Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=4[F:32])=[C:20]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:19]=3)[CH:11]=2)[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=4[F:32])=[C:20]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:19]=3)[CH:11]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: COC(=O)CC(c1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(COc3cccc(C(CC(=O)O)C4CC4)c3)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 3-cyclopropyl-3-(3-((5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)methoxy)phenyl)propanoate (90 mg) in THF (2.0 mL) and methanol (1.0 mL) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at room temperature for 4 hr. 1N Hydrochloric acid (2.0 mL) was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:4]=1)#[N:2].[CH3:37][Si](C)(C)[N-][Si](C)(C)C.[Li+].IC>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=3)[C:11](=[O:32])[N:10]2[CH3:37])=[C:5]([S:33]([CH3:36])(=[O:34])=[O:35])[CH:4]=1)#[N:2]
Reactant: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N[C@@H]1c1ccc(C#N)cc1S(C)(=O)=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)[C@@H]1c1ccc(C#N)cc1S(C)(=O)=O
Reaction time: 0.33 h
Yield: 59 %

Procedure:
The reaction was carried out under argon. Allyl (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (260 mg, 0.5 mmol) was initially charged in THF (10 ml) at −78° C., and a 1 M solution of lithium hexamethyldisilazide (LiHMDS) in THF (0.6 ml; 1.2 eq.) was added. After 20 min of stirring, iodomethane (355 mg; 5 eq.) was added, and the mixture was stirred with gradual warming from −78° C. to RT for 16 h. The reaction mixture was then concentrated, and the residue was subjected to flash chromatography on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 55:45). This gave the title compound as a solid (157 mg, 59% of theory).
Reaction SMILES: C([O:4][C:5]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)[CH:17]=[CH:16][C:6]=1[C:7]([N:9]([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])=[O:8])(=O)C.[OH-:35].[Na+].Cl.[NH2:38]O>O.C(O)C>[NH2:38][C:33](=[N:34][OH:35])[C:30]1[CH:31]=[CH:32][C:27]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:20][C:18]2[CH:17]=[CH:16][C:6]([C:7]([N:9]([CH:10]([CH3:11])[CH3:12])[CH:13]([CH3:15])[CH3:14])=[O:8])=[C:5]([OH:4])[CH:19]=2)=[CH:28][CH:29]=1
Reactant: [OH-]
Reactant: CC(=O)Oc1cc(OCCCCCOc2ccc(C#N)cc2)ccc1C(=O)N(C(C)C)C(C)C
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C(N)=NO)cc2)cc1O)C(C)C

Procedure:
A stirred solution of 2-acetoxy-4-[5-(4-cyanophenoxy)pentyloxy]-N,N-bis(1-methylethyl)benzamide (20 g, 42.9 mmol) in 20 mL of water and 350 mL of ethanol is treated with sodium hydroxide (3.43 g, 85.8 mmol) and hydroxylamine hydrochloride (5.97 g, 85.9 mmol). After refluxing overnight, the reaction is concentrated in vacuo. The resulting material is purified by chromatography on silica gel (500 g) with 65-100% ethyl acetate/hexane followed by 30% methanol/ethyl acetate as the eluent. After concentration in vacuo, the residue is recrystallized with methanol, ethyl acetate, and hexane to afford 4-[5-[4-[amino(hydroxyimino)methyl]phenoxy]pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamide as colorless crystals, mp=195°-197° C.;
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:9][CH:10]=1)=O.[NH3:24]>CO>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:8]2[CH:7]=[N:6][C:5]([C:3](=[O:2])[NH2:24])=[CH:10][N:9]=2)[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: N
Reactant: COC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)cn1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2cnc(C(N)=O)cn2)CC1
Temperature: 60 °C

Procedure:
3 mmol of 2,3,5,6-Tetrahydro-[1,2′]bipyrazinyl-4,5′-dicarboxylic acid 4-tert-butyl ester 5′-methyl ester (example 1.13 (a)) was dissolved in a 7 molar solution of gaseous ammonia in methanol. The reaction vessel was tightly closed and heated overnight at 60° C. Cooling of the reaction mixtures led to crystallisation of the title compound. MS (m/e): 308.4 (MH+, 100%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:25])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:6]=2[CH:24]=1.[ClH:26]>ClCCl.C(OCC)C.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[C:3]([F:25])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[C:6]=2[CH:24]=1.[ClH:26]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(F)c(Cl)cc32)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: ClCCl
Product: O=c1[nH]c2cc(F)c(Cl)cc2n1C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl 4-(6-chloro-5-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinecarboxylate (D4) (0.460 mmol, 170 mg) was dissolved in dichloromethane-diethyl ether, and HCl (5 ml of a 4M solution in 1,4-dioxane) was added at room temperature; the mixture was shaken at room temperature overnight. Solvent was evaporated to afford the title compound, mono hydrochloride salt, complete conversion, M++H=270.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][CH:5]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=1B(O)O>C1C=CC=CC=1.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.C(O)C>[NH2:1][C:2]1[C:7]([C:21]2[CH:22]=[C:23]([Cl:27])[CH:24]=[C:25]([Cl:26])[C:20]=2[Cl:19])=[N:6][CH:5]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[N:3]=1
Reactant: CC(=O)Nc1cnc(Br)c(N)n1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1Cl
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: CCO
Solvent: c1ccccc1
Product: CC(=O)Nc1cnc(-c2cc(Cl)cc(Cl)c2Cl)c(N)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-amino-3-bromo-6-acetamidopyrazine (7.00 g, 0.03 mole) in benzene (60.90 ml) and tetrakis(triphenylphosphine)palladium(0) was stirred under nitrogen at room temperature for 10 minutes. 2M aqueous sodium carbonate (30.24 ml) was added to the mixture followed by a solution of 2,3,5-trichlorobenzene boronic acid (6.83 g, 0.03 mole) in absolute ethanol (7.07 ml) and the mixture refluxed under nitrogen for 17 hrs. A further equivalent of 2,3,5-trichlorobenzene boronic acid in absolute ethanol was then added and the mixture refluxed for an additional 7.50 hrs. Finally, another equivalent of 2,3,5-trichlorobenzene boronic acid in absolute ethanol was added to the mixture and continued refluxing for 17 hrs. The cooled mixture was evaporated in vacuo. The residue was dissolved in chloroform (150 ml), washed with aqueous saturated sodium bicarbonate (1×100 ml) and water (1×100 ml), dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated down in vacuo. The residue was purified by ‘flash chromatography’ using chloroform to 98:2 chloroform:methanol as the eluent. Yield 3.02 g (30%), M.p. 200-203° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[CH2:9]([N:16]1[CH2:21][CH2:20][C:19]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)([C:22]#N)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O:33]CC)C>C1(C)C=CC=CC=1>[CH2:9]([N:16]1[CH2:21][CH2:20][C:19]([C:22]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=2)=[O:33])([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CCOCC
Reactant: N#CC1(c2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Product: O=C(c1ccc(F)cc1)C1(c2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under argon 11.86 g magnesium chips are placed in 50 ml anhydrous diethyl ether, then a solution of 85.4 g 4-bromofluorobenzene in 200 ml anhydrous diethyl ether is slowly added dropwise. The reaction mixture is stirred for 2 h at reflux temperature and then cooled to ambient temperature. A solution of 45.4 g 1-benzyl-4-(4-fluoro-phenyl)-piperidine-4-carbonitrile in 100 ml anhydrous toluene is added dropwise. The diethyl ether is distilled off and the remainder of the reaction mixture is stirred overnight at 80° C. After cooling the reaction mixture is combined with 500 ml ice water and 100 g NH4Cl and the product is extracted with ethyl acetate. The organic phase is washed with water and sat. NaCl solution, dried and evaporated to dryness. 70 ml glacial acetic acid and 20 ml sulphuric acid 33% are added to the residue. The reaction mixture is heated to 100° C., then cooled, combined with ice water and adjusted to pH ˜9 with 4N NaOH. Then 250 ml diisopropylether are added. The reaction mixture is then stirred overnight at ambient temperature. The precipitate formed is suction filtered, washed with diisopropylether and water and dried. 42.7 g product are obtained as a solid. M.p: 136-138.5° C.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[C:11]1([C@@H:17]2[CH2:19][C@H:18]2[NH2:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>CC#N>[C:11]1([C@@H:17]2[CH2:19][C@H:18]2[NH:20][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)CBr
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
N,N-Diisopropylethylamine (3 mL, 17.16 mmol) was added to a solution of (trans)-2-phenylcyclopropanamine hydrochloride (1.5 g, 8.58 mmol) in 70 mL of CH3CN. After complete dissolution of the amine the methyl 2-bromoacetate (930 μL, 9.44 mmol) was added and then stirred overnight at room temperature. After solvent removal the crude was purified by flash chromatography eluting with CH2Cl2/MeOH (99:1 to 90:10) to get methyl 2-((trans)-2-phenylcyclopropylamino)acetate as colourless oil (1.76 g, Yield=100%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]([O:11][CH3:12])=[O:10].Cl.[NH2:15][OH:16].O.Cl>CO>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:15][OH:16])[C:9]([O:11][CH3:12])=[O:10]
Reactant: NO
Reactant: COC(=O)C(=O)c1ccccc1O
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)C(=NO)c1ccccc1O

Procedure:
3.3 g (0.016 mol) of methyl 2-hydroxyphenylglyoxylate (HPLC: 88%, log p=1.87) (Example VI-1a) and 1.3 g (0.019 mol) of hydroxylamine hydrochloride in 50 ml of methanol are heated under reflux for one hour. The reaction mixture is poured into water, acidified with 2N hydrochloric acid and extracted with diethyl ether, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. This gives 2.4 g of crude product which, according to HPLC, contains 17.1% of methyl E-2-(2-hydroxyphenyl)-2-hydroxyimino-acetate of log p=0.95 and 68.9% of methyl Z-2-(2-hydroxyphenyl)-2-hydroxyimino-acetate of log p=1.68.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([N:15]1[CH2:16][CH2:17][CH2:18][N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:20])[CH:12]=2)[C:14]1=[O:19])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: Cc1noc(C)c1Cn1cc(N2CCCNC2=O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1cc(N2CCCN(Cc3ccccc3)C2=O)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 30.4 %

Procedure:
1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)tetrahydropyrimidin-2(1H)-one (example 9-5a) (50 mg, 0.18 mmol) and 60% sodium hydride (8 mg, 0.20 mmol) in DMF (3 mL) were stirred at room temperature for 15 minutes then cooled to 0° C. Benzyl bromide (31 mg, 0.18 mmol) was added to the mixture and allowed to warm up at room temperature then stirred for 2 hours. The reaction was quenched with methanol and concentrated. The reaction was diluted with brine (50 mL) and extracted with dichloromethane (2×, 50 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated on the rotovap. The residue was taken up in dichloromethane (5 mL) and purified by silica column chromotography (100% to 90% dichloromethane in methanol: 30 minute gradient) to afford 1-benzyl-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)tetrahydropyrimidin-2(1H)-one (20 mg, 30%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ1.85-1.91 (m, 2H), 2.10 (s, 3H), 2.37 (s, 3H), 3.12 (m, 2H), 3.55 (t, J=5.8 Hz, 2H), 4.48 (s, 2H), 5.05 (s, 2H), 7.22-7.31 (m, 5H), 7.49 (s, 1H), 7.84 (s, 1H). LC/MS; [M+H] calculated for C20H23N5O2; expected 366.19; found 366.15. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 1.65 μM.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CCN(C(C)C)C(C)C.Cl[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1COCC1>[C:4]([C:3]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=1[NH:1][C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:5])[NH2:6]
Reactant: NC(=O)c1ccc(Cl)cc1N
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)Nc1cc(Cl)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
To a solution of 2-amino-4-chlorobenzamide (393 mg, 2.30 mmol) and DIEA (0.60 mL, 3.45 mmol) in THF (15 mL) at 0° C. was added ethyl chlorooxoacetate (0.28 mL, 2.53 mmol). The solution was allowed to warm to rt and stir for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 10-50% EtOAc/hexanes to afford ethyl 2-(2-carbamoyl-5-chlorophenylamino)-2-oxoacetate as a solid (545 mg, 88%). 1H NMR (300 MHz, DMSO-d6) δ 1.32 (t, J=6.97 Hz, 3H), 4.31 (q, J=6.97 Hz, 2H), 7.34 (d, J=8.48 Hz, 1H), 7.86-8.03 (m, 2H), 8.44 (br s, 1H), 8.62 (s, 1H), 13.24 (s, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[C:16]3[S:21][CH2:20][CH2:19][CH2:18][S:17]3)[CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[OH2:24]>O1CCCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14](=[C:16]3[S:17][CH2:18][CH2:19][CH2:20][S:21]3=[O:24])[CH3:15])=[CH:12][CH:13]=2)=[CH:22][CH:23]=1
Reactant: COc1ccc(Oc2ccc(C(C)=C3SCCCS3)cc2)cc1
Reactant: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Oc2ccc(C(C)=C3SCCCS3=O)cc2)cc1
Yield: 16.2 %

Procedure:
2-[1-{4-(4-Methoxyphenoxy)phenyl}ethan-1-ylidene]-1,3-dithiane, 5 g, was dissolved in a solvent mixture of 100 ml of tetrahydrofuran and 50 ml of methanol and, 15 g of an aqueous solution containing 2.45 g of oxon was dropwise added to the solution under ice cooling. After stirring for an hour at the same temperature, water was added to the reaction mixture followed by extraction with chloroform. The organic phase was washed with a sodium thiosulfate aqueous solution and then with water. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methylene chloride) to give 0.85 g of white crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][Si](C(C)(C)C)(C)C)=[C:11]([F:23])[CH:10]=2)=[C:4]([F:24])[CH:3]=1.[CH3:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][Si:32]1(C2C=CC=CC=2)[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1.Br[CH2:46][CH:47]([F:49])[F:48]>>[CH3:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][Si@H:32]1[CH2:33][CH2:34][C@H:35]([C:2]2[CH:3]=[C:4]([F:24])[C:5]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:46][CH:47]([F:49])[F:48])=[C:11]([F:23])[CH:10]=3)=[C:6]([F:8])[CH:7]=2)[CH2:36][CH2:37]1
Reactant: COCCCCC[Si]1(c2ccccc2)CCC(=O)CC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2c(F)cc(Br)cc2F)cc1F
Reactant: FC(F)CBr
Product: COCCCCC[Si@H]1CC[C@H](c2cc(F)c(-c3ccc(OCC(F)F)c(F)c3)c(F)c2)CC1

Procedure:
The general procedure of Example 17 was repeated using 4'-bromo-2', 6'-difluoro-3-fluoro-4-(t-butyldimethylsiloxy)biphenyl, 4-(5-methoxy-n-pentyl)-4-phenyl-4-silacyclohexanone, and 1-bromo-2 ,2-difluoroethane, thereby obtaining the intended compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35])[O:12][CH2:13][C:14](=[O:27])[N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[C:40]([O:48][C:49]([F:52])([F:51])[F:50])[CH:39]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:44]([C:41]1[CH:42]=[CH:43][C:38]([O:37][CH3:36])=[CH:39][C:40]=1[O:48][C:49]([F:50])([F:51])[F:52])(=[O:46])=[O:45])[C:6](=[O:11])[C:5]2([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35])[O:12][CH2:13][C:14](=[O:27])[N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1
Reactant: COc1ccccc1C1(OCC(=O)N2CCN(c3ccccn3)CC2)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(OCC(=O)N3CCN(c4ccccn4)CC3)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Product: Cl

Procedure:
With 300 mg of the compound obtained in Step 54-1 and 201 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 370 mg of free form of the title compound (yellow amorphous) was obtained by a similar method to Example 2. In a similar procedure to Example 43, by subjecting 335 mg of the obtained free form to salt formation and solidification, 314 mg of the title compound (colorless amorphous) was obtained.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][CH:26]=3)[CH2:33][CH2:32]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(Cl)cc1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(c3ccc(Cl)cc3)CC2)cc1-c1ccc(Cl)cc1

Procedure:
111 mg (80%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propanal (80 mg, 0.275 mmol), 1-(4-chlorophenyl)piperazine (74 mg, 0.275 mmol), DIPEA (0.072 mL, 0.413 mmol) and NaBH(OAc)3 (175 mg, 0.825 mmol).
Reaction SMILES: [N:1]1([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:8])[CH2:2]1.[F:21][C:22]([F:47])([F:46])[C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[C:28]([C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=1)[CH:27]=[C:26]2[C:43](O)=[O:44].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[N:9]1([C:7]([C@@H:3]2[CH2:4][CH2:5][CH2:6][N:1]([CH:15]3[CH2:20][CH2:19][N:18]([C:43]([C:26]4[C:25]5[C:30](=[CH:31][CH:32]=[C:23]([C:22]([F:21])([F:46])[F:47])[CH:24]=5)[N:29]=[C:28]([C:33]5[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:35][CH:34]=5)[CH:27]=4)=[O:44])[CH2:17][CH2:16]3)[CH2:2]2)=[O:8])[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1
Reactant: O=C([C@@H]1CCCN(C2CCNCC2)C1)N1CCOCC1
Reactant: O=C(O)c1cc(-c2ccc(C(F)(F)F)cc2)nc2ccc(C(F)(F)F)cc12
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(c1cc(-c2ccc(C(F)(F)F)cc2)nc2ccc(C(F)(F)F)cc12)N1CCC(N2CCC[C@@H](C(=O)N3CCOCC3)C2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.6 %

Procedure:
To a solution of (3R)-[1,4′]bipiperidinyl-3-yl-morpholin-4-yl-methanone (0.314 mmol, 100 mg) and 6-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-quinoline-4-carboxylic acid (0.346 mmol, 133 mg) in anhydrous dichloromethane was added 1-hydroxybenzotriazole hydrate (0.157 mmol, 21 mg) followed by diisopropylethylamine (0.942 mmol, 0.163 mL) then benzotriazo-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 0.942 mmol, 417 mg). The solution was stirred at ambient temperature for 16 hr, diluted with dichloromethane and washed with 1M potassium hydroxide solution. The aqueous layer was separated and extracted with dichloromethane (2×25 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The residue was redissolved in toluene, evaporated to dryness and purified by chromatography on a 1 mm silica gel rotor eluting with a 0 to 10% methanol in dichloromethane gradient. Final purification from residual hexamethylphosphoramide was achieved by precipitation of the hydrochloride salt (as described above in Example 6), trituration with 1M potassium hydroxide solution, filtration and rinsing with water to give the title compound (46 mg, 23%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[N:14]1[CH:19]=[C:18](B(O)O)[CH:17]=[N:16][CH:15]=1.[NH2:23][C:24]1[S:25][CH:26]=[C:27]([Cl:29])[N:28]=1>>[Cl:29][C:27]1[N:28]=[C:24]([NH:23][C:2]2[N:3]=[CH:4][C:5]([C:18]3[CH:19]=[N:14][CH:15]=[N:16][CH:17]=3)=[C:6]3[C:11]=2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]3)[S:25][CH:26]=1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Reactant: OB(O)c1cncnc1
Reactant: Nc1nc(Cl)cs1
Product: Cc1ccc2c(-c3cncnc3)cnc(Nc3nc(Cl)cs3)c2n1

Procedure:
The title compound, MS: m/e=354.9 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 5-pyrimidineboronic acid and 2-amino-4-chlorothiazole (Example K).