Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Br[C:3]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])[C:11]([O:20][CH3:21])=[CH:10][C:4]=1[CH2:5][NH:6]C(=O)C>C(O)C>[ClH:1].[Cl:1][C:3]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])[C:11]([O:20][CH3:21])=[CH:10][C:4]=1[CH2:5][NH2:6]
Reactant: COc1cc(CNC(C)=O)c(Br)cc1OCC(O)CO
Agent: Cl
Solvent: CCO
Product: COc1cc(CN)c(Cl)cc1OCC(O)CO

Procedure:
37% Hydrochloric acid (0.2 ml) was added to a solution of 2-bromo-4-(2-hydroxyethoxy)-5-methoxy-N-acetyl benzylamine 4 (0.1 g, 0.31 mmol) in abs. ethanol (5 ml) and the mixture was refluxed for 12 hours. After cooling, the solvent was evaporated off under reduced pressure and the residue was recrystallized from a mixture of methanol/ethyl ether to afford the title compound as pale yellow solid in quantitative yield.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([N+:13]([O-])=O)[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>C(O)C.[Pd]>[CH:1]1([C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1cccc(C2=CCCCC2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(C2CCCCC2)c1
Yield: 78.9 %

Procedure:
3-(Cyclohexen-1-yl)-1-nitrobenzene(7.5 g) is dissolved in ethanol (150 ml), and thereto is added 10% palladium on carbon (750 mg), and the mixture is subjected to catalytic hydrogenation at 25° C. The catalyst is removed by filtration, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give the desired compound (5.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:28])[C@@H:15]([NH2:27])[CH:16]([CH2:22][C:23]([F:26])([F:25])[F:24])[CH2:17][C:18]([F:21])([F:20])[F:19].N1C=CC=CC=1>C(Cl)Cl.Cl>[CH3:12][O:13][C:14](=[O:28])[C@@H:15]([NH:27][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:16]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:22][C:23]([F:25])([F:26])[F:24]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)[C@@H](N)C(CC(F)(F)F)CC(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(CC(F)(F)F)CC(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.4 %

Procedure:
A solution of 4-chlorobenzenesulfonyl chloride (2.66 g, 12.2 mmol, 97% pure) in CH2Cl2 (7 mL) was added to a solution of (2S)-2-amino-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)pentanoic acid methyl ester (2.173 g, 8.14 mmol) and pyridine (1.97 mL, 24.4 mmol) in CH2Cl2 (15 mL). The reaction mixture was stirred at 25° C. for 4 hours, then cooled to 0° C. IN HCl (15 mL) was added followed by dichloromethane (10 mL) and the phases were separated. The organic phase was washed with 1N HCl (15 mL) and brine, dried over Na2SO4, and concentrated to afford 4.1 g of crude mixture as a yellow solid. The solids were recrystallized from heptane (14 mL) to afford 3.035 g of the title product (84% yield). Mass Spectrum (+ESI): 442 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:55])[C@H:19]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41]S(C3C4C=CN=CC=4C=CC=3)(=O)=O)=[CH:37][CH:36]=2)[NH:20][S:21]([C:24]2[C:25]3[CH:26]=[CH:27][N:28]=[CH:29][C:30]=3[CH:31]=[CH:32][CH:33]=2)(=[O:23])=[O:22])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=O)(O)[O-].[Na+]>CO.O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:55])[C@H:19]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=2)[NH:20][S:21]([C:24]2[C:25]3[CH:26]=[CH:27][N:28]=[CH:29][C:30]=3[CH:31]=[CH:32][CH:33]=2)(=[O:22])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCCN(C(=O)[C@H](Cc2ccc(OS(=O)(=O)c3cccc4cnccc34)cc2)NS(=O)(=O)c2cccc3cnccc23)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCCN(C(=O)[C@H](Cc2ccc(O)cc2)NS(=O)(=O)c2cccc3cnccc23)CC1
Yield: 74.7 %

Procedure:
5.50 g of the amorphous compound obtained in Example 122 was dissolved in 30 ml of methanol and 30 ml of tetrahydrofuran, to the solution was added 60 ml of 1N sodium hydroxide, and the mixture was refluxed for 2 hours and then cooled. The reaction mixture was acidified with citric acid and then alkalized with sodium bicarbonate, resulting insoluble matter was dissolved with a small amount of methanol, and the solution was extracted twice with 400 ml of chloroform. The extract was dried over magnesium sulfate and evaporated to remove the solvent under a reduced pressure, and resulting residue was applied to a silica gel column and eluted with chloroform/methanol (20:1) to obtain 3.1 g of the title compound in a colorless amorphous form.
Reaction SMILES: [C:1](=[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:13][CH3:14])[NH:6][C:5]1=[O:15])([CH3:3])[CH3:2]>[Pd].C(O)C>[CH:1]([CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:13][CH3:14])[NH:6][C:5]1=[O:15])([CH3:3])[CH3:2]
Reactant: COc1cccc2c1C(=C(C)C)C(=O)N2
Agent: [Pd]
Solvent: CCO
Product: COc1cccc2c1C(C(C)C)C(=O)N2
Yield: 80.2 %

Procedure:
A mixture of 3-isopropylidene-4-methoxy-1,3-dihydro-indol-2-one (700 mg, 3.4 mmol) and 5% palladium on carbon (88 mg) in ethanol (25 mL) is hydrogenated at 60 psi overnight. Filtration and removal of the solvent in vacuo provided 560 mg (79%) of 3-isopropyl-4-methoxy-1,3-dihydro-indol-2-one. MS (ESI+) 206.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:9]12[CH2:18][C:13]3([CH3:19])[CH2:14][CH:15]([CH2:17][C:11]([CH3:20])([CH2:12]3)[CH2:10]1)[CH2:16]2.[OH-].[Na+]>O>[CH3:19][C:13]12[CH2:14][CH:15]3[CH2:17][C:11]([CH3:20])([CH2:10][C:9]([C:1]4([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH2:2]4)([CH2:16]3)[CH2:18]1)[CH2:12]2
Reactant: CC12CC3CC(C)(C1)CC(Br)(C3)C2
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC12CC3CC(C)(C1)CC(C1(O)C=CC=CC1)(C3)C2
Yield: 37 %

Procedure:
Into a 2 liter flask equipped with a thermometer, a Dimroth condenser, an inlet for nitrogen gas and a stirrer, 77.4 g (0.822 moles) of phenol and 20.0 g (0.0822 moles) of 1-bromo-3,5-dimethyladamantane were placed. A stream of nitrogen gas was introduced into the flask, and the resultant mixture was heated under the refluxing condition in an oil bath for 30 minutes. Then, 800 ml of water was added, and the obtained mixture was heated under the refluxing condition in an oil bath for 10 minutes to obtain a fluid separated in two layers. The fluid was cooled in an ice bath, and the lower layer having an orange color was solidified to obtain a white solid substance. The white solid substance was taken out by decantation, stirred twice in 500 ml of a 2% aqueous solution of sodium hydroxide and twice in 500 ml of water and then filtered, and 7.8 g of 4-(1-(3,5-dimethyladamantyl)phenol was obtained (the yield: 37%).
Reaction SMILES: [O:1]=[C:2]([NH:13][CH2:14][C:15]1[NH:16][C:17](=[O:25])[C:18]2[CH2:24][O:23][CH2:22][CH2:21][C:19]=2[N:20]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1.[Cl:26][C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[CH2:29][CH2:30][NH:31][CH2:32]2>>[Cl:26][C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[CH2:29][CH2:30][N:31]([C:10]([CH:7]1[CH2:8][CH2:9][N:4]([CH2:3][C:2]([NH:13][CH2:14][C:15]3[NH:16][C:17](=[O:25])[C:18]4[CH2:24][O:23][CH2:22][CH2:21][C:19]=4[N:20]=3)=[O:1])[CH2:5][CH2:6]1)=[O:12])[CH2:32]2
Reactant: O=C(CN1CCC(C(=O)O)CC1)NCc1nc2c(c(=O)[nH]1)COCC2
Reactant: Clc1cccc2c1CCNC2
Product: O=C(CN1CCC(C(=O)N2CCc3c(Cl)cccc3C2)CC1)NCc1nc2c(c(=O)[nH]1)COCC2
Yield: 17.6 %

Procedure:
The title compound (44 mg, 18% yield) was prepared following the general procedure of Example 1 from 1-(2-oxo-2-((4-oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methylamino)ethyl)piperidine-4-carboxylic acid (250 mg, 0.50 mmol) and 5-chloro-1,2,3,4-tetrahydroisoquinoline (84 mg, 0.50 mmol). 1H NMR (400 MHz, DMSO-d6) δ 8.20 (br. s., 1H), 7.32 (d, J=6.6 Hz, 1H), 7.22 (d, J=8.1 Hz, 2H), 4.74 (br. s., 1H), 4.64 (s, 1H), 4.34 (s, 2H), 4.18 (d, J=5.6 Hz, 2H), 3.66-3.87 (m, 4H), 3.09-3.20 (m, 1H), 2.95 (s, 4H), 2.79-2.91 (m, 2H), 2.73 (br. s., 1H), 2.67 (br. s., 1H), 2.02-2.23 (m, 2H), 1.74 (br. s., 4H). HRMS calculated for C25H30ClN5O4 500.2065. found (ESI, [M+H]+), 500.2066. Retention time=1.36 min.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]2[NH:7][C:6]3[C:13]([C:25]([O:27]C)=O)=[CH:14][C:15]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)=[N:16][C:5]=3[C:4]=2[CH:3]=1.[NH3:29]>CO>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]2[NH:7][C:6]3[C:13]([C:25]([NH2:29])=[O:27])=[CH:14][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)=[N:16][C:5]=3[C:4]=2[CH:3]=1
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)nc2c1[nH]c1cc(OC)c(Cl)cc12
Reactant: N
Solvent: CO
Product: COc1ccc(-c2cc(C(N)=O)c3[nH]c4cc(OC)c(Cl)cc4c3n2)cc1
Temperature: 80 °C

Procedure:
A suspension of methyl 8-chloro-7-methoxy-2-(4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (29 mg, 0.073 mmol) in a 7 N solution of ammonia in MeOH (7 mL) in a sealed microwave vial was heated at 80° C. for 24 hr. The solvents were removed and preparative HPLC (100×30 mm Luna C18 column, gradient elution with A:B=30:70 to A:B=0:100 [A=10 mM NH4OAc in 5% aqueous CH3CN; B=10 mM NH4OAc in 95% aqueous CH3CN] over 20 min) afforded 8-chloro-7-methoxy-2-(4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (16 mg) as a yellow solid. MS (ESI) m/z 380.1 (M+H). 1H NMR (MeOD) δ ppm 8.36 (1H, s), 8.13 (1H, s), 8.06 (2H, d, J=8.85 Hz), 7.31 (1H, s), 7.10 (2H, d, J=8.85 Hz), 4.03 (3H, s), 3.90 (3H, s).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[S:5][C:4]2[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:3]1=2.[Cl-].[NH4+].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O>[NH:20]1[C:16]([C:14]2[CH:13]=[CH:12][C:4]3[S:5][C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:11]4[C:2](=[O:1])[C:3]=3[CH:15]=2)=[N:17][N:22]=[N:21]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2sc3ncccc3c(=O)c2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2cc(-c3nnn[nH]3)ccc2sc2ncccc12
Reaction time: 20 h
Yield: 67.1 %

Procedure:
A mixture of 4.8 g of 5-oxo-5H-[1]benzothiopyrano[2,3-b]pyridine-7-carbonitrile, 80 ml of dimethylformamide, 1.35 g. of ammonium chloride and 1.7 g of sodium azide is heated with stirring at 110° C to 120° C for 20 hours. After cooling, crystals are filtered off and added to a dilute hydrochloric acid, and the mixture is stirred. The crystals are filtered off, washed with water and recrystallized from dimethylformamide to give 3.8 g of 7-(5-1H-tetrazolyl)-5-oxo-5H-[1]benzothiopyrano[2,3-b]pyridine melting at above 300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:23]3=[C:24]([CH2:27][S:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:25]=[CH:26][N:22]3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.ClC1C=CC=C(C(OO)=[O:43])C=1>C(Cl)(Cl)Cl>[C:29]1([S:28]([CH2:27][C:24]2[CH:25]=[CH:26][N:22]3[C:23]=2[C:18]([NH:17][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=4)=[C:2]([Cl:1])[CH:3]=2)=[N:19][CH:20]=[N:21]3)=[O:43])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1cccc(COc2ccc(Nc3ncnn4ccc(CSc5ccccc5)c34)cc2Cl)c1
Solvent: ClC(Cl)Cl
Product: O=S(Cc1ccn2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12)c1ccccc1
Reaction time: 1 h
Yield: 89.5 %

Procedure:
The sulfide 7A (900 mg, 1.63 mmol) was dissolved in chloroform (25 ml), cooled in an ice bath and m-chloroperbenzoic acid (300 mg, 57 to 80%, about 1 equiv) was added in small portions over 15 min. After 1 hr., the reaction was washed with 10% aqueous NaHSO3 solution, sat. aq. NaHCO3 solution (three times) and dried (Na2SO4). Removal of the solvent afforded 7B (740 mg, 90%) as a foam. Analytical HPLC retention time=1.99 min. (YMC Xterra S7 C18, 3.0×50 mm column, 10–90% aqueous methanol over 2 minutes containing 0.1% TFA, 5 mL/min, monitoring at 220 nm) and a LC/MS M++1=506.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:24])[C:15]([C:19]([O:21]CC)=[O:20])=[CH:16][NH:17][CH:18]=2)=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+].Cl>CN(C=O)C.O>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:14](=[O:24])[C:15]([C:19]([OH:21])=[O:20])=[CH:16][N:17]([CH2:2][CH2:3][O:4][CH3:5])[CH:18]=2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Reactant: COCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1cc(C(=O)O)c(=O)c(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-Bromo-2-methoxyethane (95 μl) was added to a suspension of ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (200 mg) and cesium carbonate (499 mg) in DMF (4 ml) at room temperature. The reaction mixture was stirred at room temperature for four hours. Then the reaction mixture was stirred at 50° C. overnight. Cesium carbonate (499 mg) and 1-bromo-2-methoxyethane (95 μl) were added to the reaction mixture at 50° C. The reaction mixture was stirred at 50° C. for nine hours. Then the reaction mixture was stirred at 80° C. for three days and returned to room temperature. A 1 N aqueous sodium hydroxide solution (4 ml) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for five hours. A 1 N aqueous hydrochloric acid solution and water were added to the reaction mixture. The precipitated solid was collected by filtration, washed with water and then washed with a mixed solvent of hexane and diethyl ether [5:1 (v/v)] to give 113 mg of the title compound as a solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[N:23]1([C:29]2[N:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:26]5[CH2:27][CH2:28][N:23]([C:29]6[N:30]=[CH:31][CH:32]=[CH:33][N:34]=6)[CH2:24][CH2:25]5)=[O:20])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: c1cnc(N2CCNCC2)nc1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCN(c2ncccn2)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 2-(piperazin-1-yl)pyrimidine (1.2 equiv) to give 177 (8.7 mg, M+1 460.1)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Br:49][C:50]1[CH:62]=[CH:61][C:53]2[NH:54][C:55]([C@@H:57]([NH2:60])[CH2:58][OH:59])=[N:56][C:52]=2[CH:51]=1.BrBr>O1CCCC1.ClCCl.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([NH:60][C@H:57]([C:55]1[NH:54][C:53]2[CH:61]=[CH:62][C:50]([Br:49])=[CH:51][C:52]=2[N:56]=1)[CH2:58][OH:59])=[O:7]
Reactant: O=C(O)c1ccc(C(=O)N2CCCC2)c(Br)c1
Reactant: N[C@@H](CO)c1nc2cc(Br)ccc2[nH]1
Agent: BrBr
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C(N[C@@H](CO)c1nc2cc(Br)ccc2[nH]1)c1ccc(C(=O)N2CCCC2)c(Br)c1
Yield: 50 %

Procedure:
Prepared analogously to Example 1g from 3-bromo-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxyethylamine in tetrahydrofuran. Yield: 50%; melting point: 114° C.-116° C.; Rf value: 0.25 (silica gel: dichloromethane/ethanol=95:5); C21H20Br2N4O3 (536.22); mass spectrum: (M+H)+=535/537/539 (bromine isotope).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([NH:13][CH2:14][C:15]3[C:16]([OH:23])=[N:17][C:18]([CH3:22])=[CH:19][C:20]=3[CH3:21])=[O:12])=[C:9]([CH3:24])[N:8]([C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[C:6]=2[N:7]=1.[CH3:33][O-:34].[Na+]>CO>[OH:23][C:16]1[C:15]([CH2:14][NH:13][C:11]([C:10]2[C:5]3[CH:4]=[N:3][C:2]([O:34][CH3:33])=[N:7][C:6]=3[N:8]([C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[C:9]=2[CH3:24])=[O:12])=[C:20]([CH3:21])[CH:19]=[C:18]([CH3:22])[N:17]=1
Reactant: C[O-]
Reactant: Cc1cc(C)c(CNC(=O)c2c(C)n([C@H](C)c3ccccc3)c3nc(Cl)ncc23)c(O)n1
Agent: [Na+]
Solvent: CO
Product: COc1ncc2c(C(=O)NCc3c(C)cc(C)nc3O)c(C)n([C@H](C)c3ccccc3)c2n1
Yield: 55.4 %

Procedure:
A solution of (R)-2-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (70 mg, 0.15 mmol) in MeOH (1 mL) solution of sodium methanolate (20 mg) was stirred at 100° C. for 60 minutes under microwave (pressure: 15.3 bar, equipment power: 150 W). The mixture was concentrated in vacuo and purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to afford (R)—N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methoxy-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (37 mg, 51.9%). LRMS (M+H+) m/z: calcd 445.21. found 445. HPLC purity (214 nm): 100%. 1H NMR (400 MHz, CD3OD) δ 8.75 (s, 1H), 7.29-7.22 (m, 5H), 6.11-6.07 (m, 2H), 4.46 (s, 2H), 3.90 (s, 3H), 2.48 (s, 3H), 2.36 (s, 3H), 2.21 (s, 3H), 2.05 (d, J=7.2 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[C:12]([Cl:18])=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.O.O.O.O.O.O.O.O.O.O.O.O.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[CH:39]1([NH2:42])[CH2:41][CH2:40]1>CC1C=CC=CC=1C.O>[Cl:18][C:12]1[C:11]([NH:10][C:8]([C:7]2[C:2]([NH:42][CH:39]3[CH2:41][CH2:40]3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:9])=[C:16]([CH3:17])[CH:15]=[CH:14][N:13]=1
Reactant: NC1CC1
Reactant: Cc1ccnc(Cl)c1NC(=O)c1cccnc1Cl
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1ccnc(Cl)c1NC(=O)c1cccnc1NC1CC1
Temperature: 135 °C
Reaction time: 0.17 h

Procedure:
2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide (15 g), trisodium phosphate dodecahydrate (20.21 g), cyclopropylamine (12.12 g) were suspended in o-xylene (45 ml) and heated to 130-140° C. for 6-8 h in S.S. Bomb with occasional shaking. Then the reaction mass was cooled to 70-75° C., diluted with o-xylene (75 ml) and DM water (45 ml) and stirred for 10 min at 70-80° C. The aqueous layer was separated and washed the organic layer with DM water (45 ml) at 70-80° C. The organic layer was concentrated at 60-65° C. under reduced pressure. The concentrated mass was cooled to 5-10° C. and stirred for 30 min. Filtered the solid obtained and washed with chilled o-xylene (15 ml, 5-10° C.). Dried the obtained solid at 55-60° C. under reduced pressure.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]([CH2:6][S:7][C:8]2[C:18]3[CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13][C:12]=3[CH:11]=[CH:10][C:9]=2[Cl:26])=[CH:4][C:3]=1[F:29].[Br-].[CH3:31][CH:32]([CH3:36])[CH2:33][CH2:34][Zn+].C1COCC1>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[C:22]([O:21][C:19]([N:15]1[CH2:16][CH2:17][C:18]2[C:8]([S:7][CH2:6][C:5]3[CH:27]=[CH:28][C:2]([CH2:34][CH2:33][CH:32]([CH3:36])[CH3:31])=[C:3]([F:29])[CH:4]=3)=[C:9]([Cl:26])[CH:10]=[CH:11][C:12]=2[CH2:13][CH2:14]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Br)c(F)c3)c2CC1
Reactant: CC(C)CC[Zn+]
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [Br-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)CCc1ccc(CSc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To 6-(4-bromo-3-fluorobenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.210 mg, 0.42 mmol) and dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium(II) dichloromethane adduct (17 mg, 0.021 mmol) add 0.5 M 3-methylbutylzinc bromide in THF (4.2 mL, 2.10 mmol). Degas, purge with dry nitrogen, and stir overnight at 80° C. Cool to ambient temperature, dilute with EtOAc, wash with water, dry over anhydrous MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give 3-tert-butoxycarbonyl-7-chloro-6-[3-fluoro-4-(3-methylbutyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (85 mg, 42%). Use a method similar to the General Procedure 1-4 to give the title compound as a white solid. MS (ES+) m/z: 392 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]([NH2:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(N(CC)CC)C.Cl>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:34][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: CCCCCCCCN
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCNC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), octylamine (0.460 g, 3.56 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (50 ml), and the mixture was extracted with ethyl acetate (50 ml×3 portions). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was recrystallized from ether to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-octyl-3,4,5,6-tetrahydrophthalamide as white crystals (0.410 g, 30.2% yield).
Reaction SMILES: C([O:4][C:5]1[C:6]([I:30])=[C:7]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:8]([C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[C:9]([O:11]CC=C)[CH:10]=1)C=C.[Se](=O)=O.C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCOCC1>[OH:4][C:5]1[C:6]([I:30])=[C:7]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:8]([C:15](=[O:24])[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[C:9]([OH:11])[CH:10]=1
Reactant: C=CCOc1cc(OCC=C)c(C(=O)c2ccc(OC)cc2)c(CC(=O)OC)c1I
Agent: O=C([O-])O
Agent: O=[Se]=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC(=O)Cc1c(I)c(O)cc(O)c1C(=O)c1ccc(OC)cc1
Temperature: 75 °C
Yield: 1.8 %

Procedure:
Methyl 3,5-diallyloxy-2-iodo-6-(4-methoxybenzoyl)-phenylacetate (80 mg, 0.15 mmol) obtained in Example 15, Step 2 was dissolved in 1,4-dioxane (1.0 mL), and selenium dioxide (36 mg, 0.34 mmol) and acetic acid (0.028 mL, 0.46 mmol) were added thereto, followed by stirring at 75° C. for half a day. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by preparative thin layer chromatography (chloroform/methanol=9/1) to obtain Compound 15 (1.2 mg, 8.2%).