Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[C:2]1([C:8]2[C:9]3[S:32][CH:31]=[CH:30][C:10]=3[N:11]=[C:12](OP(N3CCOCC3)(N3CCOCC3)=O)[CH2:13][N:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>>[C:2]1([C:8]2[C:9]3[S:32][CH:31]=[CH:30][C:10]=3[N:11]=[C:12]([NH2:1])[CH2:13][N:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(OC1=Nc2ccsc2C(c2ccccc2)=NC1)(N1CCOCC1)N1CCOCC1
Reactant: N
Product: NC1=Nc2ccsc2C(c2ccccc2)=NC1

Procedure:
Gaseous ammonia was conducted into a solution of 14.4 g of dimorpholin-4-yl-phosphinic acid (5-phenyl-3H-thieno[3,2-e][1,4]-diazepin-2-yl) ester at room temperature while stirring until the starting product had reacted completely. After removal of the solvent in a vacuum the residue was extracted with dichloromethane/water in the presence of a small amount of methanol. The aqueous phase was washed several times with dichloromethane, the dichloromethane extracts were dried with sodium sulphate, filtered and evaporated in a vacuum. The residue was suspended in dichloromethane and stirred for 0.5 h. There were obtained 2.9 g of crude 5-phenyl-3H-thieno[3,2-e][1,4]diazepin-2-ylamine which was used without further purification as the starting product for the step described below.
Reaction SMILES: [N:1]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4](=[O:10])[NH:3][CH:2]=1.[Cl:11][S:12](O)(=[O:14])=[O:13].S(Cl)(Cl)=O>>[Cl:11][S:12]([C:8]1[S:7][C:6]2[N:1]=[CH:2][NH:3][C:4](=[O:10])[C:5]=2[CH:9]=1)(=[O:14])=[O:13]
Reactant: O=c1[nH]cnc2sccc12
Reactant: O=S(=O)(O)Cl
Solvent: O=S(Cl)Cl
Product: O=c1[nH]cnc2sc(S(=O)(=O)Cl)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3,4-Dihydrothieno [2,3-d] pyrimidin-4-one (50 g) was added portionwise to chlorosulphonic acid (243 ml), maintaining the temperature below 0° C. Thionyl chloride (121 ml) was added dropwise, and the mixture stirred for a further 30 minutes at room temperature; then two hours at reflux. It was then cooled, and poured carefully on to ice. The precipitate was washed and dried to give 6-chlorosulphonylthieno[2,3-d]pyrimidin-4-one (84 g). This compound (30 g) and dimethylamine (450 ml) were mixed at -10°, then allowed to stir at room temperature for two hours. The mixture was poured into water and acidified with hydrochloric acid. The precipitate was washed with water and ethanol, and dried to give the 6-dimethylsulphonamido-4-one (23.8 g). This material was converted into the 4-chloro derivative as described in Example 19 above and thence into the title compounds by treatment with amines basically as described in Example 5.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([SH:11])[C:6]1[O:10][CH:9]=[CH:8][CH:7]=1>>[CH3:2][C:1]([S:11][CH2:5][C:6]1[O:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: SCc1ccco1
Reactant: CC(=O)Cl
Product: CC(=O)SCc1ccco1

Procedure:
a. Furfurylthiol acetate was prepared by reacting acetic chloride or anhydride with furfurylmercaptan according to the method described in Houben-Weyl, 4th ed., vol. 9, 753 (1955). The product has a b.p. of 90°-92° C./12 mm. Hg.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][NH:10][CH2:11]2)=[O:5].C(N(CC)CC)C.[N:23]1[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[N:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:10]2[CH2:9][CH2:8][C:7]3[C:6]([C:4]([O:3][CH3:2])=[O:5])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11]2)=[CH:25][CH:24]=1
Reactant: O=Cc1ccncc1
Reactant: COC(=O)c1cccc2c1CCNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc2c1CCN(Cc1ccncc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.1 %

Procedure:
5-Methoxycarbonyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (1 g, 4.39 mmol) and triethylamine (666 mg, 6.58 mmol) were mostly dissolved in tetrahydrofuran (30 mL). 4-Pyridinecarboxaldehyde (494 mg, 4.61 mmol) and sodium triacetoxyborohydride (1.3 g, 6.15 mmol) were then added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous sodium bicarbonate. The tetrahydrofuran was removed under vacuum and the remaining residue was dissolved in ethyl acetate then washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and concentrated under vacuum to give 1.29 g of methyl 2-(pyridine-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate as a light yellow oil. MS (ESI, pos. ion) m/z: 283.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])=[C:15]([CH:28]=2)[O:16][CH2:17][CH:18]([O:24]C(=O)C)[N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH4+].[OH-]>CO>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:29]([F:35])([F:34])[C:30]([F:32])([F:33])[F:31])=[C:15]([O:16][CH2:17][C@@H:18]([OH:24])[N:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[CH:28]=1)=[O:9]
Reactant: CC(=O)OC(COc1cc(NC(=O)c2cccnc2Cl)ccc1C(F)(F)C(F)(F)F)N1CCCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)F)c(OC[C@@H](O)N2CCCC2)c1)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Acetic acid 2-{5-[(2-chloro-pyridine-3-carbonyl)-amino]-2-pentafluoroethyl-phenoxy}-1-pyrrolidin-1-yl-ethyl ester (408 mg) was dissolved in MeOH (15 ml) and NH4OH (6 ml) was added and the mixture was stirred at RT for 6 h. The reaction was concentrated in vacuo and dried under high vacuum. The residue was purified over silica gel column (8:92:0.6 MeOH:CH2Cl2:NH4OH). The purified fractions were concentrated in vacuo and dried again to provide (R)-2-chloro-N-[3-(2-hydroxy-2-pyrrolidin-1-yl-ethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide as a white foam.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[C:6]([C@@H:8]2[C@@H:12]([C:13]([O:15][CH3:16])=[O:14])[CH2:11][CH2:10][N:9]2C(OC(C)(C)C)=O)[CH:7]=1.[Cl:30][C:31]([O:33][CH3:34])=[O:32].Cl>N1C=CC=CC=1>[ClH:30].[CH:27]([S:24]([C:5]1[CH:4]=[CH:3][C:2]([C:31]([O:33][CH3:34])=[O:32])=[CH:7][C:6]=1[C@H:8]1[C@@H:12]([C:13]([O:15][CH3:16])=[O:14])[CH2:11][CH2:10][NH:9]1)(=[O:25])=[O:26])([CH3:28])[CH3:29]
Reactant: COC(=O)Cl
Reactant: COC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1c1cc(N)ccc1S(=O)(=O)C(C)C
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(S(=O)(=O)C(C)C)c([C@@H]2NCC[C@@H]2C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 129.1 %

Procedure:
To 61A (0.09 g, 0.21 mmol) in pyridine (1 mL) at 0° C. was added methyl chloroformate (32 μL, 0.42 mmol). After 2.0 h stirring at rt the reaction was acidified with 1M HCl to pH 3-4. The product was extracted with ethyl acetate and was washed with brine and dried over sodium sulfate. After evaporation of the solvent, the crude product was redissolved in ethyl acetate (1.5 mL) and hydrogen chloride (2 mL, 4M in dioxane) was added. The reaction was stirred for 3 h at rt. The solvent was removed and placed on the lyophilizer to give 0.11 g solid 61C. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.22-1.40 (m, 6H) 2.43-2.60 (m, 1H) 2.62-2.80 (m, 1H) 3.42 (s, 3H) 3.45-3.65 (m, 2H) 3.67-3.77 (m, 1H) 3.78 (s, 3H) 3.83-3.96 (m, 1H) 5.84 (d, J=8.56 Hz, 1H) 7.55-7.67 (m, 1H) 7.81-7.90 (m, 1H) 7.94 (d, J=8.80 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[C:27](Cl)(=[O:29])[CH3:28]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][C:27](=[O:29])[CH3:28])[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: CC(=O)Nc1cccc(CCN2CCN(c3cccc4nc(C)ccc34)CC2)c1
Yield: 52 %

Procedure:
The title compound was prepared in 52% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and acetyl chloride.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[C:11]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([F:31])=[C:21]([NH:23]C(=O)OC(C)(C)C)[CH:22]=2)[N:10]=3)=[O:5])[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+]>Cl.C(OCC)(=O)C>[NH2:23][C:21]1[CH:22]=[C:17]([NH:16][C:11]2[N:10]=[C:9]3[S:8][C:7]([NH:6][C:4]([CH:1]4[CH2:2][CH2:3]4)=[O:5])=[N:15][C:14]3=[CH:13][CH:12]=2)[CH:18]=[CH:19][C:20]=1[F:31]
Reactant: CC(C)(C)OC(=O)Nc1cc(Nc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Nc1cc(Nc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To tert-butyl [5-({2-[(cyclopropylcarbonyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}amino)-2-fluorophenyl]carbamate (3.40 g, 7.67 mmol) was added 4N hydrogen chloride/ethyl acetate (50 mL), and the mixture was stirred at 0° C. overnight. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate (50 mL×3). The organic layer was concentrated under reduced pressure to give the title compound (1.70 g, 65%) as a violet powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([CH2:15][CH3:16])[N:13]=[CH:14][C:3]=12.[CH:17]1([CH2:23][NH2:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CS(C)=O>[CH2:15]([N:12]1[C:4]2=[N:5][C:6]3[C:11]([C:2]([NH:24][CH2:23][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[C:3]2[CH:14]=[N:13]1)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH3:16]
Reactant: NCC1CCCCC1
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Solvent: CS(C)=O
Product: CCn1ncc2c(NCC3CCCCC3)c3ccccc3nc21
Reaction time: 48 h
Yield: 90.5 %

Procedure:
To a mixture of 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]quinoline (10 g, 0.043 mol) and DMSO (75 ml) was added cyclohexanemethylamine (10.75 g, 0.095 mol). The reaction mixture was refluxed for about four hours, then was allowed to stand for about 2 days. About 40-50 ml of the DMSO was removed in vacuo and the residue was pured into ice-water. A precipitate formed which was collected by filtration, washed with water and dried. The PG,13 solid precipitate was dissolved in CH2Cl2, washed with water, then brine and was then dried over MgSO4. The solvent was filtered and concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with ethyl acetate/cyclohexane (3/7) followed by recrystallization from hexane to afford 12 g (90.2%) of 1-ethyl-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, as light yellow crystals, m.p. 161°-163° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([F:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:28].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)CC>CC(C)=O>[CH2:1]([O:8][C:9]1[C:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][C:12]([C:13]([OH:28])=[O:14])=[C:11]([F:25])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(OCc2ccccc2)c(OCc2ccccc2)cc1F
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCCO
Product: O=C(O)c1cc(OCc2ccccc2)c(OCc2ccccc2)cc1F
Temperature: 0 °C
Reaction time: 19 h
Yield: 81 %

Procedure:
To a cold (0° C.) solution of 4,5-bis-benzyloxy-2-fluoro-benzaldehyde (2.15 g, 6.39 mmol) in acetone (86.0 mL) was slowly added Jones reagent (4.3 mL). The reaction mixture was stirred 19 h at 0° C. Propanol (0.43 mL) was added and the reaction mixture was stirred 40 min at 20° C. The crude mixture was filtered, washed with acetone and poured into water (50 mL). The solid was filtered, washed with water and dried in vacuo, yielding the title compound (1.82 g, 81%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][CH:37]([NH:39][CH2:40][CH2:41][NH2:42])[CH3:38]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:42][CH2:41][CH2:40][NH:39][CH:37]([CH3:38])[CH3:36])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: CC(C)NCCN
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(NCCNC(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 71.3 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (30 mg, 0.06 mmol) in THF (3 mL) was added N-(1-methylethyl)-1,2-ethanediamine (0.019 mL, 0.15 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH [7]+NH4OH[3]) provided the title compound as a white solid (23 mg, 71%). LC-MS m/z 538 (M+H)+; 1H-NMR (MeOD) δ 1.00 (d, 3H), 1.27 (d, 3H), 2.30 (s, 3H), 2.58 (m, 2H), 2.70 (m, 1H), 3.25 (m, 2H), 4.07 (s, 2H), 4.23 (m, 1H), 7.16 (m, 2H), 7.44 (d, 1H), 7.50 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: C(OC[C:6]1[CH:15]=[C:14]([CH2:16][O:17]C(=O)C)[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])(=O)C.C(=O)([O-])[O-].[K+].[K+]>>[OH:17][CH2:16][C:14]1[CH:15]=[C:6]2[C:7](=[CH:12][CH:13]=1)[C:8](=[O:9])[O:10][CH2:11]2
Reactant: COC(=O)c1ccc(COC(C)=O)cc1COC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1OCc2cc(CO)ccc21
Yield: 78.9 %

Procedure:
According to a similar procedure to that described in Example 1-(6), methyl 2,4-bis(acetoxymethyl)benzoate (6.35 g, 22.7 mmol) obtained from Example 4-(1) and potassium carbonate (373.2 mg, 2.7 mmol) were reacted, and the reaction mixture was worked up to afford, after extraction, the title compound as a crude product. The crude product was subjected to chromatography on a silica gel (200 g) column (eluent; ethyl acetate:dichloromethane=0:1˜1:10) to afford the title compound (2.94 g, 79% yield) as a colorless solid (mp. 126° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27]([NH2:29])=[O:28])[C:19]([C:33]([F:36])([F:35])[F:34])=[CH:18][N:17]=1.[CH:37](=O)[CH3:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH2:37]([N:12]1[CH2:13][CH2:14][CH:9]([C:7]2[CH:6]=[CH:5][C:4]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27]([NH2:29])=[O:28])[C:19]([C:33]([F:34])([F:35])[F:36])=[CH:18][N:17]=3)=[C:3]([O:2][CH3:1])[CH:8]=2)[CH2:10][CH2:11]1)[CH3:38]
Reactant: COc1cc(C2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2cccc(C(N)=O)c2)n1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CCN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(N)=O)c4)n3)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 16.6 %

Procedure:
To a solution of 3-(2-(2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)benzamide (5) (0.021 g, 0.04 mmol) in methanol (2.00 mL) was added acetaldehyde (0.010 mL, 0.18 mmol) followed by sodium triacetoxyborohydride (0.044 g, 0.21 mmol) under a N2 atmosphere. The mixture was then stirred at room temperature for 5 hours. The resulting mixture was concentrated under reduced pressure and purified using silica gel column chromatography (0-30% MeOH/EtOAc+1% 2 M ethanolic NH3). The product was further purified using mass directed auto-preparative HPLC to give the title compound (7) (3.5 mg, 16%); 1H NMR (400 MHz, d6-Acetone) δ 8.62 (s, 1H), 8.24 (m, 2H), 7.91 (s, 1H), 7.78 (ddd, J=7.5, 1.4, 1.4 Hz, 1H), 7.41 (m, 3H), 7.01 (d, J=1.7 Hz, 1H), 6.89 (dd, J=8.3, 1.7 Hz, 1H), 6.60 (m, 1H), 3.97 (s, 3H), 3.21 (m, 4H), 3.12 (m, 2H), 2.55 (m, 3H), 2.16 (m, 2H), 1.85 (m, 4H), 1.11 (t, J=7.2 Hz, 3H). LCMS Method C: rt 4.98 min; m/z 528.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1.[CH3:20]I.O>CN1C(=O)CCC1>[CH3:20][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([C:9]2[CH:8]=[CH:7][N:6]=[C:5]([S:4][CH3:3])[N:10]=2)=[N:12]1
Reactant: CSc1nccc(-c2n[nH]c3ccccc23)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CSc1nccc(-c2nn(C)c3ccccc23)n1
Reaction time: 0.25 h
Yield: 75.3 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 99 mg, 2.47 mmol) was added to a stirring solution of 3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-indazole (520 mg, 2.15 mmol) in NMP at 0° C. The mixture was stirred for 15 min and then methyliodide (0.14 mL, 2.25 mmol) was added and the resulting mixture was stirred for 2 h. The reaction mixture was then poured into water and extracted twice with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (hexane/EtOAc, 9/1) to give 415 mg of 1-methyl-3-(2-methylsulfanylpyrimidin-4-yl)-1H-indazole.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH2:11]O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.P(Br)(Br)[Br:24]>C1C=CC=CC=1.O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH2:11][Br:24])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(Oc2ccc(F)cc2)cc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: O
Product: Fc1ccc(Oc2ccc(CBr)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 192.4 %

Procedure:
4-(4-Fluorophenoxy)benzyl alcohol (1.92 g, 8.80 mmol) and 0.2 ml of pyridine was dissolved in 25 ml of benzene and cooled in cold water. Phosphorus tribromide (1.19 g, 4.40 mmol) in 10 ml of benzene was added dropwise and the reaction was stirred 30 minutes and allowed to warm to room temperature. The solvent was evaporated and the residue was carefully quenched with saturated sodium bicarbonate solution. After dilution with water, the mixture was extracted twice with diethyl ether. The organic extracts were washed with saturated sodium bicarbonate solution and then with brine, dried over MgSO4, and concentrated to afford 2.38 g (96%) of the subtitle compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH2:51][CH3:52]>>[CH2:51]([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[O:44][CH2:43][CH2:42][CH2:41][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1)[CH3:52]
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Reactant: CCc1ccccc1OCCCCBr
Product: CCc1ccccc1OCCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3c(c2)N(CCCOC)C(=O)CC3)cc1

Procedure:
Analogously to Method I, 0.160 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.101 g of 1-(4-bromobutoxy)-2-ethylbenzene are reacted. The title compound is obtained as a colourless oil. Rf=0.35 (2:1 EtOAc-heptane); Rt=6.48.
Reaction SMILES: CN(C=O)C.[N:6]1([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH:17]([NH:21][C:22](=[O:43])/[C:23](=[CH:28]/[C:29]2[CH:34]=[CH:33][C:32]([N:35]4[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]4)=[C:31]([O:41][CH3:42])[CH:30]=2)/[CH2:24][CH2:25][CH2:26]Cl)[CH2:16][CH2:15]3)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[H-].[Na+].O>C(OCC)(=O)C>[CH3:42][O:41][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][C:32]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1)/[CH:28]=[C:23]1/[C:22](=[O:43])[N:21]([CH:17]2[C:18]3[C:14](=[CH:13][C:12]([N:6]4[CH2:7][CH2:8][O:9][CH2:10][CH2:11]4)=[CH:20][CH:19]=3)[CH2:15][CH2:16]2)[CH2:26][CH2:25][CH2:24]/1
Reactant: COc1cc(/C=C(\CCCCl)C(=O)NC2CCc3cc(N4CCOCC4)ccc32)ccc1-n1cnc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C2\CCCN(C3CCc4cc(N5CCOCC5)ccc43)C2=O)ccc1-n1cnc(C)c1
Reaction time: 0.25 h
Yield: 81.3 %

Procedure:
To a DMF (5.0 mL) solution of ((E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (5-morpholin-4-yl-indan-1-yl)amide (2.80 g), sodium hydride (40% mineral oil content, 267 mg) was added at 0° C., and the reaction solution was agitated for 15 minutes. Water and ethyl acetate were added to the reaction solution after confirming disappearance of the starting materials, and the organic layer was partitioned. After the organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. By purifying the obtained residue by silica gel chromatography (elution solvent:a heptane-ethyl acetate system, ethyl acetate-ethanol system), 2.12 g of (E)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)-1-(5-morpholin-4-yl-indan-1-yl)piperidin-2-one racemate was obtained. Next, this compound (140 mg) was separated in CHRIALPAK™ AD-H available from Daicel Chemical Industries, Ltd. (2 cm×25 cm mobile phase; ethanol), and the title optically active substance with a retention time of 14 minutes (64 mg; >99% ee) and the title optically active substance with a retention time of 16 minutes (58 mg; >97% ee) were obtained. The physical properties of the title optically active substance with a retention time of 14 minutes are as follows.
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)[C:3]#[C:4][C:5]([O:7][CH3:8])=[O:6]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:15][C:12]1[CH:11]=[CH:10][C:9]([C:2]([C:3]#[C:4][C:5]([O:7][CH3:8])=[O:6])=[O:1])=[CH:14][CH:13]=1
Reactant: COC(=O)C#CC(O)c1ccc(C)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COC(=O)C#CC(=O)c1ccc(C)cc1
Reaction time: 0.5 h

Procedure:
A solution of 8.1 g (39.7 mmol) of methyl 4-hydroxy-4-(4-methylphenyl)-2-butynoate in 100 ml of methylene chloride was added dropwise at 0° to a suspension of 97 g (1.1 mol) of manganese dioxide in 200 ml of methylene chloride. The reaction mixture was stirred at 0° for 30 minutes, filtered over magnesium sulphate and concentrated. Crystallization of the residue from ether/hexane yielded methyl 3-(4-methylbenzoyl)propiolate of melting point 55°-56°.
Reaction SMILES: [S:1]([C:8]1[CH:14]=[CH:13][C:11]([CH3:12])=[CH:10][CH:9]=1)([O:4]CCC)(=[O:3])=[O:2]>CN(C)C=O>[CH3:12][C:11]1[CH:13]=[CH:14][C:8]([S:1]([OH:4])(=[O:3])=[O:2])=[CH:9][CH:10]=1
Reactant: CCCOS(=O)(=O)c1ccc(C)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 65 °C

Procedure:
A 12 L, three necked flask was equipped with an overhead stirrer, a temperature probe, a heating mantle, a claisen joint, a condenser, and a 500 ml addition funnel. The flask was charged with 250 grams of R(+)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole (R(+) diamine), followed by 2 L of dimethyl formamide (DMF). Under continuous stirring, the mixture was heated to a temperature of 65° C. The addition funnel was charged with a solution of 386.6 grams propyl tosylate (1.25 molar equivalents) and 322 ml diisopropylethyleamine (1.25 molar equivalents) in 500 ml DMF. This solution was added to the 12 L flask dropwise over a period of 2.0 hours. The reaction was monitored by analysis on HPLC.