Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]=[C:9]([CH:12]([F:14])[F:13])[N:10]([OH:11])[C:3]=12.[F-:15].[Na+]>>[F:15][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]=[C:9]([CH:12]([F:14])[F:13])[N:10]([OH:11])[C:3]=12
Reactant: On1c(C(F)F)nc2nccc(Cl)c21
Reactant: [F-]
Agent: [Na+]
Product: On1c(C(F)F)nc2nccc(F)c21

Procedure:
7-Chloro-1-hydroxy-2-(difluoromethyl)-1H-imidazo(4,5-b)-pyridine is reacted with sodium fluoride to obtain 7-fluoro-1-hydroxy-2-(difluoromethyl)-1H-imidazo(4,5-b)pyridine, which is then converted to its calcium salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7](Cl)=[O:8])[S:5][CH:6]=1.CCN(C(C)C)C(C)C.[NH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:8])[S:5][CH:6]=1
Reactant: NCCN1CCOCC1
Reactant: O=C(Cl)c1cc(Br)cs1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCN1CCOCC1)c1cc(Br)cs1

Procedure:
To a solution of 4-bromo-2-thiophenecarbonyl chloride (1.0 g, 4.4 mmol) in DCM (10 ml) cooled to 0° C. was added DIPEA (0.85 ml, 4.8 mml) and 4-(2-aminoethyl)morpholine (0.6 ml, 4.6 mmol) dropwise. Stirring was continued until complete consumption of the starting material was observed by LC-MS. The reaction was quenched by the addition of water, which was washed with further portions of 2N HCl, dried over sodium sulfate, filtered and concentrated in vacuo to yield the desired compound without need for further purification (1.6 g, 98%). δH (500 MHz, CHLOROFORM-d) 7.38 (1H, d, 1.3 Hz), 7.37 (1H, d, 1.1 Hz), 3.72-3.80 (4H, m), 3.53 (2H, q, 5.6 Hz), 2.59 (2H, t, 6.0 Hz), 2.48-2.54 (4H, m), TR=0.8 min.
Reaction SMILES: [CH3:1]N(C)C=O.[C:6]([O:10][C:11](=[O:47])[N:12]([CH2:34][C:35]1[C:36]([Cl:46])=[CH:37][C:38]2[S:39][CH2:40][C:41](=[O:45])[NH:42][C:43]=2[N:44]=1)[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][C:22]2=[O:33])[CH2:15][CH2:14]1)([CH3:9])([CH3:8])[CH3:7].[H-].[Na+].CI>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[C:6]([O:10][C:11](=[O:47])[N:12]([CH2:34][C:35]1[C:36]([Cl:46])=[CH:37][C:38]2[S:39][CH2:40][C:41](=[O:45])[N:42]([CH3:1])[C:43]=2[N:44]=1)[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][C:22]2=[O:33])[CH2:15][CH2:14]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N(Cc4nc5c(cc4Cl)SCC(=O)N5)C(=O)OC(C)(C)C)CC3)c2c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc2ncc(=O)n(CCN3CCC(N(Cc4nc5c(cc4Cl)SCC(=O)N5C)C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 20 mL of an N,N-dimethylformamide solution containing 0.57 g of tert-butyl(7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)(1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 0.04 g of 60% sodium hydride was added, and stirred at room temperature for 1 hour. 0.24 g of methyl iodide was added, and stirred at room temperature for 2 hours. To the reaction mixture, water, ethyl acetate and toluene were added. The organic layer was separated, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=30:1] to give 0.23 g of tert-butyl(7-chloro-4-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)(1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a pale brown foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([NH:30]S(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH2:10][N:11]([C:15]2[S:16][C:17]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH:26]=[N:25][CH:24]=[CH:23]4)=[CH:18][N:19]=2)C(=O)C)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].SCCO.C([O-])([O-])=O.[K+].[K+]>CCO.[NH4+].[Cl-].O.C(Cl)Cl.CN(C=O)C>[NH2:30][C@@H:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH2:10][NH:11][C:15]1[S:16][C:17]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[N:25][CH:24]=[CH:23]3)=[CH:18][N:19]=1
Reactant: CC(=O)N(C[C@H](Cc1cccc(Cl)c1)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1ncc(-c2ccc3cnccc3c2)s1
Agent: O=C([O-])[O-]
Agent: OCCS
Agent: [Cl-]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: N[C@H](CNc1ncc(-c2ccc3cnccc3c2)s1)Cc1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 15.7 %

Procedure:
To a stirred mixture of crude N—((S)-3-(3-chlorophenyl)-2-(4-nitrophenylsulfonamido)propyl)-N-(5-(isoquinolin-6-yl)thiazol-2-yl)acetamide (0.33 g, 0.535 mmol) in EtOH (3 mL), was added sodium hydroxide (1.1 mL, 1 M aqueous solution, 1.1 mmol) at room temperature. After addition, the reaction mixture was stirred at 80° C. overnight. The reaction mixture was then diluted with NH4Cl (10 mL (aqueous)) and water (10 mL), and diluted with DCM (5 mL). The separated aqueous layer was extracted with EtOAc (5 mL×2), and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude residue (0.2233 g, 385 μmol), to which DMF (2 mL), 2-mercaptoethanol (60 mg, 770 μmol), and K2CO3 (160 mg, 1155 μmol) were added sequentially. The resulting mixture was stirred at room temperature for 1.5 hours, and the resulting dark mixture was diluted with NH4Cl (5 mL (aqueous)) and water (5 mL) and diluted with DCM (5 mL). The separated aqueous layer was extracted with DCM (10 mL×2), and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude residue which was purified with flash column chromatography (pure DCM→5% MeOH in DCM) to obtain the desired product N—((S)-2-amino-3-(3-chlorophenyl)propyl)-5-(isoquinolin-6-yl)thiazol-2-amine (33 mg, 84 μmol) as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.Cl>N1C=CC=CC=1>[S:16]([O:1][CH2:2][C:3]([CH2:8][O:9][S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17])([CH2:6][O:7][S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17])[CH2:4][O:5][S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17])([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: OCC(CO)(CO)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(COS(=O)(=O)c2ccc(C)cc2)(COS(=O)(=O)c2ccc(C)cc2)COS(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 48 h
Yield: 90.7 %

Procedure:
A mixture of pentaerythritol (27.20 grams, 199.8 mmol; obtained from Aldrich Chemical Co., Milwaukee, Wis.) and p-toluenesulfonyl chloride (171.0 grams, 897.0 mmol; obtained from Aldrich Chemical Co., Milwaukee, Wis.) in dry pyridine (300 milliliters; obtained from Anachemia) was stirred for 48 hours under nitrogen gas. This mixture was then added to 2 liters of 6 Normal hydrochloric acid. The resulting white precipitate was filtered and washed with methanol. The solid was recrystallized from benzene to afford pure pentaerythritol tetratosylate (136.5 grams, 181.3 mmol, 91 percent yield) as white crystals: mp 155–156° C.; IR (KBr) 3047, 2958, 2926, 1907, 1599, 1468, 1367, 1296, 1174, 1180, 1096, 976, 835, 666, 607, 554 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, 8H, 3J=8.2 Hz), 7.36 (d, 8H, 3J=8.2 Hz), 3.82 (s, 8H), 2.47 (s, 12H); 13C NMR (100 MHz, CDCl3) δ 145.86, 131.50, 130.38, 128.15, 65.74, 43.41, 21.90; MS (FAB, 3-nitrobenzyl alcohol) m/e 753; Anal. Calcd for C33H36O12S4: C, 52.64; H, 4.82; S, 17.04. Found: C, 52.98; H, 4.77; S, 17.60.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)[C:9]=1[CH3:25].[O:26]1CCOCC1.[OH-].[Na+].Cl[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15]([C:16]2[NH:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[O:26])[C:9]=1[CH3:25]
Reactant: C1COCCO1
Reactant: Cc1c(SCc2ccco2)ccnc1CSc1nc2ccccc2[nH]1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [O-]Cl
Product: Cc1c(SCc2ccco2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 80 %

Procedure:
2-{[[4-(2-Furylmethylthio)-3-methyl-2-pyridinyl]methyl]thio}-1H-benzimidazole (2 mmol) are dissolved in 15 ml of dioxane + NaOH (6 mmol; 2N), and the solution is treated with 2.5 mmol of 7 percent strength sodium hypochlorite solution at 20° C. Sodium thiosulfate is added, dioxane is distilled off, the pH is brought to 9, the mixture is extracted using dichloromethane, and the product is crystallized from dichloromethane/diisopropyl ether. This gives the title compound (yield 80%) of m.p. 173° C. (decomp.) as a colorless solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].O>CN(C)C=O>[CH2:22]([O:21][C:19]([CH2:18][N:8]1[C:7]2[CH:12]=[C:13]([N+:14]([O-:16])=[O:15])[C:4]([F:3])=[CH:5][C:6]=2[S:10][C:9]1=[O:11])=[O:20])[CH3:23]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(F)cc2s1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)sc2cc(F)c([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
50% Oily sodium hydride (0.21 g) was suspended in N,N-dimethylformamide (5 ml), and the resultant suspension was cooled to 0° C. 6-Fluoro-5-nitro-2(3H)-benzothiazolone (1.0 g) was portionwise added thereto at 0° C., and the mixture was stirred at the same temperature for 30 minutes. Ethyl bromoacetate (0.86 g) was added to the reaction mixture at 0° C., and the temperature was gradually elevated to a temperature of 50° to 60° C., followed by stirring at that temperature for 3 hours. Water was added to the mixture, which was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel thin layer chromatography with a mixture of ethyl acetate and toluene (1:9) to give 0.35 g of 3-ethoxycarbonylmethyl-6-fluoro-5-nitro-2(3H)-benzothiazolone, m.p., 139.0°-140.0° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N+:15]([O-])=O)[CH:14]=1)[N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:9]2>[C].[Pd].O1CCCC1>[NH2:15][C:13]1[CH:14]=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=[C:8]2[C:12]=1[N:11]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:9]2
Reactant: CCOC(=O)c1cc2cc(OCCOC)cc([N+](=O)[O-])c2n1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)C1Cc2cc(OCCOC)cc(N)c2N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.6 %

Procedure:
A mixture of 1-tert-butyl 2-ethyl 5-(2-methoxyethoxy)-7-nitro-1H-indole-1,2-dicarboxylate (3.9 g), 10% palladium-carbon (50% containing water, 400 mg) and tetrahydrofuran (80 mL) was stirred at room temperature under hydrogen atmosphere at normal pressure for 6 hr. The catalyst was filtered off, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give the title compound (3.22 g, yield 89%) as a colorless solid from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio).
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.NCC([OH:35])C>>[OH:35][CH:11]([CH3:12])[CH2:10][NH:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: CC(O)CN
Product: CC(O)CNC(=O)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 1-amino-2-propanol instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 317 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.49 (1H, s) 10.22 (1H, s) 7.99 (1H, d, J=5.47 Hz) 7.94-7.98 (1H, m) 7.75 (1H, d, J=5.47 Hz) 7.44 (1H, d, J=5.27 Hz) 7.28 (1H, dd, J=3.42, 2.44 Hz) 6.77 (1H, d, J=5.47 Hz) 6.40 (1H, dd, J=3.42, 1.85 Hz) 4.70 (1H, d, J=4.69 Hz) 3.69-3.79 (1H, m) 3.09-3.20 (2H, m) 1.01 (3H, d, J=6.05 Hz)
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:20][CH2:21][NH:22][C:23](=[O:38])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:37][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]([NH:22][CH2:21][CH2:20][C:14]2[C:13]3[C:17](=[CH:18][CH:19]=[C:11]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:12]=3)[NH:16][CH:15]=2)=[O:38])=[CH:25][CH:26]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(NCCc1c[nH]c2ccc(Br)cc12)c1ccc(Cc2cccc(F)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(-c3ccccc3)cc12)c1ccc(Cc2cccc(F)c2)cc1
Yield: 16.4 %

Procedure:
A mixture of benzeneboronic acid (0.024 g; 0.195 mmol), N-(2-(5-bromo-1H-indol-3-yl)ethyl)-4-(3-fluorobenzyl)benzamide (0.080 g; 0.177 mmol), tetrakis(triphenylphosphine)palladium(0) (0.020; 0.017 mmol) and sodium carbonate (0.038 g; 0.355 mmol) in a mixture of DME (3 mL) and water (1 mL) was irradiated in the microwave oven at 130° C. for 20 minutes. The resulting solution was partitioned between water and ethyl acetate and the organic layer was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) and by preparative HPLC (method 2) to afford 0.013 g (16%) of the title compound as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([N:24]([CH3:35])[C:25](=[O:34])[C:26]#[C:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]O)[CH2:21][CH2:22][CH3:23].[Br:36]C(Br)(Br)Br>C(Cl)Cl>[Br:36][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C:27]#[C:26][C:25]([N:24]([CH2:20][CH2:21][CH2:22][CH3:23])[CH3:35])=[O:34]
Reactant: CCCCN(C)C(=O)C#CCCCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCN(C)C(=O)C#CCCCCCBr
Temperature: -10 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
1.205 g of triphenyl phosphine were added to a solution of 855 mg of the product of Step D in 4 ml of methylene chloride and the mixture was cooled to -10° C. 1.522 g of tetrabromomethane were added, and after stirring for one hour at -5° C., the reaction mixture was chromatographed on silica (eluant: cyclohexane-ethyl acetate 35-65) to obtain 0.98 g of the expected product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([NH:18][C:19](=[O:21])[CH3:20])=[C:13]([CH3:22])[C:12]=1[CH3:23])(=O)C.Cl.C(OCC)(=O)C.C(OC(C)C)(C)C>O.CO>[C:19]([NH:18][C:14]1[C:15]([CH3:17])=[CH:16][C:11]([OH:10])=[C:12]([CH3:23])[C:13]=1[CH3:22])(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1c(C)cc(OC(C)=O)c(C)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)OC(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)Nc1c(C)cc(O)c(C)c1C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
A solution of potassium carbonate (27 g, 195 mmol) in water (150 ml) was added to a solution of 1-acetoxy-4-acetylamino-2,3,5-trimethylbenzene (66.0 g, 324 mmol) in methanol (300 ml) and the mixture was stirred for 1 hour under an argon atmospheres. Aqueous 1N hydrochloric acid solution was added to the reaction mixture to make the mixture weak acid and the resulting mixture was diluted with water. Crystals precipitated were filtered, washed with water, dried and then recrystallized from ethyl acetate-isopropyl ether to obtain the desired compound (36.8 g, yield: 67.9%), m.p. 189°-190° C. (ethyl acetate-isopropyl ether).
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: ClCc1ccc(I)cc1
Reactant: CCOP(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1ccc(I)cc1)OCC
Reaction time: 8 h

Procedure:
4-iodobenzyl chloride and triethyl phosphite were put in a three-necked flask equipped with a reflux condenser, to which toluene was added and heated with stirring for 8 hours under reflux. The mixture was purified by the common method, to obtain diethyl 4-iodobenzylphosphonate.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([SH:8])=[CH:6][CH:7]=1.Cl.Cl[CH2:11][C:12]1[N:13]([CH2:17][CH2:18][CH3:19])[CH:14]=[N:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[N:3]=[N:4][C:5]([S:8][CH2:11][C:12]2[N:13]([CH2:17][CH2:18][CH3:19])[CH:14]=[N:15][CH:16]=2)=[CH:6][CH:7]=1
Reactant: CCCn1cncc1CCl
Reactant: Nc1ccc(S)nn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1cncc1CSc1ccc(N)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
3-amino-6-mercaptopyridazine (0.5 g), 4-chloromethyl-3-propylimidazole hydrochloride (0.62 g) and potassium carbonate (2.0 g) were added to N,N-dimethylformamide (10 ml), and the mixture was stirred overnight at room temperature. The solvent was distilled off, the residue was purified by basic silica gel column chromatography (elution solvent: methanol/ethyl acetate), to give 3-amino-6-[(3-propylimidazol-4-yl)methylthio]pyridazine (0.52 g) as yellow crystals.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH:11]([C:42](OCC)=[O:43])[CH2:12][C:13]1[CH:14]=[C:15]2[C:21]3([CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22]3)[CH2:20][N:19]([C:33]([O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])=[O:34])[C:16]2=[CH:17][CH:18]=1)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)C>[OH:43][CH2:42][CH:11]([CH2:10][OH:9])[CH2:12][C:13]1[CH:14]=[C:15]2[C:21]3([CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:22]3)[CH2:20][N:19]([C:33]([O:35][CH2:36][CH2:37][Si:38]([CH3:40])([CH3:39])[CH3:41])=[O:34])[C:16]2=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(Cc1ccc2c(c1)C1(CCN(C(=O)OC(C)(C)C)C1)CN2C(=O)OCC[Si](C)(C)C)C(=O)OCC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(CC(CO)CO)cc12
Reaction time: 1 h
Yield: 22.7 %

Procedure:
Lithium aluminum hydride (39.0 mg, 1.03 mmol) was dissolved in diethyl ether (5 mL). Thereafter, a diethyl ether (5 mL) solution of 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-(3-ethoxy-2-(ethoxycarbonyl)-3-oxopropyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (300 mg, 0.51 mmol) was added to the above obtained solution under cooling on ice, and the thus obtained mixture was then stirred at the same temperature as above for 1 hour. Thereafter, a saturated aqueous solution of sodium sulfate was added to the reaction solution, and the mixed solution was then filtered through a pad of celite, followed by washing with chloroform. The filtrate was concentrated in vacuo, and the obtained residue was then purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-(3-hydroxy-2-(hydroxymethyl)propyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (58.7 mg, 23%) in the form of a light red amorphous product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([F:18])([F:17])[F:16])[NH:11][C:10](=[O:19])[N:9]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:8]2=[O:25].C=O.[C:28](O)(=O)C.O1CCCC1>[Pd].C(#N)C.O.O>[OH:1][CH2:2][CH2:3][N:4]([CH3:28])[C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([F:18])([F:16])[F:17])[NH:11][C:10](=[O:19])[N:9]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:8]2=[O:25]
Reactant: CC(=O)O
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(NCCO)cc2c1=O
Agent: [Pd]
Agent: C=O
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: CN(CCO)c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F

Procedure:
A mixture of 370 mg (0.968 mmol) of N-[6-(2-hydroxy-ethylamino)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide, 0.074 ml (0.912 mmol) of formaldehyde solution (37% in water), 4 ml of acetic acid, 15 ml of tetrahydrofuran and 15 ml of water is hydrogenated in presence of 115 mg of palladium on carbon for 3 days. After day 1 and 2 another portion of formaldehyde (0.074 ml) is added. After filtration of the reaction mixture the tetrahydrofuran is evaporated and the remaining aqueous phase extracted with ethyl acetate. The organic phase is washed with brine, dried over Na2SO4 and concentrated to dryness leaving a brown oil that is fractionated by medium pressure chromatography on a RP-18 column (20 μm particle size) with acetonitril/water 1:2. The fractions containing the product are combined and extracted with ethyl acetate, the organic phase dried over Na2SO4 and concentrated yielding 165 mg of N-{6-[(2-hydroxy-ethyl)-methyl-amino]-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl}-methanesulfonamide as yellow powder, m.p. 220-224° C.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1)#[N:2].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[N:20]=[CH:21][N:22](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:23]=2)=[CH:14][CH:13]=1>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[N:20]([CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:21]=[N:22][CH:23]=2)=[CH:16][CH:17]=1
Reactant: N#Cc1ccc(CO)cc1
Reactant: Brc1ccc(Oc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Product: N#Cc1ccc(Cn2cncc2Oc2ccc(Br)cc2)cc1

Procedure:
The title compound was prepared as a white solid using the protocol described in example 5, step C using, 4-cyanobenzyl alcohol and 4-(4-bromophenyloxy)-1-trityl-imidazole. The title compound was purified by chromatography (Silica gel 3:7 acetone in CHCl3).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:20]([NH:22][C:23]1[CH:24]=[N:25][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:28]=1)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:39]1[CH:43]=[C:42]([CH2:44]O)[CH:41]=[N:40]1)=O)(C)(C)C>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:20]([N:22]([C:23]1[CH:24]=[N:25][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:28]=1)[CH2:44][C:42]1[CH:43]=[N:39][NH:40][CH:41]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)n1cc(CO)cn1
Reactant: Cc1ccc(OCc2ccccc2)c2c1C(C(=O)Nc1ccc(C(C)C)nc1)CCC2
Product: Cc1ccc(OCc2ccccc2)c2c1C(C(=O)N(Cc1cn[nH]c1)c1ccc(C(C)C)nc1)CCC2
Yield: 58.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 82 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-8-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.75 g) and 1-(tert-butyloxycarbonyl)-4-(hydroxymethyl)pyrazole (0.84 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-8-methyl-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.22 g) was obtained.