]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4]>[OH-].[Na+].CO>[OH:24][CH2:23][C:5]1([C:3]([OH:4])=[O:2])[C:13]2[C:8](=[CH:9][C:10]([C:15](=[O:22])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)C1(CO)CCc2cc(C(=O)c3ccccc3)c(O)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(c1ccccc1)c1cc2c(cc1O)C(CO)(C(=O)O)CC2

Procedure:
A solution of 2.8 g of 1-hydroxymethyl-5-benzoyl-6-hydroxy-indane-1carboxylic acid methyl ester in 12 ml of 2 N sodium hydroxide solution and 50 ml of methanol is heated to the reflux temperature for 5 hours. It is then evaporated in vacuo to a volume of approx. 10 ml and the evaporation residue is partitioned between twice 50 ml of water and 50 ml of ether. The aqueous phases are combined, acidifed to pH 1 with concentrated hydrochloric acid and extracted with twice 50 ml of ether. The organic extracts are washed until neutral, dried over sodium sulphate and evaporated to dryness in vacuo. Chromatography of the evaporation residue on 100 g of silica gel using ether as the eluting agent gives pure 1-hydroxymethyl-5-benzoyl-6-hydroxy-indane-1-carboxylic acid in the form of yellow crystals of melting point 104°-110° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[C:11](=[O:19])[O:12][CH:13]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[CH:6]3[CH2:5][C:4]=2[CH:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:20]1([C:2]2[CH:10]=[CH:9][C:8]3[N:7]4[C:11](=[O:19])[O:12][CH:13]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[CH:6]4[CH2:5][C:4]=3[CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(=O)NCC1OC(=O)N2c3ccc(Br)cc3CC12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)NCC1OC(=O)N2c3ccc(-c4ccccc4)cc3CC12

Procedure:
(±) (1S,9aS/1R,9aR) N-[(7-Bromo-9,9a-dihydro-3-oxo-1H,3H-oxazolo[3,4-a]indol-1-yl)methyl]acetamide (EXAMPLE 24, 129 mg) is dissolved in tetrahydrofuran (1 ml). To this mixture palladium tetrakis(triphenylphosphine) (22 mg), phenylboronic acid (61 mg) and aqueous sodium carbonate (2M, 0.45 ml) is added. The mixture is warmed for 15.5 hours in an oil bath at 68°. The mixture is then partitioned between aqueous sodium carbonate (2M, 2 ml) and methylene chloride (3 ml). After separation of the layers, the aqueous phase is extracted with additional methylene chloride (3×2 ml). The organic layers are combined, dried over magnesium sulfate and concentrated to provide a solid. This solid is taken up in methylene chloride and placed on a 20.5 cm×2.5 cm, 40-63μ silica column and eluted with ethyl acetate/methanol gradient. The appropriate fractions are pooled and concentrated to give the title compound, mp 181°-183°; NMR (CDCl3, 300 MHz) 7.43, 6.08, 4.53, 4.54, 3.83, 3.70, 3.35, 3.17 and 2.07 δ.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:22][O:23][C:24](=[O:36])[C:25]1[CH:34]=[CH:33][C:32]([NH2:35])=[C:27]([C:28]([O:30][CH3:31])=[O:29])[CH:26]=1.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:22][O:23][C:24](=[O:36])[C:25]1[CH:34]=[CH:33][C:32]([NH:35][C:17](=[O:18])[CH2:16][O:15][C:14]2[CH:13]=[CH:12][C:11]([C:1]34[CH2:10][CH:5]5[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]5)[CH2:8]3)[CH2:2]4)=[CH:21][CH:20]=2)=[C:27]([C:28]([O:30][CH3:31])=[O:29])[CH:26]=1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: COC(=O)c1ccc(N)c(C(=O)OC)c1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c(C(=O)OC)c1
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a mixture of (4-adamantan-1-yl-phenoxy)-acetic acid (229 mg, 0.8 mmol) and 4-aminoisophthalic acid dimethyl ester (301 mg, 1.4 mmol) were dissolved in DMF (5 mL), and EDCHCl (140 mg, 0.75 mmol), HOAt (163 mg, 1.2 mmol) and DIPEA (0.21 ml, 1.2 mmol) was added. The mixture was stirred overnight, and then partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=50:1) to give 4-[2-(4-Adamantan-1-yl-phenoxy)acetyl-amino]-isophthalic acid dimethyl ester as a white solid (281 mg, 76.3% yield).
Reaction SMILES: C1(S([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:21]#[N:22])=[C:18]([CH2:19][CH3:20])[C:13]=3[C:12]3[CH:23]=[CH:24][CH:25]=[N:26][C:11]2=3)(=O)=O)C=CC=CC=1.C(Cl)Cl.N>CO>[CH2:19]([C:18]1[C:13]2[C:12]3[CH:23]=[CH:24][CH:25]=[N:26][C:11]=3[NH:10][C:14]=2[CH:15]=[N:16][C:17]=1[C:21]#[N:22])[CH3:20]
Reactant: CCc1c(C#N)ncc2c1c1cccnc1n2S(=O)(=O)c1ccccc1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CCc1c(C#N)ncc2[nH]c3ncccc3c12
Temperature: 25 °C
Reaction time: 120 h
Yield: 78.7 %

Procedure:
A mixture of 9-benzenesulfonyl-5-ethyl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (60 mg, 0.16 mmol), DCM (3.0 mL) and 7N ammonia in methanol (3 mL) was stirred at room temperature for 5 days. The reaction mixture was then concentrated in vacuo and the resultant residue was triturated with methanol (2 mL) and dried in vacuo to give the title compound as an off-white solid (28 mg, 81%). LCMS (Method B): RT=2.81 min, M+H+=223.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.C(N(CC)CC)C.[S:42]1[CH:46]=[CH:45][N:44]=[C:43]1[CH:47]=O.O([BH-](OC(C)=O)OC(C)=O)C(C)=O.[Na+]>ClCCCl>[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:20][CH2:21][N:22]([CH2:47][C:43]5[S:42][CH:46]=[CH:45][N:44]=5)[CH2:23][CH2:24]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Reactant: O=Cc1nccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(Cc2nccs2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.5 %

Procedure:
To a stirred solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride (25.3 mg, 0.05 mmol) in 1,2-dichloroethane (1 mL) was added triethylamine (14 μL, 0.1 mmol), 2-thiazole-carboxaldehyde (6.6 mg, 0.05 mmol) and sodium triacetoxylborohydride (10.6 mg, 0.05 mmol). The resulting mixture was stirred for 4 hours at ambient temperature before it was quenched with saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (2×10 mL). The combined extracts was washed with brine and dried over anhydrous sodium sulfate. After evaporation of the solvents, the residue was brought to a flash chromatography on silical gel, eluting with a gradient of 0-10% methanol in ethyl acetate to afford 2-methyl-1-(8-{2-[4-phenyl-1-(1,3-thiazol-2-ylmethyl)piperidin-4-yl]ethyl}-8-azabicyclo-[3.2.1]oct-3-yl)-1H-benzimidazole (23 mg, 87%). 1H NMR (300 MHz, CDCl3) δ 7.79-7.65 (m, 2H), 7.46-7.37 (m, 2H), 7.34-7.15 (m, 7H), 5.32 (br, 1H), 3.68 (s, 2H), 3.54 (br, 2H), 2.82-2.80 (m, 2H), 2.67 (s, 3H), 2.63-2.47 (m, 4H), 2.25 (br, 4H), 2.08-1.96 (m, 8H), 1.86 (br, 2H). HRMS m/z (M+H)+ calcd: 526.3004, obsd: 526.3008.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7][S:6]1=O)=[S:4].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.C(OCC)(=O)C.C>C(Cl)Cl>[CH3:1][NH:2][C:3]([C:5]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7][S:6]1)=[S:4]
Reactant: CNC(=S)C1(c2cccc(C)n2)CCCCS1=O
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNC(=S)C1(c2cccc(C)n2)CCCCS1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.7 %

Procedure:
To a solution of N-methyl-2-(6-methyl-2-pyridyl)-2-tetrahydrothiopyrancarbothioamide 1-oxide (72.4 g) in methylene chloride (1.4 liters), phosphorus pentasulphide (28.5 g) is added at a temperature below 28° C. and in the course of 50 minutes. The reaction mixture is stirred for 1 hour 45 minutes at a temperature in the region of 25° C. and distilled water (250 cc) is then added. The organic phase is decanted and washed 3 times with distilled water (750 cc in total) and dried over anhydrous magnesium sulphate, decolorising charcoal is added and the mixture is kept for 15 hours at a temperature in the region of 5° C. After filtration, the solution is poured onto neutral silica gel (1.6 kg; 0.063-0.200 mm) contained in a column 8 cm in diameter. The column is eluted with methylene chloride, collecting one fraction (3.9 liters) and 13 fractions (900 cc). The column is then eluted with a mixture of cyclohexane and ethyl acetate (60:40 by volume), collecting 5 fractions (900 cc). Fractions 6 to 13 and 15 to 18 are combined and concentrated to dryness under reduced pressure (0.5 mm Hg; 0.06 kPa) at 45° C. To the product obtained (49.6 g) there is added some product (41.2 g) prepared under the same conditions in a previous operation, and the combined product is dissolved in boiling ethyl acetate (600 cc); decolorising charcoal (10 g) is added to the solution, which is filtered hot and then kept, after being cooled, for 4 hours at 0° C. The crystals which appear are separated by filtration, washed twice with ethyl acetate (30 cc in total) and 4 times with isopropyl ether (160 cc in total), and then dried under reduced pressure (0.2 mm Hg; 0.026 kPa) at 55° C. N-Methyl-2-(6-methyl-2-pyridyl)-2-tetrahydrothiopyrancarbothioamide (68.1 g), m.p. 139° C., is thereby obtained.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([CH3:65])[NH:5][C:6](=[O:64])[C@H:7]([CH2:58][C:59]1[N:63]=[CH:62][NH:61][CH:60]=1)[NH:8][C:9](=[O:57])[C@H:10]([CH2:48][O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[NH:11][C:12](=[O:47])[C@H:13]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:35][CH:34]=1)[NH:14][C:15](=[O:31])[C@H:16]([CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1)[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:67]([NH2:69])[CH3:68]>CO>[CH2:67]([NH:69][C:3](=[O:2])[C@@H:4]([CH3:65])[NH:5][C:6](=[O:64])[C@H:7]([CH2:58][C:59]1[N:63]=[CH:62][NH:61][CH:60]=1)[NH:8][C:9](=[O:57])[C@H:10]([CH2:48][O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[NH:11][C:12](=[O:47])[C@H:13]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:35][CH:34]=1)[NH:14][C:15](=[O:31])[C@H:16]([CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1)[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:68]
Reactant: COC(=O)[C@@H](C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](Cc1c[nH]cn1)NCc1ccccc1
Reactant: CCN
Solvent: CO
Product: CCNC(=O)[C@@H](C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](Cc1c[nH]cn1)NCc1ccccc1

Procedure:
Nα -Butoxycarbonyl-Nim -benzyl-L-histidyl-O-benzyl-L-tyrosyl-O-benzyl-L-seryl-L-histidyl-D-alanine methyl ester, 0.3 g., (Example 18) is treated with 200 ml. of methanol and 5 ml. of ethylamine at room temperature for three days. The above named product is isolated after evaporation of the solvent and the chromatographing of the residue on a silica gel column with ten percent methanol in benzene; 0.21 g.; m.p. 83°-88° C.
Reaction SMILES: [C:1]([N:4]1[CH2:7][CH:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][C:24]=3[Cl:25])[NH:21][CH:20]=[C:19]4[CH:26]=[O:27])=[CH:12][CH:11]=2)[CH2:5]1)(=[O:3])[CH3:2].CC(=CC)C.Cl([O-])=[O:34].[Na+].O.OP([O-])(O)=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(#N)C.C(O)(C)(C)C.O>[C:1]([N:4]1[CH2:7][CH:6]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][C:24]=3[Cl:25])[NH:21][CH:20]=[C:19]4[C:26]([OH:34])=[O:27])=[CH:14][CH:15]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: [O-][Cl+][O-]
Reactant: CC(=O)N1CC(COc2ccc(-c3cc4c(C=O)c[nH]c4cc3Cl)cc2)C1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: O=S([O-])[O-]
Solvent: O
Solvent: CC#N
Solvent: CC(C)(C)O
Product: CC(=O)N1CC(COc2ccc(-c3cc4c(C(=O)O)c[nH]c4cc3Cl)cc2)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 12.1 %

Procedure:
To a mixture of 5-{4-[(1-acetylazetidin-3-yl)methoxy]phenyl}-6-chloro-1H-indole-3-carbaldehyde (120 mg, 0.31 mmol) in acetonitrile (6 mL) and tert-butanol (6 mL) was added 2-methyl-2-butene (2.17 g, 31 mmol). The mixture was cooled to 0° C., and treated with a solution of sodium chlorite (418 mg, 6.2 mmol) and sodium phosphate monobasic hydrate (856 mg, 6.2 mmol) in water (6 mL). The reaction mixture was stirred at room temperature for 16 hours. A solution of sodium sulfite was added slowly to the reaction mixture, and stirred for 1 hour. The reaction mixture was partially evaporated in vacuo. The aqueous residue was extracted with ethyl acetate (10 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give a brown residue. The residue was purified by preparative HPLC to give 5-{4-[(1-acetylazetidin-3-yl)methoxy]phenyl}-6-chloro-1H-indole-3-carboxylic acid (15 mg, 12%) as a white solid. MS (ES+) 399.0 (M+H)+. 1H NMR (400 MHz, CD3OD): δ 8.01 (m, 2H), 7.57 (s, 1H), 7.39 (d, 2H), 7.03 (d, 2H), 4.40 (m, 1H), 4.21 (m, 2H), 4.15 (m, 2H), 3.90 (m, 1H), 3.11 (m, 1H), 1.90 (s, 3H).