Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH2:8].[Cl:9][C:10]1[C:15]([NH2:16])=[C:14](Cl)[N:13]=[CH:12][N:11]=1.C(N(CC)CC)C>O>[Cl:9][C:10]1[N:11]=[CH:12][N:13]=[C:14]([NH:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:15]=1[NH2:16]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: NCc1ccccn1
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1c(Cl)ncnc1NCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
A mixture of 3.7 parts of 2-pyridinemethanamine, 4.1 parts of 4,6-dichloropyrimidin-5-amine, 3.03 parts of N,N-diethylethanamine and 150 parts of water was stirred for 8 hours at room temperature. After cooling, the whole was stirred overnight. The product was filtered off, washed with water and dried overnight in vacuo at 80° C., yielding 5.35 parts (90.8%) of 6-chloro-N4 -(2-pyridinylmethyl)-4,5-pyrimidinediamine; mp. 140.3° C. (interm. 1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.O>C(Cl)Cl>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][N:14]1[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccc(F)cc1F
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2,4-difluorobenzaldehyde (3.0 g, 21.1 mmol) and t-butyl piperazine-1-carboxylate (4.3 g, 23.1 mmol) in 30 mL of dry DCM is stirred for 2 h at RT, and NaHB(OAc)3 (6.7 g, 31.6 mmol) is added in portions with stirring. After the addition, the reaction mixture is stirred further overnight at RT. Water is added and the resulting mixture is extracted twice with DCM. The organic layer is dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain t-butyl 4-(2,4-difluorobenzyl)piperazine-1-carboxylate as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 1.46 (s, 9H), 2.40 (m, 4H), 3.42 (m, 4H), 3.54 (s, 2H), 6.78 (dt, 1H, J=10.0 Hz and 2.4 Hz), 6.85 (dt, 1H, J=8.4 Hz and 2.4 Hz), 7.33 (dd, 1H, J=15.2 Hz and 8.0 Hz).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:16]3[CH:21]=[CH:20][C:19]([CH:22](O)[CH3:23])=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:26]>ClCCl>[Br:26][CH:22]([C:19]1[CH:20]=[CH:21][C:16]([C:8]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:12][N:11]3[CH:13]=[CH:14][N:15]=[C:10]3[N:9]=2)=[CH:17][CH:18]=1)[CH3:23]
Reactant: CC(O)c1ccc(-c2nc3nccn3cc2-c2ccccc2)cc1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CC(Br)c1ccc(-c2nc3nccn3cc2-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
100 mg of the product of step 1 were dissolved in dichloromethane, cooled to 0° C. and 86 mg PBr3 were added. The mixture was stirred at room temperature for 24 h. Ice was added, the mixture extracted with dichloromethane and water, the organic layer were dried over Na2SO4 and the solvent was evaporated. The crude product may be used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1.[CH2:13](I)[CH3:14].CC(C)([O-])C.[K+].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][CH2:13][CH3:14])=[CH:6][CH:5]=1
Reactant: CCI
Reactant: COC(=O)c1ccc(CO)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
4-(Hydroxymethyl)benzoic acid methyl ester (2.0 g) and ethyl iodide (3.8 g) were dissolved in N,N-dimethylformamide (60 mL), potassium tert-butoxide (2.8 g) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 5:1) to give the title compound (2.0 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.C(N(CC)CC)C.Cl[C:15]([O:17][CH3:18])=[O:16]>C(#N)C>[CH3:18][O:17][C:15](=[O:16])[NH:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1
Reactant: COC(=O)Cl
Reactant: Nc1nnn[nH]1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)Nc1nnn[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-Amino tetrazole (10.00 g, 117.56 mmol)/Triethyl amine (16.48 ml, 118.739 mmol) in acetonitrile was added Methyl chloroformate (9.1375 ml, 118.739 mmol) at 0° C. The reaction mixture was slowly brought to room temperature and stirred for about 30 minutes. After about 30 minutes the reaction warmed and was refluxed for about 2 hrs. The reaction was then cooled to room temperature and the solvent was removed under reduced pressure, leaving a residue. The residue was washed with dilyte HCl to yield a white-colored solid. The solid was then dried at 105 C for about 6 hrs, resulting in a 92% yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[F:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[F:18])[NH:14][C:13]([C:19]1[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[C:23]([NH2:25])[CH:24]=1)=[CH:12]2.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[F:18])[NH:14][C:13]([C:19]1[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[C:23]([NH:25][CH2:6][C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH:24]=1)=[CH:12]2
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Reactant: O=Cc1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NCc1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.4 %

Procedure:
2-Thiophenecarboxaldehyde (0.112 g, 1.0 mmol) was added to a stirred mixture of 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.29 g, 1.06 mmol) in methylene chloride (125 mL), followed by acetic acid (0.1 g, 1.67 mmol). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.23 g, 1.09 mmol) was added in one portion, and the resulting homogeneous solution stirred at room temperature for 6 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added and the mixture stirred for 2 hours. The mixture was shaken and the organic layer separated. The solvent was evaporated to give a brown gum. Recrystallization from methanol/water gave the product as a brown solid (120 mg), mp 190-192° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[CH:4]=[O:5].BrN1C(=O)CCC1=O.[NH2:21][C:22]([CH3:26])([CH3:25])[CH2:23][OH:24]>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[OH:24][CH2:23][C:22]([NH:21][C:4](=[O:5])[C:3]1[C:6]([O:11][CH3:12])=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=1[Cl:1])([CH3:26])[CH3:25]
Reactant: CC(C)(N)CO
Reactant: COc1cc(Cl)cc(Cl)c1C=O
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(Cl)cc(Cl)c1C(=O)NC(C)(C)CO
Temperature: 0 °C
Reaction time: 0.12 h

Procedure:
A suspension of 2,4-dichloro-6-methoxybenzaldehyde (3 g, 15 mmol) and N-bromosuccinimide (3.6 g, 20 mmol) in carbon tetrachloride (30 ml) was illuminated with a 150 W flood lamp under nitrogen with vigorous stirring on a steam bath for seven minutes. The cloudy mixture was cooled to 0° C., diluted with methylene chloride (30 ml) and treated dropwise with a solution of 2-amino-2-methylpropanol (3 ml, 30 mmol) in methylene chloride (30 ml). The ice bath was removed and the mixture was stirred at 20° C. for twenty hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]#[N:13])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].[CH2:16](I)[CH3:17]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]#[N:13])=[CH:8][N:9]2[CH2:16][CH3:17])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C#N)c[nH]c2c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1cc(C#N)c2ccc(OC)cc21
Reaction time: 0.25 h

Procedure:
A solution of 6-methoxyindole (10.0 g, 68.0 mmol) in DMF (120 mL) is cooled to 0° C. and treated with chlorosulfonyl isocyanate (7.72 mL, 88.4 mmol). After the addition, the reaction mixture is stirred at this temperature for 1 h. The dark solution is poured into ice water (600 mL) and the light brown solid is collected by filtration, washed with additional H2O and dried to afford 9.9 g (85%) of 6-methoxy-1H-indole-3-carbonitrile as a light brown solid. Step B: To a solution of 6-methoxy-1H-indole-3-carbonitrile (9.9 g, 57.6 mmol) in DMF (150 mL) is added NaH (60% dispersion in mineral oil, 3.45 g, 86.3 mmol). The reaction mixture is stirred for 15 min and then ethyl iodide (5.53 mL, 69.1 mmol) is added and the mixture is stirred at room temperature overnight. The reaction mixture is then diluted with H2O and extracted with EtOAc (2×). The organic phases are washed with H2O (3×) and saturated NaCl and then dried and concentrated to a semi-solid. The crude product is purified via column chromatography on silica gel (200 g) using CH2Cl2/hexanes (50-100%) as eluent to yield 6-methoxy-1-ethyl-1H-indole-3-carbonitrile as a tan solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:25]1[N:26]=[CH:27][S:28][CH:29]=1)CCC>>[S:28]1[CH:29]=[C:25]([C:2]2[S:6][C:5]([N:7]3[CH2:11][C@:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])=[CH:4][CH:3]=2)[N:26]=[CH:27]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)s1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2cscn2)s1

Procedure:
The title compound was prepared by a method analogous to that described in Example 5 from (R)-3′-(5-bromothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 4-(tri-n-butylstannyl)thiazole. The title compound (27 mg) was obtained as a pale solid, m/z 348 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[S:9][C:10]([CH3:18])=[C:11]([CH2:13][C:14](OC)=[O:15])[N:12]=1>C(Cl)Cl>[CH3:18][C:10]1[S:9][C:8]([NH2:7])=[N:12][C:11]=1[CH2:13][C:14]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:15]
Reactant: COC(=O)Cc1nc(N)sc1C
Reactant: C1COCCN1
Solvent: ClCCl
Product: Cc1sc(N)nc1CC(=O)N1CCOCC1
Reaction time: 1 h
Yield: 54 %

Procedure:
A suspension of alumiumchloride (0.86 g, 6.44 mmol) in DCM (50 mL) was treated dropwise with morpholine (4.7 mL, 53.7 mmol) giving a colorless solution. Methyl (2-amino-5-methyl-1,3-thiazol-4-yl)acetate (1.0 g, 5.37 mmol) was added (orange solution) and after 1 h, the reaction mixture was quenched with aqueous citric acid (3%, 10 mL) and basified with saturated aqueous sodium bicarbonate. Extraction with DCM (3×50 mL), drying (sodium sulfate) of the combined organic layers and evaporation of the volatiles gave 0.70 g of a yellow foam. Purification of the solid by flash column chromatography on silicagel eluting with DCM/methanol (10/1 v/v) gave 545 mg (42%) of an ivory solid: Anal. Calcd. (found) for C10H15N3O2S: C, 49.7 (49.5)%; H, 6.3 (6.3)%; N, 17.4 (17.3)%; S, 13.3 (13.3).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:17][C:18]1[N:22]=[C:21]([CH3:23])[NH:20][N:19]=1>CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:19]2[C:18]([CH3:17])=[N:22][C:21]([CH3:23])=[N:20]2)[N:3]=[C:4]([S:9][CH3:10])[N:5]=1
Reactant: Cc1n[nH]c(C)n1
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CSc1nc(Cl)cc(-n2nc(C)nc2C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a slurry of 4,6-dichloro-2-(methylthio)pyrimidine (1-1) (1.00 g, 5.13 mmol, 1.0 eq.) and cesium carbonate (2.70 g, 7.67 mmol, 1.5 eq.) in DMF (40 mL) at 0° C. under nitrogen was added a solution of 3,5-dimethyl-1H-1,2,4-triazole (498 mg, 5.13 mmol, 1.0 eq.) in DMF (20 mL) via a dropping funnel over 1 hour. The reaction was then warmed to room temperature. The reaction was monitored by TLC and was complete after 1 hour. The reaction was quenched by addition of water (100 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (0-50% ethyl acetate in hexanes) to afford 4-chloro-6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(methylthio)pyrimidine (1-2) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.58 (s, 1H), 2.90 (s, 3H), 2.60 (s, 3H), 2.41 (s, 3H). LRMS m/z (M+H) 256 found, 256 required.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH:11]3[CH2:15][S:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[OH:23]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH:11]3[CH2:15][S:16](=[O:23])[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:10]3=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C1CC2CSc3ccccc3C2=NN1c1ccc(Cl)cc1
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: O=C1CC2CS(=O)c3ccccc3C2=NN1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a mixture of 11.5 g of 2-(4-chlorophenyl)-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one in 200 ml of acetic acid is added 66 ml of 35% hydrogen peroxide dropwise with stirring at room temperature. After the completion of addition, the mixture is stirred at room temperature for 3 hours, poured into an excess amount of water and extracted with chloroform. The extract is washed with water, dried over magnesium sulfate anhydride and the chloroform is distilled off under reduced pressure. To the precipitated crystals is added diisopropyl ether. The crystals are collected by filtration and recrystallized from isopropyl alcohol to give 7.7 g of 2-(4-chlorophenyl)-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one 6-oxide, melting at 181°-183° C., as colorless needles.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15](Cl)=[O:16])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH:18]1[CH2:20][CH2:19]1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CO>C(Cl)Cl>[Cl:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15]([CH:27]3[O:28][CH2:29][CH2:30][NH:25][CH2:26]3)=[O:16])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH:18]1[CH2:20][CH2:19]1
Reactant: C1COCCN1
Reactant: O=C(Cl)c1ccc2nc(C3CC3)n(Cc3ccccc3Cl)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(c1ccc2nc(C3CC3)n(Cc3ccccc3Cl)c2c1)C1CNCCO1
Reaction time: 1 h

Procedure:
1-(2-Chlorobenzyl)-6-chlorocarbonyl-2-cyclopropylbenzimidazole hydrochloride (140 mg) is added at room temperature to a solution which has been prepared by adding morpholine (298 mg, a 30% methanol solution) to methylene chloride (10 ml) . After the reaction mixture is stirred for one hour at the same temperature, it is washed with water, dried and concentrated under reduced pressure. The residue is recrystallized using ether and thus, 1-(2-chlorobenzyl)-2-cyclopropyl-6-morpholino-carbonylbenzimidazole (20 mg) is obtained. (Colorless crystal). 1H-NMR (CDCl3,): 1.04-1.12 (2H, m), 1.25-1.32 (2H, m), 1.82-1.96 (1H, m), 3.68 (8H, bs), 5.56 (2H, s), 6.55 (1H, dd, J=1, 8 Hz), 7.13 (1H, dt, J=1, 8 Hz), 7.22-7.29 (2H, m), 7.30 (1H, d, J=1 Hz), 7.46 (1H, dd, J=1, 8 Hz), 7.77 (1H, d, J=8 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[OH:9][C:10]([CH3:43])([CH3:42])[CH2:11][C@:12]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:17][CH2:16][N:15]([C@H:18]([C:20]2[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][CH:21]=2)[CH3:19])[C:14](=[O:35])[CH2:13]1.C([O-])(O)=O.[Na+]>COCCOC.CCO.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>[OH:9][C:10]([CH3:43])([CH3:42])[CH2:11][C@:12]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:17][CH2:16][N:15]([C@H:18]([C:20]2[CH:21]=[CH:22][C:23]([C:2]3[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=3)=[CH:24][CH:25]=2)[CH3:19])[C:14](=[O:35])[CH2:13]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)CC1=O
Reactant: O=c1ccc(Br)c[nH]1
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: COCCOC
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)CC1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 20.2 %

Procedure:
To a solution of 5-bromopyridin-2(1H)-one (30 mg, 0.17 mmol) in DME (6 mL) was added Pd(PPh3)4 (10 mg, 0.01 mmol) under N2. The mixture was stirred at rt for 1 h. (R)-4-(2-hydroxy-2-methylpropyl)-4-phenyl-1-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)piperidin-2-one (25 mg, 0.05 mmol) in EtOH (2 mL) was added, followed by satd aq NaHCO3 (2 mL). The mixture was stirred at 100° C. for another 2 h under N2. The reaction was quenched with H2O, and extracted with EtOAc (3×). The combined organic phase was dried and concentrated to give the crude final product, which was purified by preparative TLC to give 5-(4-((S)-1-((R)-4-(2-hydroxy-2-methylpropyl)-2-oxo-4-phenylpiperidinyl)ethyl)phenyl)pyridin-2(1H)-one (4.5 mg, 20%). LC-MS Method 2 tR=1.034 min, m/z=445.2; 1H NMR (CDCl3): δ 0.86 (s, 3H), 1.02 (s, 3H), 1.41 (d, 3H), 1.82 (d, 2H), 2.00 (m, 2H), 2.11 (m, 2H), 2.62 (d, 1H), 2.85 (m, 1H), 3.42 (d, 1H), 6.0 (m, 1H), 6.69 (m, 1H), 6.88 (m, 2H), 7.09 (m, 2H), 7.17 (m, 1H), 7.25 (m, 4H), 7.51 (m, 1H), 7.78 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34]>>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[C:26]([F:25])([F:37])[F:38])(=[O:35])=[O:34])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)c3ccccc3C(F)(F)F)cc2)c2ccc3ccccc3c2N1
Yield: 94 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 2-(trifluoromethyl)benzene-1-sulfonyl chloride, the title compound (yield 94%) was obtained in the same manner as that of Example 145.
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].F[C:11]1[CH:12]=[C:13]([C:19]([CH3:34])([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:14]=[CH:15][C:16]=1[CH:17]=O.O>CS(C)=O>[CH2:8]([O:7][C:5]([C:4]1[S:3][C:11]2[CH:12]=[C:13]([C:19]([CH3:34])([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])[CH:14]=[CH:15][C:16]=2[CH:17]=1)=[O:6])[CH3:9]
Reactant: CCOC(=O)CS
Reactant: CC(C)(C)OC(=O)C(C)(C(=O)OC(C)(C)C)c1ccc(C=O)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cc2ccc(C(C)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2s1
Reaction time: 0.25 h
Yield: 22 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.19 g, 4.75 mmol) was suspended in DMSO (2.5 mL) and ethyl mercaptoacetate (0.28 mL, 2.54 mmol) was added portionwise using a water bath to moderate the exotherm. On complete addition, the water bath was removed and stirring continued for 15 minutes. A solution of di-tert-butyl (3-fluoro-4-formylphenyl)(methyl)malonate (0.81 g, 2.30 mmol) in DMSO (0.5 mL) was added in one portion. The orange solution was warmed with a heat gun to give a dark brown solution. H2O was added (150 mL) and the products were extracted into EtOAc (2×100 mL). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by MPLC gave 0.22 g of desired product (pale yellow solid, 22%). 1H NMR (CDCl3) δ 8.01 (s, 1H), 7.88 (d, J=1.8 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.48 (dd, J=8.4, 1.8 Hz, 1H), 4.39 (q, J=7.2 Hz, 2H), 1.84 (s, 3H), 1.47 (s, 18H), 1.40 (t, J=7.2 Hz, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[S:7][CH:6]=[N:5][C:4]=1[C:8](=[O:10])[CH3:9].[SH:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]([F:22])([F:21])[F:20])[N:13]=1.C(N(CC)CC)C>C(O)C>[C:8]([C:4]1[N:5]=[CH:6][S:7][C:3]=1[CH2:2][S:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]([F:22])([F:20])[F:21])[N:13]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ncsc1CBr
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)c1ncsc1CSc1nc(O)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.4 %

Procedure:
To a mixture of 1-[5-(bromomethyl)-1,3-thiazol-4-yl]ethan-1-one (615 mg, 2.8 mmol) and 2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol (255 mg, 1.3 mmol) in absolute ethanol (25 mL) at 0° C. was added triethylamine (725 μL, 5.2 mmol). The mixture was stirred at room temperature for 4 hours. The mixture was evaporated, and the solid residue was treated with diethyl ether (50 mL). The solid salts were removed by filtration. The filtrate was recovered and evaporated. The crude product was purified by flash chromatography (0-10% MeOH/CH2Cl2 and 0-5% MeOH/CH2Cl2), affording 2-{[(4-acetyl-1,3-thiazol-5-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (150 mg, 34%); 1H NMR (500 MHz, DMSO-d6): δ 2.71 (s, 3H), 4.82 (s, 2H), 6.58 (s, 1H), 8.99 (s, 1H); M+ 336.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6](Cl)([CH3:9])([CH3:8])[CH3:7]>>[C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)Cl
Reactant: c1cc[nH]c1
Product: CC(C)(C)c1ccc[nH]1

Procedure:
wherein X1, X2, Z, and R1 are as defined above. The pyrrole can reacted with t-butylchloride under Friedel-Craft alkylation condition to give the tert-butylpyrrole 2, which can then be nitrated. The ester is then hydrolyzed, e.g., with LiOH, and coupled to give amide 4. Compound 4 is then reduced to give the amine which is reacted with isocyanate to give compound 5, which is an exemplary compound of Formula I.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6]1[C:12]([C:22]([F:25])([F:24])[F:23])([O:17][Si](C)(C)C)[CH2:13][CH2:14][CH2:15][CH2:16][C:5]2=1.[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6]1[C:12]([C:22]([F:24])([F:25])[F:23])([OH:17])[CH2:13][CH2:14][CH2:15][CH2:16][C:5]2=1
Reactant: C[Si](C)(C)OC1(C(F)(F)F)CCCCc2c1[nH]c1c(Cl)cc(Cl)cc21
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: OC1(C(F)(F)F)CCCCc2c1[nH]c1c(Cl)cc(Cl)cc21
Temperature: 25 °C
Yield: 2.1 %

Procedure:
2,4-Dichloro-6-(trifluoromethyl)-6-(trimethylsilyloxy)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (0.3 g, 7.0 mmol) was dissolved in THF (5 mL) and KOH (0.2 g, 3.6 mmol) in water (5 mL) was added to the mixture. The reaction mixture was refluxed for 1 h and then cooled to room temperature, diluted with water and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography [EtOAc-hexane (1:17) as eluant] to furnish the title compound as a pale yellow solid (0.05 g, 21%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.67 (br s, 1H), 7.43 (d, J=1.5 Hz, 1H), 7.41 (d, J=1.5 Hz, 1H), 2.9 (m, 1H), 2.73 (m, 1H), 2.49 (s, 1H) 2.43-2.4 (m, 1H), 2.08-2.03 (m, 4H), 1.16-1.54 (m, 1H)