Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([SH:20])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30](Br)[CH3:31])=[CH:26][CH:25]=1.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH:30]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[CH3:31])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(S)c2CC1
Reactant: CC(Br)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2)c1ccc(F)cc1
Temperature: 45 °C
Reaction time: 0.08 h
Yield: 83.8 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (415 mg, 1.08 mmol) in methanol (20 mL) and add potassium hydroxide (1.938 g, 34.53 mmol). Heat at 60° C. for 4 h. Cool the reaction mixture to ambient temperature, add aqueous saturated ammonium chloride and concentrate in vacuo. Partition the residue between EtOAc and water. Dry the organic phase over anhydrous Na2SO4 and concentrate in vacuo to give 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.34 g, 1.086 mmol). Dissolve the crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.34 g, 1.086 mmol) in anhydrous DMF (10 mL), add sodium hydride (65 mg, 1.63 mmol, 60% in mineral oil) and stir the mixture for 5 min. Add a solution of (±)-1-(4-fluorophenyl)ethyl bromide (332 mg, 1.63 mmol) in anhydrous DMF (5 mL) and heat the solution at 45° C. overnight. Cool to ambient temperature, add water and extract the aqueous phase twice with EtOAc. Dry the combined organic extracts over anhydrous Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1 and 9:1) to give (±)-3-tert-butoxycarbonyl-7-chloro-6-[1-(4-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as oil (397 mg, 84%). MS (ES+) m/z: 336 (M+H−Boc)+.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C([N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([O:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:13]1)C1C=CC=CC=1>C(Cl)Cl>[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[Cl:25])[O:18][CH:14]1[CH2:15][CH2:16][CH2:17][N:12]([C:1]([Cl:4])=[O:2])[CH2:13]1
Reactant: Clc1ccc(OC2CCCN(Cc3ccccc3)C2)cc1Cl
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)N1CCCC(Oc2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 8 g (0.085 mole) of phosgene in 100 ml of methylene chloride at 5° C. under nitrogen gas was added slowly a solution of 27.1 g (0.081 mole) of 1-benzyl-3-(3,4-dichlorophenoxy)piperidine in 50 ml of methylene chloride. The reaction mixture was allowed to warm to room temperature over a 2 hr period and then concentrated to a light oil. The oil was triturated with hexane. Starting material, 1.6 g as fine white precipitate, was separated by filtration. The oil was triturated four more times with hexane to remove benzyl chloride. The remaining oil was taken up in 200 ml of benzene and 50 ml of pyridine was added. The mixture was allowed to stir overnight. Some quaternary benzyl chloride salt precipitated and was discarded. The title compound in solution was used in Example 12.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][CH2:9][OH:10])=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:18]=[C:19]1[O:23][C:21](=[O:22])[CH2:20]1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:21]([O:10][CH2:9][CH:8]=[CH:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)(=[O:22])[CH2:20][C:19]([CH3:18])=[O:23]
Reactant: OCC=Cc1ccncc1
Reactant: C=C1CC(=O)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OCC=Cc1ccncc1

Procedure:
495 mg (3.66 mmol)f 3-(pyridine-4-yl)-2-propene-1-ol, 0.61 ml (4.38 mmol) of triethylamine and 0.35 ml (4.54 mmol) of diketene were heated to 70° C. under stirring in 20 ml of toluene for 2 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture at room temperature. After the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: CC(C)([O-])C.[Na+].C1(C(C2C=CC=CC=2)=[NH:14])C=CC=CC=1.Cl[C:22]1[C:27]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=2)=[CH:26][CH:25]=[CH:24][N:23]=1.C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1>[CH3:37][CH:36]([C:33]1[CH:34]=[CH:35][C:30]([O:29][CH2:28][C:27]2[C:22]([NH2:14])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:31][CH:32]=1)[CH3:38]
Reactant: CC(C)c1ccc(OCc2cccnc2Cl)cc1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)c1ccc(OCc2cccnc2N)cc1
Temperature: 110 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
A mixture of sodium tert-butoxide (0.617 g), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.160 g), 1,1-diphenylmethanimine (1.008 g), 2-chloro-3-{[4-(1-methylethyl)phenoxy]methyl}pyridine (1.12 g), tris(dibenzylideneacetone)dipalladium(0) (0.118 g) and toluene (20 mL) was stirred at 110° C. for 6 hr. To the reaction mixture was added THF, and the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. To the residue were added THF (25 mL) and 1M hydrochloric acid (25 mL) at room temperature, and the mixture was stirred overnight. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane) to give the title compound (902.2 mg) containing impurity as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C@@H:11]1[C@@H:17]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[O:16][C@H:13](OC)[C@:12]1([CH2:30][CH3:31])[OH:29].Br.[Cl:33][C:34]1[N:39]=[CH:38][NH:37][C:36]2=[N:40][CH:41]=[CH:42][C:35]=12.[OH-].[K+].COCCOCCN(CCOCCOC)CCOCCOC.[Cl-].[NH4+]>ClCCl.C(#N)C.C(OCC)(=O)C>[Cl:33][C:34]1[C:35]2[CH:42]=[CH:41][N:40]([C@@H:13]3[O:16][C@H:17]([CH2:11][O:10][CH2:9][C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[C@@H:18]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[C@@:12]3([CH2:30][CH3:31])[OH:29])[C:36]=2[N:37]=[CH:38][N:39]=1
Reactant: CC[C@]1(O)[C@@H](OC)O[C@H](COCc2ccc(Cl)cc2Cl)[C@H]1OCc1ccc(Cl)cc1Cl
Reactant: Clc1nc[nH]c2nccc1-2
Agent: Br
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [Cl-]
Solvent: CC#N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.3 %

Procedure:
To a solution of the compound from Step A (1.02 mg, 2.0 mmol) in dichloromethane (40 mL) was added HBr (5.7 M in acetic acid) (1.75 mL, 10.0 mmol) dropwise at 0° C. The resulting solution was stirred at rt for 2 h, evaporated in vacuo and co-evaporated twice from toluene (10 mL). The oily residue was dissolved in acetonitrile (10 mL) and added to a vigorously stirred mixture of 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (307 mg, 2.0 mmol), potassium hydroxide (337 mg, 6.0 mmol) and tris[2-(2-methoxyethoxy)ethyl]amine (130 mg, 0.4 mmol) in acetonitrile (10 mL). The resulting mixture was stirred at room temperature overnight, and then poured into a stirred mixture of saturated ammonium chloride (100 mL) and ethyl acetate (100 mL). The organic layer was separated, washed with brine (100 mL), dried over MgSO4, filtered and evaporated in vacuo. The crude product was purified on silica gel using ethyl acetate/hexane (1:2) as eluent to give the desired product (307 mg) as a colorless foam.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[S:9])=[CH:3][CH:2]=1.S[C:12]1C=CN=CC=1.ClCC(O)=O>>[CH3:12][O:10][C:8](=[S:9])[CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: Sc1ccncc1
Reactant: OC(=S)Cc1ccncc1
Agent: O=C(O)CCl
Product: COC(=S)Cc1ccncc1

Procedure:
It is also known to use 4- or Γ-mercaptopyridine as the starting compound. For instance, in J. Chem. Soc. 1939 873-877, King and Ware described the preparation of 4-pyridylthioacetic acid by treating 4-mercapto-pyridine with ClCH2COOH in a weakly basic medium, while Takahashi et al, as described in Pharm. Bull. (Japan) 2 30-34 (1954), obtain methyl-4-pyridylthioacetate by heating 4-mercaptopyridine for one hour on a water-bath with ClCH2CO2Me. In Gazz. Chim. Ital. 84 584-594 (1954), Musante and Fabbrini mention the preparation of 4-pyridylthioacetic acid by causing 4-mercapto-pyridine to react with ClCH2CONEt2 and treating the resulting 4-(diethylcarbamoylmethylmercapto)pyridine with KOH. In Wiss. Z. Tech. Hochsch. Chem. Leuna-Merseburg 2 187-193 (1959-1960) the preparation of (2-methyl-4-pyridylthio)acetic acid from ClCH2CO2H and 4-mercapto-2-methylpyridine is mentioned, the latter product being obtained by converting 4-nitro-2-methylpyridine-N-oxide into 4-chloro-2-methyl-pyridine and causing this to react with KHS.
Reaction SMILES: [OH-].[Li+].[C:3]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12](C(OCCC(C)(C)C)=O)[C:11]([C:25]([O-:27])=[O:26])=[CH:10]2)(=[O:5])[CH3:4].CO.O>C1COCC1>[C:3]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:25]([OH:27])=[O:26])=[CH:10]2)(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1ccc2c(c1)cc(C(=O)[O-])n2C(=O)OCCC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2[nH]c(C(=O)O)cc2c1
Temperature: 50 °C
Yield: 42.7 %

Procedure:
Lithium hydroxide (0.028 g, 1.184 mmol) was added to a solution of 1-(1,1-dimethylethyl)2-ethyl 5-(acetylamino)-1H-indole-1,2-dicarboxylate (0.041 g, 0.118 mmol) in THF:MeOH:water/3:1:1. The reaction mixture was heated at 50° C. for 1 h. The solvent was evaporated. The residue was dissolved in water, acidified with 6N aqueous HCl and extracted with dichloromethane. A solid formed in the aqueous layer which was collected by filtration and dried to give the title compound (0.011 g, 43%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.85 (s, 1H), 11.63 (s, 1H), 9.79 (s, 1H), 7.97 (s, 1H), 7.22-7.38 (m, 2H), 7.01 (s, 1H), 2.01 (s, 3H). MS: m/z 219 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]4[S:31][CH:30]=[C:29]([C:32]5[N:33]=[C:34]([C@@H:37]6[CH2:41][CH2:40][CH2:39][N:38]6[C:42](=[O:52])[C@@H:43]([NH:47][C:48]([O:50][CH3:51])=[O:49])[CH:44]([CH3:46])[CH3:45])[NH:35][CH:36]=5)[C:26]=4[S:27][CH:28]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.[ClH:53].BrC1SC2=NC(N)=CN2C=1>>[ClH:53].[CH3:51][O:50][C:48](=[O:49])[NH:47][C@H:43]([C:42]([N:38]1[CH2:39][CH2:40][CH2:41][C@H:37]1[C:34]1[NH:35][CH:36]=[C:32]([C:29]2[C:26]3[S:27][CH:28]=[C:24]([C:21]4[CH:22]=[CH:23][C:18]([C:15]5[NH:14][C:13]([C@@H:9]6[CH2:10][CH2:11][CH2:12][NH:8]6)=[N:17][CH:16]=5)=[CH:19][CH:20]=4)[C:25]=3[S:31][CH:30]=2)[N:33]=1)=[O:52])[CH:44]([CH3:46])[CH3:45]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2csc3c(-c4ccc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)csc23)c[nH]1)C(C)C
Agent: Cl
Agent: Nc1cn2cc(Br)sc2n1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2csc3c(-c4ccc(-c5cnc([C@@H]6CCCN6)[nH]5)cc4)csc23)c[nH]1)C(C)C

Procedure:
Compound 80 was synthesized from compound 79 (1.36 mmol), following the procedure as described for compound 11 to give compound 80 in quantitative yield. MS (ESI, EI+) m/z=645.2 (MH+).
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].S1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([CH2:15][CH2:16][N:17]([CH2:19][C@H:20]3[C:29]4[C:24](=[C:25]([O:30][CH3:31])[CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22][CH2:21]3)[CH3:18])[CH:13]=[CH:14]C1=2.ClC1C=CC=C(C(OO)=O)C=1>>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[O:3]=[S:2]1(=[O:5])[C:1]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]([CH2:19][C@H:20]3[C:29]4[C:24](=[C:25]([O:30][CH3:31])[CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22][CH2:21]3)[CH3:18])=[CH:11][C:8]=2[CH2:9][CH2:10]1
Reactant: COc1cccc2c1CCC[C@H]2CN(C)CCc1ccc2c(c1)CCS2
Agent: CS(=O)(=O)O
Agent: O=C(OO)c1cccc(Cl)c1
Product: COc1cccc2c1CCC[C@H]2CN(C)CCc1ccc2c(c1)CCS2(=O)=O

Procedure:
The product from Example 26 is treated with two equivalents of m-chloroperbenzoic acid to yield the title compound.
Reaction SMILES: [SH:1][C:2]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6](=[O:12])[N:5]([CH3:13])[C:4](=[O:14])[CH:3]=1.Br[CH:16]([CH3:23])[C:17](=O)[C:18]([O:20][CH3:21])=[O:19]>C([O-])(=O)C.[Na+].O.C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:13][N:5]1[C:4](=[O:14])[C:3]2[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([CH3:23])[S:1][C:2]=2[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6]1=[O:12]
Reactant: CC(C)Cn1c(S)cc(=O)n(C)c1=O
Reactant: COC(=O)C(=O)C(C)Br
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1c(C)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Temperature: 0 °C
Yield: 59.2 %

Procedure:
6-Mercapto-3-methyl-1-(isobutyl)-pyrimidine-2,4(1H,3H)-dione (50 g) was dissolved in a solution of sodium acetate (95.6 g) in water (1.5 L), and methyl 3-bromo-2-oxo-butanoate (44.6 g) was added dropwise with stirring. After stirring 1 h at room temperature the mixture was extracted into ethyl acetate. The organic solution was washed with brine, dried (MgSO4) and evaporated to leave an oil. The oil (75.1 g) was dissolved in methylene chloride (800 ml) and cooled in an ice-bath under an atmosphere of nitrogen. With efficient stirring titanium tetrachloride (43.3 ml) was slowly added dropwise. The reaction mixture was stirred 1 h in the ice-bath and then 3 h at room temperature. The reaction mixture was poured slowly into vigorously stirred ice-water (2 L), and then the resulting suspension was extracted into methylene chloride. After drying, the organic solvent was removed in vacuo, and the residue was chromatographed (SiO2/1:1 ethyl acetate-isohexane) to afford the sub-title compound 42 g. Trituration with isohexane gave a white powder. δ 1HCDCl3—0.98(6H,d), 2.23-2.41 (1H,m), 2.46 (3H,s), 3.4 (3H,s), 3.75 (2H,d), 3.96 (3H,s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([OH:17])=[N:11][NH:12][C:13]=2[CH:14]([CH3:16])[CH3:15])=[C:4]([CH3:18])[CH:3]=1.[C:19]([O:22][C@@H:23]1[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:27]([O:33][C:34](=[O:36])[CH3:35])[C@@H:26]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[O:25][C@@H:24]1Br)(=[O:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].ClCCl>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.C(OCC)(=O)C.ClCCl.O>[C:19]([O:22][C@@H:23]1[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:27]([O:33][C:34](=[O:36])[CH3:35])[C@@H:26]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[O:25][C@H:24]1[O:17][C:10]1[C:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[CH3:18])=[C:13]([CH:14]([CH3:15])[CH3:16])[NH:12][N:11]=1)(=[O:21])[CH3:20]
Reactant: Cc1cc(Br)ccc1Cc1c(O)n[nH]c1C(C)C
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(Br)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 76.9 %

Procedure:
4-[(4-Bromo-2-methyl-phenyl)methyl]-5-isopropyl-1H-pyrazol-3-ol (110 g, 356 mmol), 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide (204.8 g, 498 mmol), benzyltributylammonium chloride (17.2 g, 53.4 mmol), potassium carbonate (122.9 g, 889 mmol), dichloromethane (1100 mL), and water (330 mL) are combined and the mixture is stirred at 50° C. temperature for 16 hours. Further 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide (29.26 g, 71.2 mmol) is added and the mixture stirred at 55° C. for 3 hours. The mixture is cooled to ambient temperature and stirred overnight. Further 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide (29.26 g, 71.15 mmoles) is added and the mixture is heated to reflux for 1.5 hours. The mixture is cooled to ambient temperature and water (2000 mL) is added. The phases are separated and the aqueous is extracted with dichloromethane (500 mL). The combined organic layers are washed with water (2000 mL) and saturated aqueous NaCl solution (2000 mL). The solution is dried over MgSO4 and filtered. The filtrate is concentrated under reduced to provide a solution of approximately 500 mL. This solution is poured onto a silica column and is purified by flash chromatography (5 Kg silica), eluting first with 100% dichloromethane, then with 40% ethyl acetate/dichloromethane, to provide the title compound (175 g, 77% yield). Mass spectrum (m/z): 639/641 (M+1).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:33][CH2:32][N:31]([C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@@H]1CCNC1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@@H]1CCN(C(=O)[C@H](C)O)C1

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f4) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1)[CH3:2].[OH-].[K+].[CH3:19][C:20]1[CH:25]=[N:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1>CN1CCCC1=O.O>[CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([CH3:19])=[CH:25][N:24]=3)[C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1cnc(C)cn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1ccc2c(c1)c1c(n2CCc2cnc(C)cn2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.8 %

Procedure:
To a solution of 8-Ethyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.054 g. 0.25 mmol) in N-methyl 2-pyrolidone (2.0 mL) was added powdered potassium hydroxide (0.112 g, 0.002 mol) and allowed to stir for 10 min at RT. 2-methyl-5-vinyl pyrazine (0.033 g, 0.75 mmol) was added and stirred for further 1 h. at 60 deg C. After completion (TLC), reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide the desired compound as yellow oil (0.05 g, 60% yield). 8-Ethyl-2-methyl-5-[2-(5-methyl-pyrazin-2-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.05 g, 0.000149 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.019 g, 0.000149 mol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.035 g, 50% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH:7]([CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[CH2:6]2.ClC1C=CC=C(C(OO)=[O:30])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH:7]([CH2:15][C:16]1[CH:21]=[CH:20][N+:19]([O-:30])=[CH:18][CH:17]=1)[CH2:6]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc2c(cc1OC)C(=O)C(Cc1ccncc1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(=O)C(Cc1cc[n+]([O-])cc1)C2
Reaction time: 4 h

Procedure:
4-[(5,6-Dimethoxy-1-indanon-2-yl)methyl]pyridine (1.2 g) was dissolved in methylene chloride (18 ml) and chilled. m-Chloroperbenzoic acid (0.9 g) was added to reaction mixture and then stirred for 4 hours. Reaction mass was stirred with 10% aqueous solution of sodium bicarbonate. The organic layer was separated and washed with 50 ml water. Organic layer was distilled off, title compound is obtained (1.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][N:29]=2)[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][N:29]=2)[CH2:26][CH2:27]1)=[O:8]
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Oc2cccc(F)c2)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)nc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Oc4cccc(F)c4)C3)CC2)nc1
Yield: 24.2 %

Procedure:
The title compound (D159) (22.4 mg) was prepared according to the experimental procedure described in Description 146 starting from 5-chloro-2-(3-(3-fluorophenoxy)azetidin-1-yl)nicotinic acid (D103) (60 mg, 0.186 mmol) and methyl 6-(1-aminocyclopropyl)nicotinate hydrochloride (D12) (28.5 mg, 0.186 mmol).
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[CH3:12][O:13][C:14](=[O:29])[CH2:15][N:16]1[C:21]2[CH:22]=[C:23]([CH2:26][OH:27])[CH:24]=[CH:25][C:20]=2[O:19][CH2:18][C:17]1=[O:28]>C(Cl)Cl>[CH3:12][O:13][C:14](=[O:29])[CH2:15][N:16]1[C:21]2[CH:22]=[C:23]([CH:26]=[O:27])[CH:24]=[CH:25][C:20]=2[O:19][CH2:18][C:17]1=[O:28]
Reactant: COC(=O)CN1C(=O)COc2ccc(CO)cc21
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)CN1C(=O)COc2ccc(C=O)cc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of PCC (4.2 g, 0.019 mol) and celite (4 g) in dry CH2Cl2 (100 mL) was cooled to 0° C. and slowly added a solution of methyl-[6-(hydroxymethyl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]acetate (1.2 g, 0.0048 mol) in CH2Cl2 (30 mL) under N2. The reaction mixture was stirred at RT for 2 h, passed through celite, washed with CH2Cl2 (50 mL) and concentrated to give crude product, which was purified on silica gel affording 1.05 g (87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[C:21]([O:28][CH2:29][CH3:30])=[N:22][C:23]([S:26][CH3:27])=[N:24][CH:25]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:31](Cl)([Cl:33])=[O:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:31]([Cl:33])=[O:32])[C:10]([C:20]3[C:21]([O:28][CH2:29][CH3:30])=[N:22][C:23]([S:26][CH3:27])=[N:24][CH:25]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1nc(SC)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Product: CCOc1nc(SC)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
Using the procedure as described in example 1, cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5-dihydro-1H-imidazole was reacted with phosgene to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride. The carbonyl chloride was then coupled with 2-piperazinone (Alfa) to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one. HR-MS (ES, m/z) calculated for C27H27N6O3SCl2 [(M+H)+] 585.1237, observed 585.1236.