Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]([C@@H:9]2[CH2:18][C:17]3[C:12](=[C:13]([F:20])[CH:14]=[C:15]([F:19])[CH:16]=3)[O:11][CH2:10]2)[C:7](=[S:21])[NH:6][CH:5]=1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.ClCCl>CO>[CH2:22]([NH:1][CH2:2][CH2:3][C:4]1[N:8]([C@@H:9]2[CH2:18][C:17]3[C:12](=[C:13]([F:20])[CH:14]=[C:15]([F:19])[CH:16]=3)[O:11][CH2:10]2)[C:7](=[S:21])[NH:6][CH:5]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1ccccc1
Reactant: NCCc1c[nH]c(=S)n1[C@H]1COc2c(F)cc(F)cc2C1
Solvent: ClCCl
Solvent: CO
Product: Fc1cc(F)c2c(c1)C[C@@H](n1c(CCNCc3ccccc3)c[nH]c1=S)CO2
Reaction time: 64 h

Procedure:
To (R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione (2.36 g, 7.58 mmol) and benzaldehyde (0.85 ml, 8.34 mmol) in a mixture of methanol (15 ml), and dichloromethane (15 ml) sodium cyanoborohydride (0.67 g, 10.66 mmol) was added at 20-25° C. in portions. The mixture was stirred for 64 h, quenched with 1N HCl (12 ml) with stirring followed by 3N NaOH (12 ml). The mixture was extracted with DCM (100 ml), the organic phase was washed with brine (50 ml), dried (MgSO4) and evaporated to dryness. The residue was purified on a silica gel column with ethyl acetate and a mixture of ethyl acetate with methanol (9:1) as eluents. Fractions containing the product were collected, evaporated under reduced pressure to approx 20 ml then cooled on ice. The precipitate was collected, washed with ethyl acetate—petroleum ether (1:1) mixture, dried on air. Yield was 1.25 g (41%), the product having a mp 188-90° C. (2-propanol-DCM).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:21]([N:29]=[C:30]=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C(Cl)Cl>[C:14]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:30](=[O:31])[NH:29][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: Oc1ccccc1-c1ccccc1
Reactant: CCCCCCCCN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCNC(=O)Oc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.8 %

Procedure:
Triethylamine (3.3 mL, 23.7 mmol) is added dropwise under a nitrogen atmosphere to a solution of 2-phenylphenol (5.0 g, 29.3 mmol) and octyl isocyanate (5.5 g, 35.5 mmol) in 75 mL of methylene chloride. After the addition, the solution is stirred overnight at room temperature. The solution is washed with 1N HCl, dried (MgSO4) and the solvent removed under reduced pressure to give 10.09 g of a tan solid. Recrystallization from diisopropyl ether-hexane gives the title compound as a white crystalline solid (6.88 g, 72%), mp 59°-60° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]([NH2:15])([CH3:14])[CH3:13])[C:3]=1[C:4]#[N:5].C([O-])(O)=O.[Na+].[C:21](=O)([O:30]N1C(=O)CCC1=O)[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.O>[NH2:1][C:2]1[C:3]([C:4]#[N:5])=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:11][C:12]([NH:15][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:13])[CH3:14]
Reactant: CC(C)(N)COc1cccc(N)c1C#N
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(COc1cccc(N)c1C#N)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
To a solution of 2-amino-6-(2-amino-2-methylpropoxy)benzonitrile (Example Dd, 30.5 g, 148.6 mmol) in THF/H2O (1:1, 400 mL) was added NaHCO3 (24.7 g, 294 mmol), followed by benzyl (2,5-dioxopyrrolidin-1-yl) carbonate (44.0 g, 176 mmol) at room temperature. The reaction was stirred at room temperature for 4 h then the organic layer was separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine and dried over MgSO4. After filtration, the solvent was evaporated and the crude oil was purified by chromatography on silica gel (eluent: 0-60% EtOAc in hexane) to give the title compound as yellow oil (44.8 g, 89%). 1H NMR (400 MHz, DMSO-d6) δ 1.30 (s, 6H), 4.02 (s, 2H), 4.96 (s, 2H), 5.98 (s, 2H), 6.14 (d, J=8.0 Hz, 1H), 6.32 (dd, J=0.8, 8.4 Hz, 1H), 7.12 (t, J=8.4 Hz, 1H), 7.38-7.21 (m, 6H). MS 340 (MH+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[S:6]1(=[O:24])=[O:23].[CH3:25][NH2:26].Cl>>[ClH:1].[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:26][CH3:25])[S:6]2(=[O:24])=[O:23])=[CH:16][CH:17]=1
Reactant: COc1ccc(N2c3ccccc3CN(CCCCl)S2(=O)=O)cc1
Reactant: CN
Agent: Cl
Product: CNCCCN1Cc2ccccc2N(c2ccc(OC)cc2)S1(=O)=O

Procedure:
In an analogous manner to Example 1, step 8, 3-(3-chloropropyl)-1-(4-methoxyphenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (105 mg) was reacted with methylamine and then treated with HCl to provide 3-[1-(4-methoxyphenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine hydrochloride (32 mg):
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[C:12]([O:15][CH2:16][CH2:17][CH2:18]Br)(=[O:14])[CH3:13]>CN(C=O)C>[C:12]([O:15][CH2:16][CH2:17][CH2:18][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)(=[O:14])[CH3:13]
Reactant: CC(=O)OCCCBr
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCCn1ccc2ccccc21
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
To a stirred 0° C. DMF (400 mL) suspension of NaH (60% in mineral oil, 0.705 moles, 28.2 g, 1.5 eq.) in a three-neck flask fitted with a reflux condenser and an addition funnel was added a DMF (150 mL) solution of indole (55 g, 0.47 moles) dropwise. After 30-60 minutes, a DMF (50 mL) solution of the alkyl halide, 3-bromopropyl acetate (170 g, 0.94 moles) was added. The reaction was heated at 50° C. for 6 hours and then allowed to stir at room temperature for 5-15 hours.
Reaction SMILES: [C:1]([N:20]1[C:24]([CH2:25]O)=[C:23]([CH3:27])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P([N:42]=[N+:43]=[N-:44])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[N:42]([CH2:25][C:24]1[N:20]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:21]=[N:22][C:23]=1[CH3:27])=[N+:43]=[N-:44]
Reactant: Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1CO
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1CN=[N+]=[N-]
Temperature: 60 °C

Procedure:
To a solution of 1-trityl-4-methyl-5-imidazolemethanol (3.7 g, 10 mmol) and DPPA (3.0 ml, 13 mmol) in THF (100 ml) was added DBU (2.0 ml, 13 mmol). The resulting solution was heated to 60° C. for 2 h. The solvents were removed in vacuo and the residue purified by flash chromatography (2:1 hexane/ethyl acetate) to give of the title compound. 1H NMR (CDCl3) d 1.42 (s, 3 H), 4.22 (s, 2 H), 7.10-7.35 (m, 16 H).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].CS(O[C@@H:10]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1)(=O)=O>CN(C)C=O.O>[NH2:1][C@H:10]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Temperature: 25 °C

Procedure:
Sodium azide (4.4 g, 67.4 mmol) was added to a solution of 1,1-dimethylethyl (3R)-3-[(methylsulfonyl)oxy]-pyrrolidine-1-carboxylate (14.3 g, 54 mmol) in dry dimethylformamide (75 mL) and the resultant suspension heated at 65° C. for 8 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted into diethyl ether. The organic phase was washed two further times with water, then brine. The organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with diethyl ether/cyclohexane (20:80 to 40:60), to give the title compound as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:46](=[O:50])[CH:47]([CH3:49])[CH3:48].O>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[NH:11][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:47]([CH3:49])([CH3:48])[CH:46]2[OH:50])=[O:19])[CH3:2]
Reactant: CC(C)C=O
Reactant: CCOC(=O)c1ccc(N=Cc2ccccc2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1ccccc1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.4 %

Procedure:
To a mixture of 4-(benzylidene-amino)-benzoic acid ethyl ester (5.1 g, 20.0 mmol) and ytterbium(III) triflate hydrate (1.3 g, 2.0 mmol) in dry tetrahydrofuran (20.0 mL) at 25° C. was added isobutyraldehyde (18.2 mL, 200 mmol) and water (0.36 mL, 20.0 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 4-hydroxy-3,3-dimethyl-2-phenyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (6.6 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C20H23NO3 (M+H)+: 326.40, observed: 308.0.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>C(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=[O:19]
Reactant: CSc1ccc(C#N)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ccc(C#N)cc1
Temperature: -78 °C

Procedure:
A stirred solution of 4-(methylthio)benzonitrile (Aldrich Chemical Co.) (36 mmol) in methylene chloride (50 mL) at -78° C. is treated dropwise with a slurry of m-chloroperbenzoic acid (36 mmol) in 50 mL of methylene chloride over a period of 30 minutes. The mixture is stirred an additional hour at -78° C. and then allowed to warm to room temperature. The reaction mixture is washed with 3N sodium hydroxide solution (50 mL), dried (magnesium sulfate) and concentrated at reduced pressure to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Br:10].P([O-])(OCC)(SCC)=[S:12].Cl>C(O)C>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[S:12])[NH2:7])=[CH:4][C:3]=1[Br:10]
Reactant: CCOP([O-])(=S)SCC
Reactant: N#Cc1ccc(N)c(Br)c1
Agent: Cl
Solvent: CCO
Product: NC(=S)c1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 12.6 %

Procedure:
A stirred solution of 4-amino-3-bromobenzonitrile (6.92 g, 35.1 mmol) and diethyl dithiophosphate (17.7 mL, 105 mmol, 3 eq.) in absolute ethanol (160 mL) at 0° C. was perfused with hydrogen chloride gas at a moderate rate for 30 minutes. The resulting reaction mixture was stirred at room temperature for 12 hours, and then solvent was removed via evaporation under reduced pressure. The residue was suspended in a saturated solution of sodium hydrogen carbonate (25 mL), and this aqueous mixture was extracted with ethyl acetate (3×25 mL). The organic extracts were combined, dried (MgSO4), and evaporated under reduced pressure. The residue was chromatographed using silica gel (approximately 300 g) and elution with an acetone gradient in methylene chloride [1:50 to 1:20] to afford the title compound (1.02 g, 25%) as an amorphous yellow solid: 1H NMR (DMSO-d6) δ 9.41 (br s, NH), 9.13 (br s, NH), 9.13 (br s, NH), 8.11 (d, J=2.1 Hz, 1H), 7.78 (dd, J=2.1 and 8.6 Hz, 1H), 6.72 (d, J=8.7 Hz, 1H), 6.03 (s, 2NH); TLC: RB1 =0.15[1% diethyl ether in methylene chloride].
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[CH:13]([Mg]Br)=[CH2:14]>O1CCCC1>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[C:5]([CH:6]([OH:7])[CH:13]=[CH2:14])[CH:8]=[CH:9][CH:10]=1
Reactant: C=C[Mg]Br
Reactant: O=Cc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: C=CC(O)c1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
3-(Trifluoromethyl)benzaldehyde (100 g) was added to a pre-cooled (0 to 5° C.) solution of vinyl magnesium bromide (862 mL; 1M) in tetrahydrofuran under the nitrogen atmosphere. The reaction mixture was stirred at room-temperature for one hour. After completion, the reaction was quenched with de-ionized water (500 mL) and dichloromethane (500 mL) was added. The dichloromethane layer was washed with sodium bicarbonate solution (7%; 500 mL), layers were separated and organic layer was concentrated under vacuum at 40° C. to 45° C. to give 1-[3-(trifluoromethyl)phenyl]prop-2-en-1-ol as oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=1.[ClH:37].C(O)C.C(=O)([O-])[O-].[NH4+:45].[NH4+]>ClCCl.C(O)C>[ClH:37].[ClH:37].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25](=[NH:45])[NH2:26])=[CH:23][CH:24]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1cccnc1
Yield: 86 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 86% of theory, C27H29N7O3 (499.6) Rf value: 0.09 (silica gel; dichloromethane/ethanol=4:1 EKA mass spectrum: (M+H)+ =500
Reaction SMILES: [CH2:1]([CH:3]([CH2:19][CH3:20])[CH:4]([NH2:18])[C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:8]=[CH:7][CH:6]=1)[CH3:2].C(N(CC)CC)C.[Cl:28][C:29]1[S:33][C:32]([S:34](Cl)(=[O:36])=[O:35])=[CH:31][CH:30]=1>C(Cl)Cl>[Cl:28][C:29]1[S:33][C:32]([S:34]([NH:18][CH:4]([C:5]2[N:9]([C:10]3[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[N:8]=[CH:7][CH:6]=2)[CH:3]([CH2:1][CH3:2])[CH2:19][CH3:20])(=[O:36])=[O:35])=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CCC(CC)C(N)c1ccnn1-c1ccc(OC)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)s1)c1ccnn1-c1ccc(OC)cc1
Yield: 54 %

Procedure:
To a stirred solution of the {2-ethyl-1-[1-(4-methoxyphenyl)-1H-pyrazol-5-yl]butyl}amine (0.77 g, 2.8 mmol) in CH2Cl2 (30 mL) was added triethylamine (0.59 mL, 4.2 mmol) and 5-chlorothiophene-2-sulfonylchloride (0.73 g, 3.4 mmol). The reaction mixture was concentrated in vacuo, diluted with EtOAc, washed twice with 1N HCl, dried (MgSO4), filtered and concentrated in vacuo. The resulting oil was purified by column chromatography (SiO2, EtOAc/hexane, 1:4) to yield a tan solid in 54% yield.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.Cl.[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1>>[C:13]1([C:12]#[C:11][C:8]2[CH:7]=[N:6][C:5]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]3)=[N:10][CH:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Product: O[C@H]1CC[C@H](Nc2ncc(C#Cc3ccccc3)cn2)CC1

Procedure:
The title compound, MS: m/e=294.3 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and trans-4-aminocyclohexanol hydrochloride.
Reaction SMILES: CSC1SC(C(OC)=O)=CC=1N[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.[NH2:25][C:26]1[CH:27]=[C:28]([C:32]([O:34][CH3:35])=[S:33])[S:29][C:30]=1[CH3:31].C1(C2C=CC(B(O)O)=CC=2)C=CC=CC=1>>[C:16]1([C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26]3[CH:27]=[C:28]([C:32]([O:34][CH3:35])=[S:33])[S:29][C:30]=3[CH3:31])=[CH:23][CH:24]=2)[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)c1cc(Nc2ccc(-c3ccccc3)cc2)c(SC)s1
Reactant: COC(=S)c1cc(N)c(C)s1
Agent: OB(O)c1ccc(-c2ccccc2)cc1
Product: COC(=S)c1cc(Nc2ccc(-c3ccccc3)cc2)c(C)s1
Yield: 19.1 %

Procedure:
Methyl 5-methylthio-4-[(4-phenylphenyl)amino]thiophene-2-carboxylate: Using a procedure similar to Example 208, step (a), 74.4 mg (0.36 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed to react with 142.5 mg (2 equiv, 0.72 mmol) of 4-phenylphenyl boronic acid to give 24.5 mg (19.1%) of methyl 4-[(4-phenylphenyl)amino]-5-methylthiothiophene-2-carboxylate. 1H NMR (CDCl3, 400 MHz) δ 2.45 (s, 3H), 3.92 (s, 3H), 6.38 (bs, 1H), 7.08-7.14 (m, 2H), 7.33 (m, 1H), 7.43-7.46 (m, 211), 7.54-7.60 (m, 4H), 7.82 (s, 1H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14].CN(C)[CH:19]=[O:20]>O1CCCC1>[F:14][C:13]([F:16])([F:15])[C:12]1[C:7]([CH:19]=[O:20])=[CH:8][N:9]=[CH:10][CH:11]=1
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1ccncc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cnccc1C(F)(F)F
Reaction time: 0.17 h

Procedure:
n-Butyl lithium (1.65 mL, 0.00265 mol, 1.6 M) was added to a solution of 3-bromo-4-(trifluoromethyl)pyridine (E; 0.5 g, 0.022 mol) in anhydrous tetrahydrofuran (15 mL), at −78° C. The reaction mixture was stirred for 10 min followed by the addition of dimethylformamide (0.2 mL, 0.00265). It was stirred for 30 min at same temperature. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution (25 mL) and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organic extracts were combined and then washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over sodium sulphate and concentrated to afford 4-(trifluoromethyl)nicotinaldehyde. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 9.25 (s, 1H), 9.10-9.09 (d, J=4 Hz, 1H), 7.95-7.94 (d, J=4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[OH:20])=[O:11])[N:5]=[CH:4][C:3]=1[NH:21][C@@H:22]1[CH2:27][C@@H:26]2[CH2:28][C@@H:24]([C:25]2([CH3:30])[CH3:29])[C@H:23]1[CH3:31].[CH3:32][CH:33](O)[CH3:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[O:20][CH:33]([CH3:34])[CH3:32])=[O:11])[N:5]=[CH:4][C:3]=1[NH:21][C@@H:22]1[CH2:27][C@@H:26]2[CH2:28][C@@H:24]([C:25]2([CH3:30])[CH3:29])[C@H:23]1[CH3:31]
Reactant: CC(C)O
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccncc3O)c(=O)c1Cl)C2(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)Oc1cnccc1CNC(=O)Cn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 15.3 %

Procedure:
2-[5-Chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-[(3-hydroxypyridin-4-yl)methyl]acetamide (26.6 mg, 0.06 mmol) in tetrahydrofuran (1 mL) was mixed with 2-propanol (10.9 mg, 0.18 mmol), triphenylphosphine (23.6 mg, 0.09 mmol) and diethyl azodicarboxylate in toluene (2.2 M, 0.04 mL, 0.09 mmol) at 0° C. and stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was evaporated under reduced pressure, and the resulting residue was purified by silica gel chromatography (ethyl acetate/methanol 20/1) to give the desired product (4.48 mg, 15%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH:5]([C:10]2[CH:11]=[C:12]([C:17]3[N:18]=[N:19][N:20]([CH3:22])[N:21]=3)[CH:13]=[C:14]([F:16])[CH:15]=2)[C:6]([F:9])([CH3:8])[CH3:7])[CH2:2]1.Br[CH:24]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29].CCN(C(C)C)C(C)C>C(#N)C>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([CH:24]([N:1]2[CH2:2][CH:3]([CH:5]([C:10]3[CH:11]=[C:12]([C:17]4[N:18]=[N:19][N:20]([CH3:22])[N:21]=4)[CH:13]=[C:14]([F:16])[CH:15]=3)[C:6]([F:9])([CH3:8])[CH3:7])[CH2:4]2)[C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[C:28]#[N:29])=[CH:38][CH:37]=1
Reactant: Cn1nnc(-c2cc(F)cc(C(C3CNC3)C(C)(C)F)c2)n1
Reactant: N#Cc1cccc(C(Br)c2ccc(Cl)cc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1nnc(-c2cc(F)cc(C(C3CN(C(c4ccc(Cl)cc4)c4cccc(C#N)c4)C3)C(C)(C)F)c2)n1

Procedure:
A mixture of 240 mg (0.78 mmol) of 5-[3-(1-azetidin-3-yl-2-fluoro-2-methylpropyl)-5-fluorophenyl]-2-methyl-2H-tetrazole, 530 mg (1.56 mmol) of 3-[bromo(4-chlorophenyl) methyl]benzonitrile, 1.1 mL(6.26 mmol) of DIEA in 8 mL of acetonitrile was heated to reflux for 4 h. Then, it was concentrated. The mixture was poured into 30 mL of CH2Cl2 and 5 mL of aq NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The compounds were purified by silica gel chromatography. Single diastereomers were separated by a chiral AD column; Mass Spectrum: m/e=533 (M+1, 35Cl), 535 (M+1, 37Cl).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:32])[N:12]([CH:29]([CH3:31])[CH3:30])[CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:17])[N:10]=2)[CH2:3]1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[CH:29]([N:12]([CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17])[C:11]([C:9]1[N:10]=[C:6]([N:4]2[CH2:5][CH:2]([O:1][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:3]2)[S:7][CH:8]=1)=[O:32])([CH3:30])[CH3:31]
Reactant: CC(C)N(CCNC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N(CCNC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 0 °C
Yield: 45.8 %

Procedure:
A solution of 3-hydroxy-1-(4-{N-isopropyl-N-[2-(p-nitrobenzyloxycarbonylamino)-ethyl]-carbamoyl}-1,3-thiazol-2-yl)azetidine (1.43 g, 3.09 mmol) (obtained as described in Reference Example 60(3)) in methylene chloride (72 ml) were added methanesulfonyl chloride (0.29 ml, 3.70 mmol) and triethylamine (0.52 ml, 3.70 mmol) in an ice bath, and the mixture was stirred in the ice bath for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate ethyl acetate:methanol (20:1) as the eluant to afford 1-(4-{N-isopropyl-N-[2-(p-nitrobenzyloxycarbonylamino)ethyl]-carbamoyl}-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (766 mg, yield 46%) as a pale yellow solid.