Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].Br[CH2:14][CH3:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:14]([O:12][C:5]1[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([CH2:2][OH:1])[CH:4]=1)[CH3:15]
Reactant: O=[N+]([O-])c1ccc(O)cc1CO
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc([N+](=O)[O-])c(CO)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 3-hydroxymethyl-4-nitro-phenol (510 mg, 3.0 mmol) in 5 mL of dry DMF was added bromoethane (540 mg, 5.0 mmol) and K2CO3 powder (500 mg). The resulting reaction mixture was warmed to 50° C. and stirred for 1 h. It was quenched by addition of 20 mL of H2O, extracted with diethyl ether (2×20 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO4), filtered, and concentrated in vacuo to afford (5-ethoxy-2-nitro-phenyl)-methanol as a pale yellow oil: 1H NMR (CDCl3, 500 MHz) δ 8.20 (d, 1H), 7.36 (s, 1H), 6.89 (m, 1H), 5.00 (s, 2H), 4.16 (q, 2H), 2.57 (br t, 1H), 1.49 (t, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1>>[NH:10]1[CH2:11][CH:12]=[C:13]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:14][CH2:15]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Product: C1=C(c2c[nH]c3ccccc23)CCNC1

Procedure:
Alternately, for example in step a, an appropriate indole of formula (1) is condensed with an appropriate piperid-4-one of formula (2) to give a 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole of formula (3). The reaction may carried out in the presence of a suitable acid, typically phosphoric acid or sulfuric acid. The reaction is carried out in a suitable solvent, such as acetic acid and water. Typically, about 2-6 molar equivalents of the piperid-4-one of formula (2) are used. The reaction is generally carried out at temperatures of about 40° C. to 100° C. The reaction typically requires 8-72 hours. In general, the acidic conditions are favored for the condensation above compounds of formula (1) having a 5-hydroxy. The product can be isolated and purified by techniques well known in the art, such as precipitation, filtration, extraction, evaporation, trituration, chromatography, and recrystallization.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([O:9][CH3:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[C:11]1([CH3:29])[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[CH3:10][O:9][C:4]1[C:3]([CH2:2][N:24]([C:21]2[CH:20]=[CH:19][C:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]([CH3:29])=[CH:12][CH:13]=3)=[CH:23][CH:22]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: COc1ncccc1CCl
Reactant: Cc1ccc(Oc2ccc(NS(C)(=O)=O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncccc1CN(c1ccc(Oc2ccc(C)cc2)cc1)S(C)(=O)=O
Temperature: 70 °C

Procedure:
A mixture of 3-chloromethyl-2-methoxy-pyridine (0.2 g, 1.29 mmol) from Step A, N-(4-p-tolyloxy-phenyl)-methanesulfonamide (0.38 g, 1.35 mmol) from Step B and K2CO3 (0.44 g, 3.22 mmol) in dry DMF (5 mL) was heated at 70° C. overnight. The reaction was then diluted with EtOAc/H2O. The aqueous layer was extracted with EtOAc (×2) and the combined organics were brought to the usual work-up. The resulting crude material was purified by chromatography (silica gel, 40% EtOAc/hexanes) to give the desired product. MS (EI) 399 (M+H)+.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[NH:4]1.CCN(C(C)C)C(C)C.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][CH:34]=1.O>C(Cl)Cl>[F:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40]([N:4]2[CH:3]([CH3:2])[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]2[C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:17][CH:18]=2)=[O:41])=[CH:35][CH:34]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC1Cc2ccccc2C(c2ccc(C(F)(F)F)cc2)N1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC1Cc2ccccc2C(c2ccc(C(F)(F)F)cc2)N1C(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline hydrogen chloride (370 mg, 1.27 mmol) and DIEA (1.1 mL, 6.35 mmol) in DCM (5 mL) was added 4-fluorophenyl isocyanate (143 μL, 1.27 mmol). The mixture was then stirred at RT for 0.5 h. Water (10 mL) was added and the mixture was extracted with DCM (2×15 mL). The combined organic extracts were dried over MgSO4 and concentrated to give the title compound as a light yellow solid. MS (ESI, positive ion) m/z: 429 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[N:17][N:18]([CH3:21])[C:19]=3[CH3:20])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[O:46][CH:45]=[N:44][CH:43]=3)=[CH:38][CH:37]=2)O1>CN(C)C(=O)C.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>[ClH:1].[CH3:21][N:18]1[C:19]([CH3:20])=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:3]3[C:2]([C:36]4[CH:37]=[CH:38][C:39]([C:42]5[O:46][CH:45]=[N:44][CH:43]=5)=[CH:40][CH:41]=4)=[N:7][CH:6]=[CH:5][N:4]=3)[CH2:9][CH2:10]2)[CH:16]=[N:17]1
Reactant: CC1(C)OB(c2ccc(-c3cnco3)cc2)OC1(C)C
Reactant: Cc1c(CN2CCN(c3nccnc3Cl)CC2)cnn1C
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: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1c(CN2CCN(c3nccnc3-c3ccc(-c4cnco4)cc3)CC2)cnn1C
Product: Cl
Temperature: 120 °C
Yield: 65.1 %

Procedure:
Stir 3′-chloro-4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (153 mg, 0.50 mmol), potassium carbonate (166 mg, 1.20 mmol), 5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazole (163 mg, 0.60 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.006 g, 0.005 mmol) in N,N-dimethylacetamide (2 mL). Add water (1 mL), degas for 5 min., and then heat at 120° C. for 17 hr. Cool to room temperature, add water (5 mL) and extract with DCM (3×5 mL). Pass the combined DCM extracts through an IST Phase Separator Frit®. Concentrate the filtrate and purify by SCX-2® chromatography washing with methanol then eluting with 2.5 M ammonia in methanol. Recrystallize from DMSO:methanol (50:50, 2.4 mL), filter and wash with diethyl ether. Collect precipitate from filtrate, then combine solids to give the free base 4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3′-(4-oxazol-5-yl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl as a yellow solid (147 mg, 71%). Dissolve the free base (82 mg, 0.20 mmol) in acetonitrile, add 2 M aq. HCl then water. Lyophilize to give the title compound as yellow powder (65 mg, 72%). MS (ES): m/z=416 [M+H].
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]([NH:11][NH2:12])=[CH:9][C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[CH:27]=O>CN(C=O)C>[CH:1]1([CH2:4][N:5]2[C:10]([NH:11][N:12]=[CH:27][C:20]3[C:19]4[C:24](=[CH:25][CH:26]=[C:17]([Cl:16])[CH:18]=4)[N:23]=[CH:22][CH:21]=3)=[CH:9][C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:2][CH2:3]1
Reactant: O=Cc1ccnc2ccc(Cl)cc12
Reactant: Cn1c(=O)cc(NN)n(CC2CC2)c1=O
Solvent: CN(C)C=O
Product: Cn1c(=O)cc(NN=Cc2ccnc3ccc(Cl)cc23)n(CC2CC2)c1=O

Procedure:
A solution of 49 mg (0.23 mmol) 1-(cyclopropylmethyl)-6-hydrazino-3-methylpyrimidine-2,4(1H,3H)-dione and 44 mg (0.23 mmol) 6-chloroquinoline-4-carbaldehyde in 1 mL DMF was stirred at room temperature for 5 h to form 6-chloroquinoline-4-carbaldehyde[3-(cyclopropylmethyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl]hydrazone. Added was 38 mg (0.34 mmol) 1-methyl-1H-imidazole-5-carbaldehyde and 20 μL piperidine. The mixture was heated at 110° C. for 12 via microwave irradiation. Purification was achieved by preparative HPLC (20%-40% gradient of CH3CN-water with 0.1% TFA) to give the title compound as the bis-TFA salt.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[C:18]2[C:13](=[N:14][C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][CH:17]=2)[N:12]([CH2:26][CH2:27][CH:28]2[CH2:30][O:29]2)[N:11]=1.C1COCC1.CC([BH-](C(C)C(C)C)C(C)C(C)C)C(C)C.[Li+]>C(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]1[C:18]2[C:13](=[N:14][C:15]([NH:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][CH:17]=2)[N:12]([CH2:26][CH2:27][CH:28]([OH:29])[CH3:30])[N:11]=1
Reactant: Cc1cccc(C)c1Nc1nn(CCC2CO2)c2nc(Nc3ccccc3)ncc12
Agent: CC(C)C(C)[BH-](C(C)C(C)C)C(C)C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cccc(C)c1Nc1nn(CCC(C)O)c2nc(Nc3ccccc3)ncc12
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
A solution of 9 mg (0.02 mmol) of N3-(2,6-dimethylphenyl)-1-(2-(oxiran-2-yl)ethyl)-N6-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine 42 (Example 9, Step A) in 2.5 mL of CH2Cl2 was cooled to 0° C. and treated with 120 μl (1.0 M, 0.12 mmol) of a THF solution of LS-Selectride. The resulting tan solution was stirred at 0° C. for 1.25 h. The reaction mixture was quenched with saturated aqueous sodium potassium tartrate (8 mL) and stirred vigorously at room temperature overnight. The mixture was extracted with CH2Cl2 (10 mL), and the organic layer was dried over Na2SO4 and filtered. The filtrate was purified by chromatography on silica gel (eleuens CH2Cl2:MeOH, 98:2) to give the title compound 46. 1H-NMR (CD3OD) δ 1.16 (d, J=6.3 Hz, 3H), 1.80-1.99 (m, 2H), 2.26 (s, 6H), 3.64-3.72 (m, 1H), 4.13-4.23 (m, 2H), 7.00 (t, J=7.4 Hz, 1H), 7.10-7.17 (m, 3H), 7.30 (t, J=8.0 Hz, 2H), 7.75 (d, J=7.7 Hz, 2H), 8.08 (s, 1H). Mass Spectrum (ESI) m/e=403.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][NH:5][C@H:6]([C:11]([OH:13])=[O:12])[CH2:7][CH2:8][S:9][CH3:10].[Cl-].[Al+3].[Cl-].[Cl-].[Br:22]Br>C(O)(=O)C>[NH2:1][C:2]1[CH:17]=[CH:16][C:15]([Br:22])=[CH:14][C:3]=1[CH2:4][NH:5][C@H:6]([C:11]([OH:13])=[O:12])[CH2:7][CH2:8][S:9][CH3:10]
Reactant: BrBr
Reactant: CSCC[C@H](NCc1ccccc1N)C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(=O)O
Product: CSCC[C@H](NCc1cc(Br)ccc1N)C(=O)O
Reaction time: 24 h
Yield: 45 %

Procedure:
2.54 gm (0.01 mol) of N-(2-amino-benzyl)-methionine and 100 gm of aluminum chloride were dissolved in 50 cc of anhydrous acetic acid while gently heating. Then, the mixture was brought to room temperature and, while stirring, 0.52 cc (0.01 mol) of bromine diluted in 20 cc of acetic acid was added slowly. A light-colored precipitate was formed. After the addition of bromine was finished, the precipitate was centrifuged off, washed with ample acetic acid and then with anhydrous ether, and dried in a dryer. Then, the product was dissolved in 40 cc of water, and the pH of the solution was adjusted to 6 by addition of dilute ammonia while cooling it on an ice water bath. The mixture was allowed to stand for 24 hours, whereupon the new precipitate was centrifuged off, washed with water and dried in drying chamber. (Solvent of the crystallizate: alcohol at 50° C.). The melting point of the product was 207° C., and the yield was 45% of theory.
Reaction SMILES: [C:1]([CH2:3][C:4]([N:6]([CH:17]([CH3:19])[CH3:18])[C:7]1[CH:16]=[CH:15][C:10]2[N:11]=[C:12]([SH:14])[S:13][C:9]=2[CH:8]=1)=[O:5])#[N:2].[H-].[Na+].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C1COCC1>[C:1]([C:3](=[C:28]([OH:29])[C:27]1[CH:31]=[CH:32][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:25][CH:26]=1)[C:4]([N:6]([CH:17]([CH3:19])[CH3:18])[C:7]1[CH:16]=[CH:15][C:10]2[N:11]=[C:12]([SH:14])[S:13][C:9]=2[CH:8]=1)=[O:5])#[N:2]
Reactant: CC(C)N(C(=O)CC#N)c1ccc2nc(S)sc2c1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)N(C(=O)C(C#N)=C(O)c1ccc(C(F)(F)F)cc1)c1ccc2nc(S)sc2c1
Reaction time: 0.25 h

Procedure:
Cooled a 0.1 M solution of α-cyano-N-isopropyl-N-(2-mercaptobenzothiazol-6-yl)acetamide (50 mg, 0.172 mmol) in anhydrous THF to 0° C. Added 60% sodium hydride in mineral oil (69 mg, 1.720 mmol) and stirred 15 minutes. 4-(trifluoromethyl)benzoyl chloride (36 μl, 0.189 mmol) was added dropwise and the mixture stirred an additional 30 minutes. The reaction was quenched by addition of 0.1 M aqueous HCl. The mixture was extracted with ethyl acetate three times, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (5% methanol, 95% dichloromethane) to yield 27 mg (34%). 1H NMR (CDCl3) δ1.17 (d, 6H), 5.01 (m, 1H), 7.12 (d, 1H), 7.21 (dd, 1H), 7.31 (s, 1H), 7.64 (app q, 4H); ESIMS: m/z 462 (M-H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([OH:14])[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].Cl>C(OC)(C)(C)C>[C:22]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([OH:14])[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)[C@@H](O)Cc1cccc(O)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](O)Cc1cccc(OC(=O)C(C)(C)C)c1
Temperature: 10 °C
Reaction time: 17 h
Yield: 87 %

Procedure:
Methyl (2S)-3-(3-hydroxyphenyl)-2-hydroxypropionate (8.93 kg, 45.1 mol) was dissolved in tert-butylmethyl ether (133 L), and triethylamine (12.7 L, 91 mol) was added to the reaction mixture at room temperature, followed by cooling. Pivaloyl chloride (5.89 L, 48 mol) was added dropwise to the reaction mixture at an internal temperature of 2° C. After the end of the dropwise addition, the reaction mixture was stirred at 10° C. for 17 hours. To the reaction mixture was added 43 L of a 1N hydrochloric acid aqueous solution before stirring, followed by allowing to stand and then separating the mixture. The organic layer was washed twice each with a 0.25N sodium hydroxide aqueous solution (45 L) and water (45 L), and further washed with 42 L of a 5% sodium chloride solution, and then the organic layer was subjected to vacuum concentration at 50° C. After that, 1,2-dimethoxyethane (45 L) was added to the residue and then again subjected to vacuum concentration to obtain 11.0 kg of the title compound (yield: 86%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:17][CH2:16]S[CH2:14][CH2:13]3)[C:7](=[O:18])[C:6]3([CH3:23])[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1.O[O:25][S:26]([O-:28])=O.[K+]>CO.O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:13][CH2:14][S:26](=[O:28])(=[O:25])[CH2:16][CH2:17]3)[C:7](=[O:18])[C:6]3([CH3:23])[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1
Reactant: CC12COCCN1c1nc(Cl)ncc1N(C1CCSCC1)C2=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC12COCCN1c1nc(Cl)ncc1N(C1CCS(=O)(=O)CC1)C2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.4 %

Procedure:
To a solution of 2-chloro-6a-methyl-5-(tetrahydro-2H-thiopyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (9.4 mg, 0.026 mmol) in MeOH (1 ml) at 0° C. was added dropwise a solution of oxone (40.7 mg, 0.066 mmol) in water (1 ml), and the reaction mixture was stirred at room temperature for 16 h, followed by solvent removal in vacuo. The residue was partitioned between EtOAc and water. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were dried and concentrated in vacuo to give 2-chloro-5-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6a-methyl-6a,7,9,10-tetrahydro[1,4]oxazino[3,4-h]pteridin-6(5H)-one (6.5 mg, 0.017 mmol, 63% yield) as a white solid. This was used in the next step without further purification. MS [M+H] found 387.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[F:32][C:33]([F:45])([F:44])[C:34]1[CH:35]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:40]([C:36]1[CH:37]=[CH:38][CH:39]=[C:34]([C:33]([F:32])([F:44])[F:45])[CH:35]=1)(=[O:42])=[O:41]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 3-(trifluoromethyl)benzene sulfonyl chloride (8 uL, 0.052 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 16 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-3-(trifluoromethyl)benzenesulfonamide (percentage yield: 54%), was obtained.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][SH:15])=[CH:10][CH:9]=1.CS([C:20]1[C:24]([C:25]([NH2:27])=[O:26])=[C:23]([NH:28][C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[S:22][N:21]=1)(=O)=O>C1COCC1.O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][S:15][C:20]2[C:24]([C:25]([NH2:27])=[O:26])=[C:23]([NH:28][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[S:22][N:21]=2)=[CH:10][CH:9]=1
Reactant: SCc1ccc(Cl)cc1
Reactant: CS(=O)(=O)c1nsc(Nc2ccncc2)c1C(N)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1c(SCc2ccc(Cl)cc2)nsc1Nc1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.4 %

Procedure:
Potassium tertbutoxide (318 mg, 2.84 mmol) is dissolved in anhydrous THF (5 mL) and (4-Chlorophenyl)-methanethiol (0.375 mL, 2.84 mmol) is then added and stirred for 30 min room temperature. This resulting solution is then added to a solution of crude 9 (170 mg) dissolved in anhydrous THF (3 mL). The reaction is stirred for 4 hours at room temperature and then heated to 60° C. for 18 hours. The reaction is diluted with water and extracted with a solution containing 5% methanol and 95% methylene chloride (10 mL×3). The combined organics are dried over sodium sulfate, filtered and then concentrated in vacuo. Chromatography (3% MeOH/methylene chloride) provides 3-(4-Chloro-benzylsulfanyl)-5-(pyridin-4-ylamino)-isothiazole-4-carboxylic acid amide (18 mg, 2.5%-2 steps). 1H NMR (d6 DMSO): δ 8.17 (2H, broad s), 7.45 (2H, d, J=8.4 Hz), 7.37 (2H, d, J=8.4 Hz), 6.99 (2H, broad s), 4.32 (2H, s); LRMS (M+): 376.9, (M−): 375.0.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[CH2:23][CH2:22][C:21]([C:33]([O:35]C)=[O:34])=[CH:20][C:19]=3[CH:37]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)[CH2:23][CH2:22][C:21]([C:33]([OH:35])=[O:34])=[CH:20][C:19]=3[CH:37]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3c2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3c2ccc(OC)cc2)cc1
Temperature: 50 °C
Yield: 73.1 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(4-methoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.38 g). To the solution was added 1N sodium hydroxide solution (8 ml), and the mixture was heated at 50° C. overnight, concentrated, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-(4-methoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.27 g) as yellow crystals.
Reaction SMILES: C(OC(=O)[N:7]([CH2:32][CH:33]1[CH2:35][CH2:34]1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[CH:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)[N:17]=2)=[CH:12][CH:11]=1)(C)(C)C.C(=O)(O)[O-].[Na+]>>[CH:33]1([CH2:32][NH:7][CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[N:20]=[CH:19][N:18]([C:21]4[CH:22]=[CH:23][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:25][CH:26]=4)[N:17]=3)=[CH:14][CH:15]=2)[CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)CC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Product: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(CCNCC4CC4)cc3)n2)cc1

Procedure:
The title compound was prepared from tert-butyl(cyclopropylmethyl)(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)carbamate (CB66), neutralized with aqueous sodium bicarbonate, and isolated as a white solid (0.125 g, 100%): mp 162-166° C.; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.15-8.09 (m, 2H), 7.81-7.75 (m, 2H), 7.38 (dq, J=8.9, 0.9 Hz, 2H), 7.34-7.29 (m, 2H), 3.22 (dd, J=10.2, 6.0 Hz, 2H), 3.09 (dd, J=10.0, 6.1 Hz, 2H), 2.84 (d, J=7.3 Hz, 2H), 1.11 (ddd, J=12.7, 8.1, 4.8 Hz, 1H), 0.86 (dd, J=12.8, 5.8 Hz, 1H), 0.69-0.58 (m, 2H), 0.37-0.29 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 403 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[CH3:18][S:19]([C:22]1[CH:23]=[C:24]([C:34](O)=[O:35])[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:26][CH:27]=1)(=[O:21])=[O:20]>>[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:24]([C:34]([N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:16])[F:17])=[CH:5][CH:6]=3)[CH2:15][CH2:14]2)=[O:35])[CH:23]=1)(=[O:20])=[O:21]
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Reactant: FC(F)(F)Oc1ccc(N2CCNCC2)cc1
Product: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)N2CCN(c3ccc(OC(F)(F)F)cc3)CC2)c1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from 1-(4-Trifluoromethoxy-phenyl)-piperazine [187669-62-1] and 4-Methanesulfonyl-biphenyl-2-carboxylic acid (Example V). MS (ISP): 505.4 MH+.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]2[C:6]([C:18]#[C:19][CH2:20][N:21]3C(=O)C4=CC=CC=C4C3=O)=[CH:7][CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.CN>C(O)C>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:33]=[CH:32][C:5]2[C:6]([C:18]#[C:19][CH2:20][NH2:21])=[CH:7][CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CC#CC1=CCN=C(c2ccccc2F)c2cc(Cl)ccc21
Agent: CN
Solvent: CCO
Product: Cl
Product: NCC#CC1=CCN=C(c2ccccc2F)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.3 g (2.9 mmoles) of 8-chloro-5-(1-phthalimido-2-propyn-3-yl)-1-(2-fluorophenyl)-3H-2-benzazepine, 50 ml of ethanol and 10 ml of 40% aqueous methylamine was stirred at room temperature for 1 hr. The mixture was poured into ice water and extracted with ether. The ether solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was dissolved in an excess of ethanolic hydrogen chloride and the resulting salt precipitated by the addition of ether to give an off-white solid, mp 211°-216° C. Recrystallization from a mixture of methanol and ether gave gray needles, mp 216°-218° C. dec.