Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=4[N:14]([CH3:22])[CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[F:23][C:24]([F:36])([F:35])[C:25]1[N:30]=[C:29]([CH2:31][C:32](O)=[O:33])[CH:28]=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O.O>[CH3:22][N:14]1[C:15]2[N:16]=[CH:17][N:18]=[C:19]([NH2:21])[C:20]=2[C:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:3]([C:32](=[O:33])[CH2:31][C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:24]([F:23])([F:36])[F:35])[N:30]=2)[CH2:4][CH2:5]3)=[CH:13]1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)n1
Reactant: Cn1cc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2ccc3c(c2)CCN3C(=O)Cc2cccc(C(F)(F)F)n2)c2c(N)ncnc21
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
A solution of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2HCl (150 mg, 0.443 mmol), [6-(trifluoromethyl)-2-pyridinyl]acetic acid (91 mg, 0.443 mmol), HATU (169 mg, 0.443 mmol), and DIEA (0.310 mL, 1.774 mmol) in N,N-Dimethylformamide (DMF) (3 mL) were stirred overnight at room temperature. LCMS analysis at this time indicated good conversion, so the reaction mixture was poured into water (10 mL) and stirred for 30 min. The resulting precipitate was collected by filtration, dried at the pump for an hour, adsorbed onto silica and purified by flash chromatography (0-10% MeOH in EtOAc) to afford 7-methyl-5-(1-{[6-(trifluoromethyl)-2-pyridinyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (80 mg, 39.9% yield) as a beige solid. LC-MS (ES) m/z=453 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.26 (t, J=8.34 Hz, 2H), 3.74 (s, 3H), 4.21 (s, 2H), 4.31 (t, J=8.46 Hz, 2H), 5.85-6.26 (m, 2H), 7.23 (d, J=8.34 Hz, 1H), 7.26 (s, 1H), 7.34 (s, 1H), 7.71 (d, J=7.83 Hz, 1H), 7.83 (d, J=7.58 Hz, 1H), 8.05-8.13 (m, 2H), 8.15 (s, 1H).
Reaction SMILES: N1(C(OC(C)(C)C)=O)C[CH2:4][CH2:3][CH:2]1[C:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7].[C:22]([O:26][C:27]([N:29]1CCC(C(O)=O)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1(O)C=CC=CC=1.C1CCC(N=C=NC2CCCCC2)CC1>>[N:29]1([C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:4][CH2:3][CH:2]([C:6]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:7])[CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Oc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Oc2ccccc2)C1
Yield: 83 %

Procedure:
The compound 24 was prepared according to the method described for compound 22 employing 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (500 mg, 2.32 mmol), phenol (198 mg, 2.12 mmol) and DCC (522 mg, 2.53) to give pale white solid compound 24 (510 mg, 83%). 1H NMR (400 MHz, CDCl3) δ 1.40 (s, 9H), 1.84-1.57 (m, 1H), 2.21 (m, 2H), 3.17-3.70 (m, 4H), 7.00 (s, 1H), 7.02 (s, 1H), 7.17 (t, J=7.8 Hz, 1H), 7.32 (t, J=7.8 Hz, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([CH2:20]Cl)[C:17]([C:22](OCC)=[O:23])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(O)CC(C)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][C:17]3[C:22](=[O:23])[N:33]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1CCl
Reactant: NC1CCCCC1
Solvent: CC(C)CCO
Product: O=C1c2cnc(N3CCN(Cc4ccccc4)CC3)nc2CN1C1CCCCC1
Yield: 63.1 %

Procedure:
Dissolved in 40 ml of isoamyl alcohol was 2.0 g (5.34 mmol) of ethyl 2(4-benzylpiperazino)-4-chloromethylpyrimidine-5-carboxylate, followed by an addition of 10.5 g (107 mmol) of cyclohexylamine. The resultant mixture was refluxed for 6 hours. After completion of the reaction, the solvent was distilled off and the residue was washed with ether to obtain 1.32 g of the above-identified compound as crystals (yield: 63%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:26][CH2:25][C:11]2[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.[CH3:34][O:35][C:36]1[CH:44]=[N:43][C:42]([O:45][CH3:46])=[C:41]2[C:37]=1[C:38]([C:47](=[O:51])C(O)=O)=[CH:39][NH:40]2.CCN(C(C)C)C(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl>[C:19]1([N:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]3[CH2:9][N:8]([C:6](=[O:7])[C:47]([C:38]4[C:37]5[C:41](=[C:42]([O:45][CH3:46])[N:43]=[CH:44][C:36]=5[O:35][CH3:34])[NH:40][CH:39]=4)=[O:51])[CH2:26][CH2:25][C:11]2=3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ncc(OC)c2c(C(=O)C(=O)O)c[nH]c12
Reactant: CC(C)(C)OC(=O)N1CCc2c(c3ccccc3n2-c2ccccc2)C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ncc(OC)c2c(C(=O)C(=O)N3CCc4c(c5ccccc5n4-c4ccccc4)C3)c[nH]c12
Reaction time: 1 h
Yield: 33.6 %

Procedure:
General Method: A solution of 5-phenyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (0.054 g, 0.155 mmol) in dry CH2Cl2 (2 mL) was treated with TFA (0.20 mL). After stirring the mixture for 1 h, the solvent was evaporated in vacuo and the residue was dissolved in CHCl3 (5 mL). To this mixture was added 4,7-dimethoxy-6-azaindol-3-yl-oxoacetic acid (0.042 g, 0.155 mmol), i-Pr2NEt (0.27 mL, 1.55 mmol) and then BOP-Cl (0.039 g, 0.153 mmol). The mixture was allowed to stir at room temperature for 2 h and then the solvent was removed in vacuo. The residue was partitioned with EtOAc-H2O, the organic phase was separated and the aqueous phase was re-extracted with EtOAc (2×). The combined organic layers were washed (H2O, brine), dried (Na2SO4) and evaporated. The residue was purified by preparative HPLC to give the title compound (0.025 g, 33%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.27 (s, 0.67H), 9.22 (s, 0.33H), 8.06 (d, J=3.0 Hz, 0.67H), 8.00 (d, J=3.0 Hz, 0.33H), 7.59-7.07 (m, 10H), 4.11 (m, 1H), 4.05 (s, 3H), 3.88 (s, 1H), 3.85 (m, 2H), 3.72 (s, 2H), 2.88 (m, 1H), 2.78 (m, 2H); LCMS: m/e 481 (M+H)+.
Reaction SMILES: CS([C:5]1[N:9]([CH3:10])[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]=1)(=O)=O.[C:15]([NH:18][CH2:19][CH2:20][NH2:21])(=[O:17])[CH3:16].[OH-].[Na+]>O>[CH3:10][N:9]1[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]=[C:5]1[NH:21][CH2:20][CH2:19][NH:18][C:15](=[O:17])[CH3:16]
Reactant: CC(=O)NCCN
Reactant: Cn1c(S(C)(=O)=O)nc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)NCCNc1nc2ccccc2n1C
Yield: 30 %

Procedure:
A mixture of 2-methylsulfonyl-1-methyl-1H-benzimidazole (7.0 g, 0.033 mol) and N-acetylethylenediamine (17.0 g, 0.167 mol) was heated at 120°-125° C. for 8 hours. The mixture was cooled, diluted with H2O, made basic (pH8) with 2.5N NaOH, and filtered. The filtrate was extracted with EtOAc, and the combined extracts were washed with brine, dried, and concentrated to give a yellow solid 2.3 g (30%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Cl:15][CH2:16][C:17]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:18]
Reactant: Nc1ccccn1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)Nc1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-amino-pyridine (1.0 g) in dry dichloromethane (10.6 mL) under nitrogen at 0° C. was treated with triethylamine (1.63 mL) followed by slow addition of chloroacetyl chloride (0.93 mL). The reaction mixture was allowed to warm up to room temperature. After 2 hours, the mixture was partitioned between dichloromethane and water. The phases were separated and the aqueous layer was extracted with dichloromethane (×2). The combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated to give the crude product which was purified by silica gel chromatography eluting with 0-30% ethyl acetate/cyclohexane to give the title compound (1.43 g) as a pink solid. Further purification was achieved by trituration with 40-60 petroleum ether to give 1.15 g of the desired product. Crystallisation of a 0.94 g portion of the material from refluxing acetonitrile (2.4 mL) gave the sub-titled compound as a pink solid (0.73 g).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[CH3:34])[CH2:29]Cl>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:29][C:28]3[CH:31]=[CH:32][C:33]([CH3:34])=[C:26]([CH3:25])[CH:27]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: Cc1ccc(CCl)cc1C
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: Cc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1C

Procedure:
The title compound (0.003 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using 3,4-dimethylbenzyl chloride (0.6 mL) in place of benzyl chloride. MS (ESI): exact mass calculated for C22H24ClN3, 365.17; found, m/z 366.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.40-7.38 (m, 2H), 7.35-7.32 (m, 2H), 6.98-6.96 (m, 1H), 6.90-6.86 (m, 1H), 6.72-6.69 (m, 1H), 5.30 (s, 1H), 5.19 (s, 1H), 2.90-2.87 (m, 2H), 2.86-2.82 (m, 2H), 2.77-2.73 (m, 2H), 2.72-2.68 (m, 2H), 2.21 (s, 3H), 2.17 (s, 3H).
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: COC(=O)C(=O)C(C)Br
Reactant: CC(C)Cn1c(S)cc(=O)n(C)c1=O
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: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Cl[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=1.[OH-].[K+]>CS(C)=O>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([O:2][C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)=[N:11][CH:12]=1
Reactant: Oc1ccc(O)cc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 150 °C
Reaction time: 2 h
Yield: 35.6 %

Procedure:
40 ml of dimethyl sulfoxide, 4.2 g of hydroquinone, 5.0 g of 2-chloro-5-trifluoromethylpyridine and 2.3 g of potassium hydroxide were reacted with stirring in a nitrogen gas stream at 150° C. for 2 hours to obtain 2.5 g of 4-(5-trifluoromethyl-2-pyridyloxy)phenol. The thus-obtained 4-(5-trifluoromethyl-2-pyridyloxy)phenol was dissolved in 20 ml of methyl ethyl ketone, and 1.7 g of anhydrous potassium carbonate was added thereto. The mixture was reacted with stirring under reflux for 1 hour, and the reaction product thusobtained was cooled to 40° C., and 2.5 g of ethyl 4-bromo-2-pentenoate was dropwise added thereto gradually. The mixture was allowed to stir for 30 minutes and then to react under reflux for 7 hours. After completion of the reaction, the reaction product was thrown into 100 ml of water, and an oily matter was extracted with methylene chloride. The extracted phase was washed with water several times, and dried over anhydrous sodium sulfate. The solvent was evaporated off to obtain a crude product which was subsequently subjected to silica gel column chromatography using toluene as an eluent to obtain 1.5 g of the object product having a refractive index, nD23, of 1.5145. This was found to have a boiling point of 148°-151° C./l mm Hg with some decomposition.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].[Cl:6][C:7]1[CH:8]=[C:9]([CH:17]([CH2:21][C@H:22]2[CH2:42][CH2:41][C:24]3([O:28][C@H:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@@H:26]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[O:25]3)[CH2:23]2)[C:18]([OH:20])=O)[CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(#N)C.C(OCC)(=O)C.C(N(CC)CC)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH:17]([CH2:21][C@H:22]2[CH2:42][CH2:41][C:24]3([O:28][C@H:27]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C@@H:26]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[O:25]3)[CH2:23]2)[C:18]([N:4]([O:3][CH3:2])[CH3:5])=[O:20])[CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)C(=O)O)cc1Cl
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CON(C)C(=O)C(C[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
A solution of N-methoxymethanamine hydrochloride (936 mg) in acetonitrile (40 mL) was neutralized with triethylamine (3.35 mL), and 2-[3-chloro-4-(methylsulfonyl)phenyl]-3-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]propanoic acid (4.33 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (2.30 g) and 1-hydroxybenzotriazole (612 mg) were added under ice-cooling. The reaction mixture was stirred overnight at room temperature, diluted with ethyl acetate, and washed with water and saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (3.05 g, yield 69%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (3:1, volume ratio).
Reaction SMILES: [CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:14][CH:13]=2)[C:10](=[O:25])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:26](I)[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:26]([N:22]1[CH2:23][CH2:24][CH:19]([O:18][C:15]2[CH:14]=[CH:13][C:12]([N:11]3[C:10](=[O:25])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]3[CH3:1])=[CH:17][CH:16]=2)[CH2:20][CH2:21]1)[CH3:27]
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccc(OC2CCNCC2)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCC(Oc2ccc(-n3c(C)nc4ccccc4c3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
2-methyl-3-[4-(4-piperidinyloxy)phenyl]-4(3H)-quinazolinone (50 mg, 0.15 mmol), ethyl iodide (23 mg, 0.15 mmol) and potassium carbonate (0.30 mmol) were mixed in dimethylformamide (1 mL), and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, ethyl acetate and 1N sodium hydroxide aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with distilled water, dried with anhydrous sodium sulfate, and the product was purified by silica gel column chromatography (chloroform/methanol=30/1) to obtain the title compound (25 mg, 46%) as a colorless solid.
Reaction SMILES: [OH-].[Na+:2].CO.[CH3:5][C:6]1[CH:7]=[N:8][C:9]([CH2:15][S+:16]([O-:28])[C:17]2[NH:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[CH:23][C:24]=3[N:25]=2)=[C:10]([CH3:14])[C:11]=1[O:12][CH3:13].ClCCl>C(#N)C>[CH3:5][C:6]1[CH:7]=[N:8][C:9]([CH2:15][S+:16]([O-:28])[C:17]2[N-:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[CH:23][C:24]=3[N:25]=2)=[C:10]([CH3:14])[C:11]=1[O:12][CH3:13].[Na+:2]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 29 °C

Procedure:
3.47 g of sodium hydroxide and 105 ml of methanol were taken into a round bottom flask and stirred at 29° C. A solution of 30 g of esomeprazole in 150 ml of acetonitrile was added to the above methanolic sodium hydroxide solution and stirred for 1 hour at 26° C. The reaction mass was then distilled under a vacuum of 300 mm Hg at 38° C. The residue was then co-distilled with 450 ml of acetonitrile in three equal lots. To the residue obtained, 60 ml of dichloromethane was added and stirred at 29° C. for 1.5 hours. The separated solid was filtered and washed with 30 ml of acetonitrile to give 42.6 g of Form J of esomeprazole sodium.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=1)=O.Cl.[NH2:17]N>C(O)C>[CH3:14][S:13][C:9]1[N:8]=[C:7]([C:5]2[NH:17][N:2]=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CSc1nccc(C(=O)/C=C/N(C)C)n1
Reactant: NN
Agent: Cl
Solvent: CCO
Product: CSc1nccc(-c2ccn[nH]2)n1

Procedure:
A solution of (2E)-3-(dimethylamino)-1-[2-(methylthio)pyrimidin-4-yl]prop-2-en-1-one (1-4, 1.0 g, 4.48 mmol, 1 equiv) and hydrazine hydrochloride (0.62 g, 8.96 mmol, 2 equiv) in ethanol(20 mL) was heated at reflux for 20 hours. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate(2×50 mL) and sat. sodium bicarbonate solution. The combined organic extracts were dried over magnesium sulfate and concentrated to a solid which was triturated with ether to provide 2-(methylthio)-4-(1H-pyrazol-5-yl)pyrimidine (4-1) as a tan solid. 1H NMR (500 MHz, CDCl3) δ 10.8 (br s, 1H), 8.55 (d, 1H, J=5 Hz), 7.68 (d, 1H, J=5 Hz), 7.40 (br s, 1H), 6.96 (br s, 1H), 2.63 (s, 3H).
Reaction SMILES: [CH:1]([Si:4]([C:11]#[CH:12])([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(N(CC)CC)C.O=O.[Br:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1>O1CCCC1.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:12]#[C:11][Si:4]([CH:5]([CH3:6])[CH3:7])([CH:1]([CH3:3])[CH3:2])[CH:8]([CH3:10])[CH3:9])=[CH:25][CH:24]=1
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Reactant: Brc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: O=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)[Si](C#Cc1ccc(Br)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
11.6 mL triisopropylsilylacetylen and 14.4 mL triethylamine followed by 0.2 g copper iodide and 0.73 g bis-(triphenylphosphine)-palladium dichloride are added under argon to an oxygen-free solution of 15.0 g 4-bromo-1-iodo-benzene in 150 mL dry tetrahydrofuran. The solution is stirred for 16 h at ambient temperature and then filtered through Celite and evaporated down. The residue is purified by chromatography on silica gel (cyclohexane).
Reaction SMILES: [CH2:1]([C:6]1[CH:7]([OH:11])[CH2:8][CH2:9][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C[C:13](C)([C:17]([O-:19])=[O:18])[C:14]([O-:16])=O.[CH:21](OC(C)C)(C)C>>[C:17]([O:19][CH3:21])(=[O:18])[CH2:13][C:14]([O:11][C@@H:7]1[CH2:8][CH2:9][CH:10]=[C:6]1[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[O:16]
Reactant: CC(C)OC(C)C
Reactant: CCCCCC1=CCCC1O
Reactant: CC(C)(C(=O)[O-])C(=O)[O-]
Product: CCCCCC1=CCC[C@H]1OC(=O)CC(=O)OC
Temperature: 21.5 °C

Procedure:
A suspension of racemic 2-(pentyl)-2-cyclopenten-1-ol (100 mg; 0.649 mmol), dimethylmalonate (100 mg; 0.757 mmol), ground KHCO3 (7 mg; 0.05 mmol), diisopropyl ether (1.8 ml) and lipase (100 mg) was stirred in a 10 ml flask at room temperature (20-23° C.). Results are shown in the table below. The reaction was followed by GC method and the ee was determined by treating samples collected at the times indicated with N-methyl-N-trimethylsilyl-trifluoracetamide in dipropyl ether to silylate unreacted alcohol and effecting a chiral GC analysis (Megadex 5).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:16][CH2:17][C@@H:18]([OH:20])[CH3:19]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:16]([CH2:17][C@@H:18]([OH:20])[CH3:19])[C:5]=32)=[CH:10][CH:9]=1
Reactant: O=CCC1Cc2ccc(F)cc2C1=O
Reactant: C[C@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H](O)Cn1ccc2c1-c1cc(F)ccc1C2
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
A solution of 1.92 g of (RS)-2-(2-oxoethyl)-6-fluoro-1-indanone and 80 mg of p-toluenesulfonic acid in 90 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (S)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 30 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 2:3). 1.51 g (65%) of (S)-1-(7-fluoro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[NH:35][C:36]([C:38]1[C:46]2[N:45]=[C:44]([O:47]C)[NH:43][C:42]=2[CH:41]=[CH:40][CH:39]=1)=[O:37])[C:6]([N:8]([CH3:31])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)=[O:23])=[O:7]>Cl.CO.O1CCOCC1>[OH:47][C:44]1[NH:43][C:42]2[CH:41]=[CH:40][CH:39]=[C:38]([C:36]([NH:35][C:34]3[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH3:31])[C:9]4[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=4[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[O:23])=[O:7])=[CH:4][C:3]=3[O:2][CH3:1])=[O:37])[C:46]=2[N:45]=1
Reactant: COc1nc2c(C(=O)Nc3ccc(C(=O)N(C)c4ccc(C)cc4OCCCCCC(=O)N4CCN(C)CC4)cc3OC)cccc2[nH]1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(O)nc12
Reaction time: 8 h
Yield: 39 %

Procedure:
A solution of 3-methoxy-4-(2-methoxy-1H-benzimidazol-4-yl)carbonylamino-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (139 mg) in 10% hydrogen chloride in methanol (2 ml) was stirred at ambient temperature for 2 hours and 4N hydrogen chloride in 1,4-dioxane (2 ml) was added to the mixture. After being allowed to stand at ambient temperature overnight, the reaction mixture was concentrated in vacuo and the residue was diluted with a mixture of chloroform and saturated aqueous sodium bicarbonate solution. The organic layer was separated and washed with water and brine. The solution was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform-methanol=10:1) to give 4-(2-hydroxy-1H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (53 mg) as a powder.