Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[S:19](=[O:21])(=[O:20])[N:18]([CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:17](=[O:28])[CH2:16]2)=[C:11]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:10]=1.C(N(C(C)C)CC)(C)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48].Cl>C(Cl)Cl>[CH2:30]([O:29][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[N:15]1[CH2:16][C:17](=[O:28])[N:18]([CH2:22][CH2:23][Si:24]([CH3:26])([CH3:27])[CH3:25])[S:19]1(=[O:21])=[O:20])[CH2:8][C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]1[NH:1][S:47]([CH3:46])(=[O:49])=[O:48])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C[C@@H]3CCCC[C@H]3N)cc2OCc2ccccc2)S1(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C[C@@H]3CCCC[C@H]3NS(C)(=O)=O)cc2OCc2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 5-[4-((1S*,2R*)-2-aminocyclohexylmethyl)-2-benzyloxy-phenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (153 mg, 0.238 mmol) and diisopropylethylamine (92 mg, 0.712 mmol) in methylene chloride (5 mL) is added methanesulfonyl chloride (30 mg, 0.258 mmol) and the mixture is stirred at RT for 14 h. The mixture is poured into 1N HCl and extracted with EtOAc and the organic phase is washed with saturated NaHCO3. The organic phase is dried over magnesium sulfate and the solvent removed under reduced pressure to give the title compound.
Reaction SMILES: CS([Cl:5])(=O)=O.[Cl:6][C:7]1[C:8]([CH:22](O)[CH3:23])=[C:9]2[C:14](=[CH:15][C:16]=1[Cl:17])[N:13]=[C:12]([O:18][CH3:19])[C:11]([O:20][CH3:21])=[N:10]2.C(N(CC)CC)C>ClCCl.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+].O>[Cl:5][CH:22]([C:8]1[C:7]([Cl:6])=[C:16]([Cl:17])[CH:15]=[C:14]2[C:9]=1[N:10]=[C:11]([O:20][CH3:21])[C:12]([O:18][CH3:19])=[N:13]2)[CH3:23]
Reactant: CS(=O)(=O)Cl
Reactant: COc1nc2cc(Cl)c(Cl)c(C(C)O)c2nc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1nc2cc(Cl)c(Cl)c(C(C)Cl)c2nc1OC
Reaction time: 0.5 h
Yield: 17 %

Procedure:
Methanesulphonyl chloride (239 mg, 2.09 mmol) was added to a solution of 6,7-dichloro-2,3-dimethoxy-5-(1-hydroxyethyl)quinoxaline (527 mg, 1.74 mmol) (Preparation 2) and triethylamine (264 mg, 2.61 mmol) in dry dichloromethane (20 mL) at 20° C. The mixture was stirred for 30 minutes, then tetra-n-butyl ammonium chloride (726 mg, 2.61 mmol) was added in portions. After a further 30 minutes at 20° C., brine (20 mL) was added and the organic layer separated. The aqueous layer was extracted with dichloromethane (2×20 mL), and the combined extracts were dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography using hexane/dichloromethane (1:1) gave 5-(1-chloroethyl)-6,7-dichloro-2,3-dimethoxyquinoxaline (95 mg, 17%), as a white solid.
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=[O:4].C(O)(=O)C=O.[CH2:12]1[O:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13]1>C1(C)C=CC=CC=1>[CH2:12]1[O:20][C:15]2[CH:16]=[CH:17][C:18]([CH:3]([OH:4])[C:2]([OH:6])=[O:5])=[CH:19][C:14]=2[O:13]1
Reactant: O=CC(=O)O
Reactant: c1ccc2c(c1)OCO2
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)C(O)c1ccc2c(c1)OCO2
Reaction time: 3.5 h
Yield: 76.3 %

Procedure:
If, instead of glyoxylic acid monohydrate, an equivalent amount of 50% strength aqueous glyoxylic acid is employed and the mixture is stirred for 6 hours instead of 3.5 hours, 8.58 g of bis-3,4-methylenedioxyphenylacetic acid are obtained from the toluene phase and 73.4 g of 3,4-methylenedioxymandelic acid, corresponding to a yield of 76.3% of theory, relative to 1,2-methylenedioxybenzene employed, are obtained from the aqueous phase.
Reaction SMILES: Cl[CH2:2][C@@H:3]([CH3:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C@H:3]([CH3:13])[CH2:2][N:28]2[CH2:29][CH2:30][CH:25]([C:21]3[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=3)[CH2:26][CH2:27]2)=[CH:7][CH:8]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: C[C@H](CCl)COc1ccc(Br)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@@H](C)COc3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 4-bromophenyl(2S)-3-chloro-2-methylpropyl ether and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 473.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]=[O:14])[CH:7]=[CH:6]2.[C-:15]#[N:16].[Na+].C(O)(=O)C.O>C(O)C>[C:15]([C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[CH2:13][OH:14])#[N:16]
Reactant: COc1ccc2cc(C=O)ccc2c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COc1ccc2c(C#N)c(CO)ccc2c1

Procedure:
6.5 g of 6-methoxy-2-naphthaldehyde are treated with a solution of 4.28 g of sodium cyanide in 115 ml of 95% ethanol. 11.5 ml of acetic acid are then added dropwise at 0° C. over a period of 1 hour. The mixture is left to react overnight and then 400 ml of water are needed. The mixture is extracted three times with ether, the ether extracts are washed with 10% potassium bicarbonate solution and semisaturated and saturated sodium chloride solution. The extracts are dried over sodium sulfate and evaporated to yield α-cyano-(6-methoxy-2-naphthyl)methanol which, without further purification, is reacted with cyclopropane carboxylic acid chloride in the process of Example 2. The resulting product is cyclopropane carboxylic acid α-cyano-(6-methoxy-2-naphthyl)methyl ester; nD20 =1.5765.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:16][C:17]([C:19]1[CH:20]=[N:21][N:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]=1[CH:24]1[CH2:26][CH2:25]1)=O)(=O)OC.O.[NH2:32][NH2:33]>>[C:27]([N:22]1[C:23]([CH:24]2[CH2:26][CH2:25]2)=[C:19]([C:17]2[CH:16]=[C:3]3[C:2]([CH:1]4[CH2:7][CH:4]3[CH2:5][CH2:6]4)=[N:33][N:32]=2)[CH:20]=[N:21]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C1C(=O)C2CCC1C2
Reactant: COP(=O)(CC(=O)c1cnn(C(C)(C)C)c1C1CC1)OC
Reactant: NN
Solvent: O
Product: CC(C)(C)n1ncc(-c2cc3c(nn2)C2CCC3C2)c1C1CC1

Procedure:
off-white solid. MS (ESI): 309.1 (MH+). Prepared from bicyclo[2.2.1]heptane-2,3-dione, [2-(1-tert-Butyl-5-cyclopropyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[C@@H:4]([NH:15]C(=O)OC(C)(C)C)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29]([NH2:31])=[O:30].C(OCC)C>CC#N>[BrH:1].[N+:12]([C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C@@H:4]([C:3]2[N:31]=[C:29]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)[O:30][CH:2]=2)[NH2:15])=[CH:11][CH:10]=1)([O-:14])=[O:13]
Reactant: NC(=O)c1cccs1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)CBr
Solvent: CC#N
Solvent: CCOCC
Product: Br
Product: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1coc(-c2cccs2)n1
Temperature: 25 °C

Procedure:
A mixture of (S)-tert-butyl 4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate, 7, (38.7 g, 100 mmol), and thiophene-2-carboxamide (14 g, 110 mmol) (available from Alfa Aesar) in CH3CN (500 mL) is refluxed for 5 hours. The reaction mixture is cooled to room temperature and diethyl ether (200 mL) is added to the solution. The precipitate which forms is collected by filtration. The solid is dried under vacuum to afford the desired product which can be used for the next step without purification.
Reaction SMILES: Cl.C[N:3](C)[C:4](=N)[CH2:5][S:6][C:7](=[O:9])[CH3:8].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](Cl)=[O:18].ClCCl.C(N(CC)CC)C.C(=O)=[O:31].CC(C)=O>>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]([NH:3][C:4](=[O:31])[CH2:5][S:6][C:7](=[O:9])[CH3:8])=[O:18]
Reactant: O=C(Cl)c1cccs1
Reactant: O=C=O
Reactant: CC(=O)SCC(=N)N(C)C
Agent: Cl
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)SCC(=O)NC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A reaction mixture comprising 9.8 g. of N,N-dimethyl-2-(acetylthio)acetamidine hydrochloride and 7.0 ml. of thiophene-2-carbonyl chloride in 200 ml. of dichloromethane, under a nitrogen blanket, was cooled to -30° to -48° C. in dry ice/acetone. There was then added 25 ml. of triethylamine in 50 ml. of dichloromethane, and the reaction mixture was allowed to warm to room temperature, where it was kept for 2 hours. The reaction mixture was concentrated in vacuo and the residue was extracted between 300 ml. of dichloromethane, 100 ml. of 2.5 N hydrochloric acid, and 100 ml. of water. The organic layer was separated and the aqueous layer was extracted once with 100 ml. of chloroform. The combined organic layers were washed with water, dried over sodium sulfate, and concentrated to give 13.5 g. of dark brown oil. The oil was chromatographed on 1 kg. of silica gel, eluting with 50% ether/hexane, to give 0.75 g. of final product.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1.Cl[C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34].[C:45]1([C:51]2[CH:52]=[C:53]([CH:58]3[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]3)[C:54](=[O:57])[NH:55][N:56]=2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:28])[F:29])=[CH:24][N:25]=[C:20]2[C@H:19]([NH:31][C:33]([N:61]2[CH2:62][CH2:63][CH:58]([C:53]3[C:54](=[O:57])[NH:55][N:56]=[C:51]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH:52]=3)[CH2:59][CH2:60]2)=[O:34])[CH2:18][CH2:17]1
Reactant: O=c1[nH]nc(-c2ccccc2)cc1C1CCNCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21)N1CCC(c2cc(-c3ccccc3)n[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.9 %

Procedure:
Triethylamine (33 μL, 0.24 mmol) was added to a solution of the hydrochloride salt of (6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-amine (33 mg, 0.08 mmol) and 4-nitrophenyl chloroformate (16 mg, 0.08 mmol) in tetrahydrofuran (1 mL) at 0° C. After 15 min, a solution of 6-phenyl-4-piperidin-4-ylpyridazin-3(2H)-one (20 mg, 0.08 mmol) in dichloromethane (1 mL) and triethylamine (22 μL, 0.16 mmol) were added and the mixture allowed to warm to ambient temperature. After 2 h, saturated aqueous sodium carbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol) gave the title compound (22 mg). MS 627.2498 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([C@@H:7]([CH3:9])[OH:8])[NH2:6].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[C:16](O)=[O:17].CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([C@@H:7]([CH3:9])[OH:8])[NH:6][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:21]([N+:22]([O-:24])=[O:23])=[C:13]([O:12][CH3:11])[CH:14]=1
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)c1ccc([N+](=O)[O-])c(OC)c1)[C@@H](C)O
Yield: 94.6 %

Procedure:
The same operation as in Example (102a) was performed using threonine methyl ester hydrochloride (2.88 g, 17 mmol), 3-methoxy-4-nitrobenzoic acid (3 g, 15.2 mmol), WSC hydrochloride (3.83 g, 20 mmol), DMAP (0.18 g, 1.5 mmol), N,N-diisopropylethylamine (2.58 g, 20 mmol) and dichloromethane (40 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/2, 1/1, 2/1, 1/0) to obtain 4.49 g of the title compound as a light yellow amorphous solid (95%).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][O:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[C:10]=1[CH2:24][CH3:25])C1C=CC=CC=1.CCO.CCOC(C)=O>CN(C)C=O.[Pd]>[CH2:24]([C:10]1[N:11]([CH2:16][CH2:17][O:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:12]=[CH:13][C:14](=[O:15])[C:9]=1[OH:8])[CH3:25]
Reactant: CCc1c(OCc2ccccc2)c(=O)ccn1CCOC(=O)C(C)C
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1c(O)c(=O)ccn1CCOC(=O)C(C)C
Reaction time: 96 h
Yield: 37 %

Procedure:
3-Benzyloxy-2-ethyl -1-[2-(α-methylpropionyloxy)ethyl]pyridin-4-one was dissolved in 35 ml of dimethylformamide and about 0.1 g of palladium on activated charcoal (5%) was added. The solution was left under H2 for four days and the reaction was monitored by tlc (silica; 50% EtOH:50% EtOAc). The solution was filtered three times and rotary evaporated under high vacuum. The oily residue was then treated with activated charcoal in ethyl acetate, filtered and rotary evaporated to dryness. After crystallization from ethyl acetate the pure title compound was obtained in 37% yield, m.p., i.r., n.m.r. and mass spectra as quoted in Example 4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH3:17])[C:15](=[O:18])[N:14]([CH3:19])[C:13](=[N:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].[CH2:34]([CH:36]1[O:38][CH2:37]1)Cl>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH3:17])[C:15](=[O:18])[N:14]([CH3:19])[C:13](=[N:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:34][CH:36]4[O:38][CH2:37]4)=[CH:25][CH:26]=3)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: ClCC1CO1
Reactant: COc1ccc(-c2cc(=Nc3ccc(O)cc3)n(C)c(=O)n2C)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(-c2cc(=Nc3ccc(OCC4CO4)cc3)n(C)c(=O)n2C)cc1OC

Procedure:
To a solution of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-4-(4-hydroxyphenylimino)-2(1H)-pyrimidinone (1.5 g) in acetone (30 ml) was added potassium carbonate (0.56 g) and epichlorohydrin (0.32 ml). After the mixture was refluxed for 7 hours, an additional epichlorohydrin (1.6 ml) was added thereto, and further the mixture was refluxed for 38 hours. The resulting mixture was evaporated and chromatographed on silica-gel eluting with chloroform to give crude 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-4-[4-(2,3-epoxypropoxy)phenylimino]-2(1H)-pyrimidinone, which was recrystallized from diethyl ether.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7](=[O:30])[C@@H:8]1[CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10][N:9]1[C:18](=[O:29])[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:21].O>CN(C)C=O>[CH3:5][O:6][C:7](=[O:30])[C@@H:8]1[CH2:12][C@@H:11]([N:1]=[N+:2]=[N-:3])[CH2:10][N:9]1[C:18](=[O:29])[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH3:21]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)CN(C)C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 3 h
Yield: 105.7 %

Procedure:
Sodium azide (675 mg) was added to a solution of 1-(N-tert-butoxycarbonyl-N-methylglycyl)-cis-4-methanesulfonyloxy-L-proline methyl ester (B, 0.82 g) in N,N-dimethylformamide (10 mL)-water (1 mL). After stirring at 70° C. for 3 hr, the solvents were removed in vacuo, and the residue was diluted with chloroform. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to afford the title compound (0.75 g) as a pale yellow oil.
Reaction SMILES: [S:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.Br[C:14]1[S:18][C:17]([S:19]([N:22]2[CH:26]=[CH:25][CH:24]=[CH:23]2)(=[O:21])=[O:20])=[CH:16][CH:15]=1>>[S:1]1[C:5]([C:14]2[S:18][C:17]([S:19]([N:22]3[CH:26]=[CH:25][CH:24]=[CH:23]3)(=[O:20])=[O:21])=[CH:16][CH:15]=2)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Product: O=S(=O)(c1ccc(-c2cc3ccccc3s2)s1)n1cccc1
Yield: 68 %

Procedure:
N-[5-(benzo[b]thien-2-yl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as described in Example 32C from benzo[b]thiophene-2-boronic acid (426 mg, 2.39 mmol) and N-(5-bromothiophene-2-sulfonyl)pyrrole (700 mg, 2.39 mmol). Purification by column chromatography using 2% ethyl acetate/hexanes gave the pure sulfonamide in 68% yield as a brownish-red solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([C:25](O)=[O:26])[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:43]([NH2:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1.C(OCC)(=O)C>[CH2:43]([NH:50][C:25](=[O:26])[C@@H:4]([CH2:3][O:2][CH3:1])[NH:5][C:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: COC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: COC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of Example 2 product (i.e., O-methyl-N-trityl-D-serine, 50 g) in tetrahydrofuran (500 ml), N-methyl morpholine (20.9 g) was added at −15° C. in 5-10 minutes. The reaction mixture was stirred for 15 minutes and then isobutylchloroformate (18.8 g) diluted with tetrahydrofuran was added to it at −15° C. under nitrogen atmosphere in 15-20 minutes. The solution was stirred for 15 minutes and benzyl amine (14.7 g) was added to it at −15° C. in 15 minutes. The solution was allowed to cool to room temperature and stirred for 2 hours. The solvent was recovered from the solution. Dichloromethane (250 ml) was added to the crude product and stirred for 5 minutes to dissolve. The dichloromethane layer was washed or stirred for 5 minutes with water (250 ml). The layers were separated and the dichloromethane layer was again washed with 5% NaHCO3 (250 ml). The layers were separated and then the dichloromethane layer was sequentially washed with 5% citric acid solution (250 ml) and then with water (250 ml). The solvent was recovered at 40° C. to 45° C. to get oil. Ethyl acetate was added to the oil and the mixture was heated to 60° C. to 65° C. to dissolve. The clear solution so formed was cooled up to room temperature and then hexanes (350 ml) were added to it. It was stirred for 1 hour at room temperature, filtered and then dried to get compound of Formula Va. Yield=30 gm.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.Cl.[S:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19](=[NH:21])[NH2:20].O=[C:23]([CH3:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C([O-])(=O)C.[Na+]>C(O)C>[CH3:30][C:23]1[NH:20][C:19]([C:15]2[S:14][CH:18]=[CH:17][N:16]=2)=[N:21][CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[C:2]([F:12])([F:11])[F:1])[C:24]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: N=C(N)c1nccs1
Reactant: CCOC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(c2nccs2)=NC1c1ccccc1C(F)(F)F
Temperature: 80 °C
Yield: 63.8 %

Procedure:
A mixture of 2-(trifluoromethyl)benzaldehyde (8.7 g, 50 mmol), thiazole-2-carboximidamide hydrochloride (8.2 g, 50 mmol), ethyl 3-oxobutanoate (7.8 g, 60 mmol) and sodium acetate (5.33 g, 65 mmol) in ethanol (90 mL) was refluxed at 80° C. for 12 hours under N2. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=3/1) to give the title compound as a yellow solid (12.62 g, 64%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][N:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:64][C:65]1[CH:72]=[C:71]([C:73]([F:76])([F:75])[F:74])[CH:70]=[CH:69][C:66]=1[CH2:67][NH2:68]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:29])[NH:68][CH2:67][C:66]4[CH:69]=[CH:70][C:71]([C:73]([F:74])([F:75])[F:76])=[CH:72][C:65]=4[F:64])=[CH:24][N:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: NCc1ccc(C(F)(F)F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(C(=O)O)cn3)c2CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(C(=O)NCc4ccc(C(F)(F)F)cc4F)cn3)c2CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Dissolve 3-tert-butoxycarbonyl-6-(5-carboxypyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (300 mg, 0.67 mmol) in DMF (5.0 mL). Treat successively with HATU (305 mg, 0.802 mmol), N,N-diisopropylethylamine (140 μL, 0.804 mmol) and 2-fluoro-4-(trifluoromethyl)benzylamine (260 mg, 1.34 mmol). Stir overnight at 40° C. Dilute the mixture with water, extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (3:1) to give 3-tert-butoxycarbonyl-7-chloro-6-[5-(2-fluoro-4-trifluoromethyl-benzylcarbamoyl)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a foam (409g, 98%). Use a method similar to the General Procedure 1-4 to give, after basic work-up and a method similar to the General Procedure 2-1, the title compound as an off-white solid. MS (APCI+) m/z: 524 (M+H)+.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([N:15]([CH3:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:14][C:8]=2[C:7]=1[OH:23])=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27]>C[O-].[Na+].CO>[OH:23][C:7]1[C:8]2[S:14][C:13]([N:15]([CH3:22])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:12][C:9]=2[CH:10]=[N:11][C:6]=1[C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5]
Reactant: CCOC(=O)c1ncc2nc(N(C)c3ccccc3)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(c1ccccc1)c1nc2cnc(C(=O)NCC(=O)O)c(O)c2s1
Temperature: 25 °C
Yield: 82.6 %

Procedure:
A mixture of 7-hydroxy-2-(methyl-phenyl-amino)-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (87 mg, 0.26 mmol) and glycine (399 mg, 5.31 mmol) in 0.5 M sodium methoxide/methanol (10.1 mL) was refluxed for three days before it was cooled to room temperature and concentrated in vacuo. It was dissolved in water (20 mL) and extracted twice with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (6.5 mL). The precipitate was filtered, washed with water and dried under vacuo to give the title compound as a white solid (77 mg): 1H NMR (DMSO-d6, 200 MHz): δ=9.18 (br s, 1H), 8.37 (s, 1H), 7.57 (m, 5H), 3.95 (d, J=6.2 Hz, 2H), 3.61 (s, 3H); MS: (+) m/z 359.0 (M+1).