Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:10]=[C:11]=[O:12])[CH2:8][CH3:9].[CH3:13][C:14]1[NH:18][N:17]=[C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=2[C:29]([F:32])([F:31])[F:30])[CH:15]=1.Cl>C(OCC)(=O)C>[CH2:7]([NH:10][C:11]([N:18]1[C:14]([CH3:13])=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=2[C:29]([F:30])([F:31])[F:32])=[N:17]1)=[O:12])[CH2:8][CH3:9]
Reactant: Cc1cc(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)n[nH]1
Reactant: CCCN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCCNC(=O)n1nc(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
Potassium carbonate (0.61 g, 4.4 mmol) and propyl isocyanate (0.34 g, 4.0 mmol) were added to a solution of 5-methyl-3-(4-nitro-2-trifluoromethylphenyloxy)pyrazole (1.15 g, 4.0 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered co remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/5), to give a yellow viscous substance of N-propyl-5-methyl-3-(4-nitro-2-trifluoromethylphenyloxy)pyrazole-1-carboxamide (1.08 g, yield: 72.5%). 1H-NMR (CDCl3, TMS, ppm): δ 0.97 (t, J=7.4 Hz, 3H), 1.62 (tq, J=7.4 and 7.4 Hz, 2H), 2.64 (d, J=0.7 Hz, 3H), 3.25-3.40 (m, 2H), 5.88 (q, J=0.7 Hz, 1H), 6.80-7.05 (m, 1H), 7.42 (d, J=9.2 Hz, 1H), 8.40 (dd, J=2.7 and 9.2 Hz, 1H), 8.59 (d, J=2.7 Hz, 1H).
Reaction SMILES: [CH2:1]([C:4]1[NH:12][C:7]2=[N:8][CH:9]=[CH:10][N:11]=[C:6]2[N:5]=1)[CH2:2][CH3:3].Br[CH2:14][C:15]1[CH:34]=[CH:33][C:18]2/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=3[O:22][CH2:23][C:17]=2[CH:16]=1>>[F:28][C:25]1[CH:26]=[CH:27][C:20]2=[C:21]([CH:24]=1)[O:22][CH2:23][C:17]1[CH:16]=[C:15]([CH2:14][N:12]3[C:7]4=[N:8][CH:9]=[CH:10][N:11]=[C:6]4[N:5]=[C:4]3[CH2:1][CH2:2][CH3:3])[CH:34]=[CH:33][C:18]=1/[C:19]/2=[C:29](/[CH3:32])\[C:30]#[N:31]
Reactant: CCCc1nc2nccnc2[nH]1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: CCCc1nc2nccnc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 73.7 %

Procedure:
[step 2] Using 2-propyl-1H-imidazo[4,5-b]pyrazine (68 mg, 0.42 mmol) obtained in step 1 and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (153 mg, 0.43 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (136 mg, 74%) was obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:49]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([NH2:63])[CH:58]=1)#[N:50]>CN(C=O)C>[C:49]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([NH:63][C:22]([C:17]2[C:18](=[O:21])[O:19][C:20]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[OH:10])=[O:24])[CH:58]=1)#[N:50]
Reactant: N#Cc1ccccc1-c1cccc(N)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-c1cccc(NC(=O)c2cc3cccc(O)c3oc2=O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 27.2 %

Procedure:
DIEA (0.015 mL, 0.085 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.016 g, 0.077 mmol) and HATU (0.032 g, 0.085 mmol) in 0.45 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′-cyano-biphenyl-3-ylamine (0.015 g, 0.077 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and lyophilized for 48 hours to give 0.008 g of product in 26% yield: LCMS (ESI) m/z 383 (MO.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:34](=[O:37])[CH2:35][CH3:36])[C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:19]=[CH:20][C:21]([OH:23])=[O:22])[CH:17]=3)[N:12]([C:24](=[O:32])[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C@@H:11]([CH3:33])[CH2:10]2)=[CH:4][CH:3]=1.Br[C:39]1C=C2C(=CC=1)N(C(=O)C1C=CC(F)=CC=1)[C@@H](C)C[C@H]2N(C1C=CC(Cl)=CC=1)C(=O)CC.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC)(=O)C=C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:39][O:22][C:21](=[O:23])[CH:20]=[CH:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:24](=[O:32])[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)[C@@H:11]([CH3:33])[CH2:10][C@H:9]2[N:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:34](=[O:37])[CH2:35][CH3:36]
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(C=CC(=O)O)cc21
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(Br)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C=CC(=O)OC
Solvent: CN(C)C=O
Product: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(C=CC(=O)OC)cc21
Temperature: 80 °C
Yield: 44 %

Procedure:
(±)-Cis-3-[4-[(4-chloro-phenyl)-propionyl-amino]-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-6-yl]-acrylic acid was made from (±)-cis-N-[6-bromo-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-(4-chloro-phenyl)-propionamide. To a solution of (±)-cis-N-[6-bromo-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-(4-chloro-phenyl)-propionamide (250 mg, 0.47 mmol), TEA (0.2 ml, 1.4 mmol), palladium acetate (11 mg, 0.047 mmol), 1,3-Bis(diphenylphosphino)propane (39 mg, 0.094 mmol), in 10 ml DMF was added 0.13 ml methyl acrylate (1.41 mmol). The resulting reaction mixture was heated to 80° C. overnight. The mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with ethyl acetate-hexane (2:3) to give (±)-cis-3-[4-[(4-chloro-phenyl)-propionyl-amino]-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-6-yl]-acrylic acid methyl ester (110 mg, 44%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9]([OH:10])=[C:8]([C:11]([O:13]CC)=[O:12])[CH:7]=[N:6][N:5]2[CH:16]=1.[OH-].[Na+]>CO.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9]([OH:10])=[C:8]([C:11]([OH:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:16]=1
Reactant: CCOC(=O)c1cnn2cc(F)cc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnn2cc(F)cc2c1O
Temperature: 65 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
To a solution of ethyl 6-fluoro-4-hydroxypyrrolo[1,2-b]pyridazine-3-carboxylate (700 mg, 3.12 mmol) in methanol (3 mL) and THF (3 mL) was added 3 N aq. sodium hydroxide (5.20 mL, 15.61 mmol) and the resulting mixture was stirred at 65° C. for 3 h. The mixture was cooled and concentrated to remove the methanol and THF and the obtained residue was cooled in an ice bath and 3N aq. HCl was added dropwise with stirring until pH of the mixture was ˜2. The resulting slurry was stirred for 30 min, and filtered to collect the solid. The solid was rinsed with water and dried to afford 550 mg (90%) of the title compound as a white solid. HPLC (condition B): retention time=2.37 min. LCMS (condition B): m/z 197+ve.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][S:7](=[O:17])(=[O:16])[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[H-].[Na+].[CH2:20]1[O:30][C:29]2[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][C:22]=2[O:21]1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:24]2[CH:27]=[CH:28][C:29]3[O:30][CH2:20][O:21][C:22]=3[CH:23]=2)[S:7](=[O:17])(=[O:16])[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4]
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1Cc1ccc2c(c1)OCO2
Reaction time: 0.08 h
Yield: 71.7 %

Procedure:
To 4-hydroxy-1,1-dioxo-1,2-dihydro-1λ6 -benzo[e][1,2]thiazine-3-carboxylic acid methyl ester (1.48 g, 5.84 mmol) in DMF (10 mL) was added sodium hydride (0.257 g, 60%, 6.4 mmol) and the mixture stirred for 5 minutes. 3,4-methylenedioxybenzyl chloride (2.2 g, 50 wt. % in dichloromethane, 6.4 mmol) was added and the mixture stirred at room temperature for 18 hours. Diluted with ethyl acetate (100 mL), washed with water (2×80 mL), brine (80 mL), dried over magnesium sulfate, removed solvent in vacuo, and crystallized from ethyl acetate/heptane to give the title compound (1.63 g, 72%);
Reaction SMILES: C(OP(OCC)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:8]=1)=O)C.[H-].[Na+].[H][H].[CH3:25][C:26]([C:28]1[CH:29]=[CH:30][C:31]2[S:37][CH2:36][C:35]([CH3:39])([CH3:38])[CH2:34][CH2:33][C:32]=2[CH:40]=1)=O>CN(C)C=O>[CH3:38][C:35]1([CH3:39])[CH2:34][CH2:33][C:32]2[CH:40]=[C:28](/[C:26](/[CH3:25])=[CH:6]/[C:7]3[CH:8]=[CH:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:12]=3)[CH:29]=[CH:30][C:31]=2[S:37][CH2:36]1
Reactant: [H][H]
Reactant: CC(=O)c1ccc2c(c1)CCC(C)(C)CS2
Reactant: CCOC(=O)c1ccc(CP(=O)(OCC)OCC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)CCC(C)(C)CS3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.85 g of ethyl α-(diethoxyphosphinyl)-p-toluate were slowly added dropwise to 1.3 g of sodium hydride (50% in mineral oil) in 28 ml of dimethylformamide. The reaction mixture was stirred at room temperature until the evolution of hydrogen had finished. Thereafter, 4.2 g of 2,3,4,5-tetrahydro-3,3-dimethyl-benzothiepin-7-yl methyl ketone were added and the reaction mixture was stirred at room temperature for 2 hours. Thereafter, the mixture was poured on to ice/sodium chloride, extracted with ether, the ethereal solution was washed with water and dried and evaporated. Chromatography on silica gel (petroleum ether/ethyl acetate (95:5)) and recrystallization from hexane yielded ethyl p-[(E)-2-(2,3,4,5-tetrahydro-3,3-dimethyl-1-benzothiepin-7-yl)propenyl]benzoate of melting point 96°-97° C.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][CH:5]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=2[S:28]([CH3:31])(=[O:30])=[O:29])[C:4]=1[C:32](OCC)=[O:33].[C:37]1([NH:43][NH2:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCOCC1>[O:19]=[C:7]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=2)[C:3]2[CH2:2][N:43]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[NH:44][C:32](=[O:33])[C:4]=2[CH:5]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=2[S:28]([CH3:31])(=[O:29])=[O:30])[NH:6]1
Reactant: CCOC(=O)C1=C(CBr)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1S(C)(=O)=O
Reactant: NNc1ccccc1
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)NN(c1ccccc1)C2

Procedure:
Ethyl 6-(bromomethyl)-4-[4-cyano-2-(methylsulphonyl)phenyl]-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (150 mg, 0.256 mmol; Example 19A) was initially charged in dioxane (3.5 ml). Phenylhydrazine (83.0 mg, 0.767 mmol) was added dropwise to the reaction mixture, and the mixture was then stirred at boiling point for 3 h. The reaction mixture was then separated directly by preparative HPLC (Method 12). This gave 9 mg (6% of theory) of the target compound.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si]([O:19][CH:20]1[CH2:29][C:28]2[C:27]([NH2:30])=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21]1)(C(C)(C)C)(C)C.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:30][C:27]1[C:28]2[CH2:29][CH:20]([OH:19])[CH2:21][CH2:22][C:23]=2[CH:24]=[CH:25][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC1CCc2cccc(N)c2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cccc2c1CC(O)CC2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
Benzylchloroformate (6.96 g, 40.8 mmol) was added dropwise to a solution of Example 18B (10.3 g, 37.1 mmol,) and diisopropylethylamine (7.20 g, 55.7 mmol) in 120 mL CH2Cl2 at 0° C. The mixture was stirred for 18 hours gradually warming to ambient temperature after which the volatiles were evaporated under reduced pressure. The residue was purified on silica gel eluting with 25% EtOAc/hexanes which yielded the benzyl carbamate as a light brown oil (15.2 g, 36.9 mmol). This product was taken up in 100 mL THF followed by addition of 1.79 g (111 mmol) of triethylamine trihydrofluoride. After 24 hours, the mixture was concentrated under reduced pressure and the residue partitioned between EtOAc and 1N aq. HCl. The separated organic layer was washed with 1N aq. HCl, brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was triturated with Et2O, and the solid was collected by vacuum filtration and dried under vacuum at 50° C. resulting 8.82 g (80%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 8.82 (s, 1H), 7.45-7.30 (m, 5H), 7.14 (d, J=7.0 Hz, 1H), 7.05 (t, J=7.0 Hz, 1H), 6.90 (d, J=7.0 Hz, 1H), 5.12 (s, 2H), 4.77 (d, J=3.7 Hz, 1H), 3.87 (m, 1H), 2.86 (m, 2H), 2.72 (m, 1H), 2.43 (m, 1H), 1.84 (m, 1H), 1.58 (m, 1H); MS (ESI+) m/z 298 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].CO.[CH:14]1[CH2:18][CH:17]=[CH:16][CH:15]=1.C1COCC1>CC(CC(C)=O)C>[CH2:16]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11])[CH:15]=[CH:14][CH2:18][CH3:17]
Reactant: C1=CCC=C1
Reactant: Oc1ccc2ccccc2c1
Solvent: CC(=O)CC(C)C
Solvent: CO
Solvent: C1CCOC1
Product: CCC=CCc1c(O)ccc2ccccc12
Temperature: 25 °C

Procedure:
Into a 2-liter flask having a stirrer, a condenser and a thermometer, 144 g of 2-naphthol, 200 g of methanol and 40 g of PTS were introduced, and a solution of mixture of 66 g of cyclopentadiene and 60 g of methanol was added dropwise over a period of 3 hours while stirring the mixture at room temperature, followed by further stirring for 4 hours at room temperature. To the reaction solution thus obtained, THF and MIBK were added, and the resultant solution was washed with 200 ml of an aqueous 10% sodium hydroxide solution five times, and thereafter further washed with water until it turned neutral, followed by removal of the solvent using an evaporator. The results of analysis by GPC thereof are shown in FIG. 11. Its yield determined by GPC was 90% (area ratio). An NMR spectrum of the 1-(2-penten-1-yl)-2-naphthol obtained is shown in FIG. 12.
Reaction SMILES: Cl[C:2]1[C:3]2[S:23](=[O:24])[CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[NH2:25][C@H:26]([CH:29]([CH3:31])[CH3:30])[CH2:27][OH:28].C(N(C(C)C)CC)(C)C.O>O1CCOCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[N:7]=[C:2]([NH:25][C@H:26]([CH:29]([CH3:31])[CH3:30])[CH2:27][OH:28])[C:3]4[S:23](=[O:24])[CH2:22][CH2:21][C:4]=4[N:5]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: CC(C)[C@@H](N)CO
Reactant: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(Cl)c21
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](CO)Nc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1S(=O)CC2
Temperature: 120 °C

Procedure:
220 mg 4-chloro-2-[4-(4-chloro-phenyl)-piperazin-1-yl]-6,7-dihydro-thieno[3,2-d]pyrimidine 5-oxide (cf Example 124), 118.43 mg (R)-(−)-2-amino-3-methyl-butan-1-ol and 197.52 μl diisopropylethylamine are placed in 4 ml dioxane, and the mixture is heated to 120° C. in the microwave for 0.3 hours. Then the reaction mixture is mixed with water, the precipitate formed is suction filtered, washed and dried. The diastereomers are separated by preparative HPLC (method B). 25.5 mg of Diastereomer 1 (Example 54) and 40.5 mg of Diastereomer 2 (Example 57) are obtained as a powder. Analytical HPLC (method A): Diastereomer I: RT=3.61 min; Diastereomer 2, RT=3.71 min.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:31]CCl>C(O)C.CC(C)=O>[ClH:31].[CH2:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOc2ccccc2Cc2ccccc2)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCOc2ccccc2Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The above ester (1.7 g, 4.6 mmol) was dissolved in ethanol (10 ml) and 4N sodium hydroxide (3.5 ml) was added. The mixture was stirred at ambient temperature for 5 h. Excess concentrated hydrochloric acid was added followed by dichloromethane (300 ml). The phases were separated and the organic phase was dried (Na2SO4). The solvent was evaporated in vacuo to give a foamy residue which was dissolved in acetone (15 ml). The solid which formed was isolated by filtration and dried to give 1.3 g of the title compound as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[Br:12]Br.[CH2:14]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O1CCOCC1>[CH3:10][CH:9]([N:24]1[CH2:25][CH2:26][CH:21]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:22][CH2:23]1)[CH:8]([OH:11])[C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1.[BrH:12]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(O)cc1
Reactant: c1ccc(Cc2ccncc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: Br
Product: CC(C(O)c1ccc(O)cc1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 75 %

Procedure:
To 4 ml of dioxane were added 6.0 g of 4'-hydroxypropiophenone. 6.4 Grams of bromine were added dropwise to the mixture with stirring at room temperature, and the reaction liquid was stirred for an additional 5 minutes. To the reaction liquid were then added 7.5 g of 4-benzylpyridine, 100 ml of methanol and 2.0 g of potassium carbonate, and the mixture was refluxed under heating for 5 hours. The reaction mixture was then treated in the same manner as described in Example 26, whereby 12.2 g (75.0%) of ifenprodil hydrobromide were obtained as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[OH:14].C(N(CC)CC)C.Cl[CH2:23][C:24](Cl)=[O:25].[H-].[Na+]>C1COCC1>[C:8]1([C:6]2[CH:5]=[CH:4][C:3]3[O:14][CH2:23][C:24](=[O:25])[NH:1][C:2]=3[CH:7]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1cc(-c2ccccc2)ccc1O
Reactant: O=C(Cl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1COc2ccc(-c3ccccc3)cc2N1
Yield: 98.7 %

Procedure:
Using 2-amino-4-phenylphenol (1 g, 5.4 mmol), triethylamine (0.97 mL, 7.0 mmol) and chloroacetyl chloride (0.72 g, 5.9 mmol) in THF (35 mL) followed by sodium hydride (0.27 g of a 60% suspension in oil, 6 mmol) to yield the title compound as a pale yellow solid (1.2 g, 91%). δH (DMSO-d6) 4.62 (2H, s), 7.29-7.56 (8H, m), 10.81 (1H, s).
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[C:17]([CH2:19][C:20]1[C:28]2[C:27](=[O:29])[NH:26][C:25]([C:30]([O:32]CC)=O)=[N:24][C:23]=2[S:22][CH:21]=1)#[N:18].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:78]2[CH:82]=[N:81][C:80]([O:83][CH2:84][CH2:85][O:86][C:87]3[CH:88]=[C:89]([CH2:93][NH2:94])[CH:90]=[CH:91][CH:92]=3)=[N:79]2)C=CC=CC=1>>[C:17]([CH2:19][C:20]1[C:28]2[C:27](=[O:29])[NH:26][C:25]([C:30]([NH:94][CH2:93][C:89]3[CH:90]=[CH:91][CH:92]=[C:87]([O:86][CH2:85][CH2:84][O:83][C:80]4[N:81]=[CH:82][NH:78][N:79]=4)[CH:88]=3)=[O:32])=[N:24][C:23]=2[S:22][CH:21]=1)#[N:18]
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Reactant: CCOC(=O)c1nc2scc(CC#N)c2c(=O)[nH]1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: N#CCc1csc2nc(C(=O)NCc3cccc(OCCOc4nc[nH]n4)c3)[nH]c(=O)c12

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 5-cyanomethyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 61 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (85.4 mg, 38%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([C:23](=[O:25])[CH3:24])[CH:10]=[CH:11][C:12]=2[CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]([CH3:22])([CH3:21])[CH2:14]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:26](=O)[CH2:27][CH3:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)C.O1CCCC1>[CH2:26]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[C:9]([C:23](=[O:25])[CH3:24])[CH:10]=[CH:11][C:12]=2[CH:13]2[CH2:14][C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:19])([CH3:20])[CH2:18]2)[CH2:2][CH2:3]1)[CH2:27][CH3:28]
Reactant: CCC=O
Reactant: CC(=O)c1ccc(C2CC(C)(C)CC(C)(C)C2)c(N2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCN1CCN(c2cc(C(C)=O)ccc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-[3-piperazin-1-yl-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]ethanone (19 mg, 0.0555 mmol) produced in Example (82b), propionaldehyde (0.0119 mL, 0.166 mmol) and tetrahydrofuran (0.3 mL) was added sodium triacetoxyborohydride (35 mg, 0.166 mmol), followed by stirring for 1 hour at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with diethyl ether. The solvent was distilled off by nitrogen stream to the separated organic layer. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-[3-(4-propylpiperazin-1-yl)-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]ethanone.