Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:23]=[C:22]([O:24][CH3:25])[C:5]2[N:6]([CH2:18][CH2:19][O:20][CH3:21])[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[CH3:26][N:27](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:15]([C:12]1[CH:11]=[CH:10][C:9]([C:7]2[N:6]([CH2:18][CH2:19][O:20][CH3:21])[C:5]3[C:22]([O:24][CH3:25])=[CH:23][C:2]([C:26]#[N:27])=[CH:3][C:4]=3[N:8]=2)=[CH:14][CH:13]=1)([CH3:17])[CH3:16]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(Br)cc(OC)c21
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C#N)cc(OC)c21
Temperature: 180 °C

Procedure:
A mixture of 430 mg (1.07 mmol) 5-bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole (example 22), 125 mg (1.07 mmol) zinc cyanide and 20 mg tetrakis(triphenylphosphine) palladium in 5 ml DMF is heated in a microwave oven for 75 min (180° C.). After that the reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (3×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=3:1) to afford 250 mg of the title compound as a colorless solid.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1.[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC>C(C1C(O)=CC=C(CCCC)C=1C)CCC.C1(C)C=CC=CC=1>[C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:22]=[CH2:23])=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: Cc1ccccc1-c1cccc(Nc2ccc(Br)cc2)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: CCCCc1ccc(O)c(CCCC)c1C
Solvent: Cc1ccccc1
Product: C=Cc1ccc(Nc2cccc(-c3ccccc3C)c2)cc1
Temperature: 100 °C
Reaction time: 76 h
Yield: 83.1 %

Procedure:
In a reactor equipped with a stirrer and a reflux condenser, 2.0 g (0.0059 mol) of m-tolyl(p-bromophenyl)phenylamine, 0.18 g (0.00015 mol) of tetrakistriphenylphosphine palladium (0), 0.005 g of 2,6-dibutylhydroxytoluene and 20 ml of toluene were added and dissolved, and then 2.1 ml (0.0071 mol) of tributyl(vinyl)tin was added to the mixture in an argon gas atmosphere at room temperature. The mixture was heated to 100° C. and continuously stirred for 76 hours. After air cooling, the solvent was distilled off, and the residue was purified by silica gel column chromatography (developing solvent: hexane) to yield 1.4 g of m-tolyl(p-vinylphenyl)phenylamine as a colorless liquid at a yield of 81%.
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH2:10](N(CC)CC)[CH3:11].CC(C)(O)C#C>ClCCl.C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Br:9][C:5]1[CH:6]=[C:7]2[C:2](=[N:3][CH:4]=1)[NH:1][CH:11]=[CH:10]2
Reactant: CCN(CC)CC
Reactant: Nc1ncc(Br)cc1I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: C#CC(C)(C)O
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.3 %

Procedure:
A suspension of 2-amino-5-bromo-3-iodopyridine (5.0 g, 16.7 mmol), bis-(triphenylphosphine)-palladium(II)-dichloride (43 mg, 0.061 mmol), copper(I)iodide (29.4 mg, 0.15 mmol) and triethylamine (2.21 g, 21.8 mmol) in dichloromethane (20 mL) was treated at 23 to 30° C. within 1 to 2 hours with a solution of 1,1-dimethyl-2-propyn-1-ol (1.85 g, 21.7 mmol) in dichloromethane (10 mL) and the resulting mixture was stirred at 25° C. for 4 hours. The mixture was diluted with dichloromethane (10 mL) and washed with water (2×25 mL). The organic phase was then treated with 1 M HCl (40 mL). The layers were separated and the organic layer was extracted with 1 M HCl (15 mL). The combined product containing aqueous layers were washed with dichloromethane (2×8 mL). The pH of the aqueous layer was adjusted to pH 7-9 by the drop wise addition of sodium hydroxide solution (28% in water). The resulting suspension was stirred at 20° C. over night and the crystals were then filtered off and washed with water (2×5 mL). The wet crystals were dissolved in N-methylpyrrolidone (50 mL) and treated within 2 hours at 60° C. and 50-100 mbar with an aqueous solution of lithium hydroxide (2.4 M, 32 mL). The resulting mixture was heated to 75° C. and stirred at this temperature and under reduced pressure (50-100 mbar) for 15-20 hours. Toluene (20 mL) and water (20 mL) were then added and the layers were separated. The aqueous layer was extracted with toluene (3×25 mL). The combined organic layers were washed with water (3×10 mL) and then concentrated to dryness. The residue was dissolved in N-methylpyrrolidone (50 mL) and treated at 60° C. with potassium tert.-butylate (3.52 g, 30.7 mmol). After stirring for 3 hours at 60° C., the mixture was cooled to ambient temperature and diluted with toluene (40 mL) and water (40 mL). The aqueous layer was separated and back extracted with toluene (3×50 mL). The combined toluene layers were washed with water (3×10 mL) and then concentrated to dryness. The residue was dissolved in a hot mixture of toluene and n-heptane (20 mL). The clear solution was cooled to −5° C. within 4 to 6 hours whereupon crystals precipitated. The suspension was stirred at −5° C. for 2-4 hours. The crystals were filtered off, washed with heptane and dried at 45° C./<30 mbars over night to afford 5-bromo-7-azaindole (2.05 g, 62% yield) as slightly yellow crystals with a purity of 99.6% (HPLC, area %).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][N:5]=1)([O-:3])=[O:2].[OH:11][CH:12]1[CH2:15][NH:14][CH2:13]1.C(N(CC)C(C)C)(C)C.CN(C)C(=O)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[N+:1]([C:4]1[N:5]=[CH:6][C:7]([N:14]2[CH2:15][CH:12]([OH:11])[CH2:13]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: OC1CNC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(N2CC(O)C2)cn1
Temperature: 120 °C
Yield: 49 %

Procedure:
A 500-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was purged with nitrogen and charged with 2-nitro-5-bromopyridine (3.00 g, 14.8 mmol), 3-hydroxyazetidine hrdrochloride (2.91 g, 26.56 mmol), N,N-diisopropylethyl amine (5.67 g, 43.91 mmol) and tetrabutylammonium iodide (8.17 g, 22.1 mmol) and N,N-dimethylacetamide (15 mL). This mixture was heated at 120° C. (bath temperature) for 14 h. After this time, the reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (4×100 mL). The combined organic layers were washed with brine (250 mL) and dried over sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using a silica gel column, eluting the desired product with 80% ethyl acetate in hexanes to afford a 49% yield (1.43 g) of 120a as a yellow semi-solid: 1H NMR (500 MHz, DMSO-d6) δ 8.13 (d, 1H, J=9.0 Hz), 7.70 (d, 1H, J=2.5 Hz), 6.91 (m, 1H), 5.83 (d, 1H, J=6.0 Hz), 4.65 (m, 1H), 4.31 (m, 2H), 3.83 (m, 2H); MS (ESI+) m/z 196.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].CCO[C:18]([CH3:20])=O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:5][N:4]1[CH:20]=[C:18]([C:5]2[N:4]=[N:3][C:2]([NH2:1])=[CH:7][CH:6]=2)[CH:2]=[N:3]1
Reactant: Nc1ccc(Cl)nn1
Reactant: CCOC(C)=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cn1cc(-c2ccc(N)nn2)cn1

Procedure:
3-Amino-6-chloropyridazine (7.76 g, 59.9 mmol) was introduced in a round bottom flask with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole (13.1 g, 59.9 mmol) and dissolved in 2-dimethoxyethane (160 mL). An aqueous solution of 2 M Na2CO3 (110 mL, 220 mmol) was added to this mixture and also tetrakis-(triphenylphosphine)-palladium (3.5 g, 2.99 mmol). The RM was refluxed for 26 h under nitrogen. Then was taken up with EtOAc and washed with 1N NaOH and brine. The organic layer was dried over Na2SO4 and the solvent was removed. The residue was triturated with Et2O to afford the title compound as a yellow solid (tR 0.9 min (conditions 2), MH+=176).
Reaction SMILES: [F:1][CH2:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[NH2:13][NH2:14].O.Cl.CO>CN(C=O)C>[ClH:12].[F:1][CH2:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:13][NH2:14])=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: NN
Reactant: O=S(=O)(CF)c1ccc(Cl)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: NNc1ccc(S(=O)(=O)CF)cc1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 49.4 %

Procedure:
A mixture of 4-chlorophenyl fluoromethyl sulfone (1.97 g, 9.44 mmol, prepared according to the method of Ukrainskill Khimicheskill Zhurnal, 1972, 38, 1034) and hydrazine anhydrous (1.84 g, 57.5 mmol) in DMF (30 mL) was heated to 120° C. for 16 hours, and cooled down to room temperature. The reaction mixture was poured into water (150 mL) and the whole was extracted with ethyl acetate/hexane/ether (2/1/1, 60 mL×3). The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The resulting solid (1.56 g, 7.64 mmol) was added HCl—MeOH reagent 10 (10 mL) at room temperature and stirred for 10 minutes. The mixture was concentrated in vacuo to give the subtitle compound (0.91 g, 49.4% yield).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:24][CH3:25])=[C:7]([O:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH:8]=1.[CH2:26]([N:28](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[K+]>ClCCl.O.CN(C=O)C>[C:26]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:24][CH3:25])=[C:7]([O:9][CH2:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:15][CH2:16]2)[CH:8]=1)#[N:28]
Reactant: COc1ccc(CO)cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CC#N)cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 40.7 %

Procedure:
To a solution of 1,1-dimethylethyl 4-({[5-(hydroxymethyl)-2-(methyloxy) phenyl]oxy}methyl)piperidine-1-carboxylate (1.88 g, 5.4 mmol) in dichloromethane (14 mL) was added triethylamine (2.3 mL, 16.2 mmol). The resulting mixture was cooled with an ice bath, and methanesulfonyl chloride (0.84 mL, 10.8 mmol) was added dropwise. The mixture was allowed to warm to room temperature and a white precipitate formed. After 2.5 h, the solvent was removed and the residue was dissolved in water, which was subsequently extracted twice with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to provide a yellow oil. To the oil was added DMF (10 mL) and potassium cyanide (703 mg, 10.8 mmol). The resulting mixture was stirred at rt for 15 h. Water was then added, and the aqueous mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (60% hexanes, 40% ethyl acetate) to provide 800 mg of 1,1-dimethylethyl 4-({[5-(cyanomethyl)-2-(methyloxy)phenyl]oxy}methyl)piperidine-1-carboxylate (2.2 mmol, 41% yield). 1H NMR (400 MHz, CDCl3): δ6.89-6.81 (m, 3H), 4.15 (br m, 2H), 3.86 (s, 3H), 3.86-3.83 (m, 2H), 3.69 (s, 2H), 2.76 (br m, 2H), 2.10-2.00 (m, 1H), 1.87 (br d, 2H), 1.47 (s, 9H), 1.31-1.20 (m, 2H); MS (EI) for C20H28N2O4: 383 (MNa+).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[NH2:33][CH:34]1[CH2:37][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:35]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][C:27]([CH2:30][NH:33][CH:34]6[CH2:35][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:37]6)=[CH:28][CH:29]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC(NCc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)C1

Procedure:
To a suspension of the aldehyde 47 (1.0 g, 2.25 mmol, scheme 15) in NMP (12 mL) were added 3-amino-1-N-Boc-azetidine (0.600 g, 3.38 mmol) and acetic acid (0.19 mL, 3.38 mmol) at RT and stirred for 30 mill. Then NaBH(OAc)3 (1.2 g, 5.63 mmol) was added and stirred for 3 days. The reaction mixture was poured into saturated aqueous solution of NaHCO3 to form a precipitate that was collected by filtration, rinsed with water and purified via Biotage [linear gradient 2-20%, (methanol/dichloromethane; SiliaFlash 25 g cartridge]. Title compound 430 was obtained as a beige solid (960 mg, 71% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.71 (s, 1H), 8.56 (d, J=1.2 Hz, 1H), 8.51 (d, J=5.2 Hz, 1H), 8.32 (s, 1H), 8.23 (d, J=8.0 Hz, 1H), 7.89 (dd, J=8.0, 2.0 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 7.23-7.18 (m, 1H), 6.64 (dd, J=5.2, 1.2 Hz, 1H), 6.56 (bd, J=2.4 Hz, 1H), 3.98-3.83 (m, 2H), 3.69 (s, 2H), 3.62-3.47 (m, 3H), 2.58-2.51 (m, 1H), 1.36 (s, 9H), 0.68-0.62 (m, 2H), 0.45-0.40 (m, 2H), one NH is missing. MS (m/z): 605.46 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[C:6]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:5]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.O>C(O)(=O)C>[CH3:1][N:2]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)=[C:6]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:5]=1
Reactant: CN1CCNCC1
Reactant: CN(Cc1ccccc1)C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Solvent: O
Solvent: CC(=O)O
Product: CN1CCN(c2ccc(C(=O)N(C)Cc3ccccc3)cc2S(N)(=O)=O)CC1
Reaction time: 48 h

Procedure:
33.8 Grams of 4-chloro-3-sulfamoylbenzoic acid-N-methylbenzylamide (0.1 mole) were heated with 80 ml of N-methylpiperazine for 4 hours under reflux. Subsequently the solution was introduced into 0.4 l of water, the pH value of the mixture was adjusted to 9.0 by means of glacial acetic acid, and the mixture was then allowed to stand for 2 days at room temperature. The crystalline precipitate was separated and was recrystallized from a mixture of ethanol and water.
Reaction SMILES: [F:1][C:2]1[C:3]([C:21]2[S:25][C:24]([C:26]3([OH:30])[CH2:29][NH:28][CH2:27]3)=[N:23][CH:22]=2)=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.C=O.Cl[CH:34](Cl)C.C(O)(=O)C.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>>[F:1][C:2]1[C:3]([C:21]2[S:25][C:24]([C:26]3([OH:30])[CH2:29][N:28]([CH3:34])[CH2:27]3)=[N:23][CH:22]=2)=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cnc(C5(O)CNC5)s4)c(F)cnc32)cc1
Reactant: CC(Cl)Cl
Agent: C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cnc(C5(O)CN(C)C5)s4)c(F)cnc32)cc1
Temperature: 90 °C

Procedure:
A round-bottomed flask equipped with a reflux condenser was charged with 3-(5-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)azetidin-3-ol (100 mg, 0.225 mmol) (Example 103A), paraformaldehyde (33.8 mg, 1.125 mmol), dichloroethane (2.5 mL), and acetic acid (0.064 mL, 1.125 mmol). Sodium cyanoborohydride (0.059 ml, 1.125 mmol) was added in three portions, and the mixture heated to 90° C. for 1 hour. The reaction mixture was slowly cooled to room temperature, and then to 0° C. in an ice-bath. Saturated sodium bicarbonate solution was added, and the mixture stirred vigorously for about an hour. The layers were separated, and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated to give the title compound. MS APCI(+) m/z 459.24 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1)[S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](O)=[O:11])(=[O:6])=[O:5])[CH3:2].ClCCl.C(Cl)(=O)C(Cl)=O.[NH2:35][C:36]1[S:37][C:38]2[CH2:66][CH2:65][CH2:64][CH2:63][C:39]=2[C:40]=1[C:41]([NH:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][CH2:51][CH2:52][C:53]2[CH:62]=[CH:61][C:56]([C:57]([O:59][CH3:60])=[O:58])=[CH:55][CH:54]=2)=[CH:46][CH:45]=1)=[O:42]>CN(C=O)C.N1C=CC=CC=1>[CH2:1]([N:3]([C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1)[S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH:35][C:36]1[S:37][C:38]2[CH2:66][CH2:65][CH2:64][CH2:63][C:39]=2[C:40]=1[C:41]([NH:43][C:44]1[CH:45]=[CH:46][C:47]([CH2:50][CH2:51][CH2:52][C:53]2[CH:54]=[CH:55][C:56]([C:57]([O:59][CH3:60])=[O:58])=[CH:61][CH:62]=2)=[CH:48][CH:49]=1)=[O:42])=[O:11])(=[O:6])=[O:5])[CH3:2]
Reactant: CCN([C@H]1CC[C@H](C(=O)OC)CC1)S(=O)(=O)c1cccc(C(=O)O)c1
Reactant: COC(=O)c1ccc(CCCc2ccc(NC(=O)c3c(N)sc4c3CCCC4)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCN([C@H]1CC[C@H](C(=O)OC)CC1)S(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 332 mg of 3-{ethyl[trans-4-(methoxycarbonyl)cyclohexyl]sulfamoyl}benzoic acid, one drop of DMF, and 3 mL of dichloromethane was added 0.11 mL of oxalyl chloride under ice-cooling, followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and then to a mixture of the obtained crude product and 3 mL of dichloromethane were added 0.11 mL of pyridine and 300 mg of methyl 4-[3-(4-{[(2-amino-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)propyl]benzoate, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate and hexane-chloroform) to obtain 241 mg of methyl 4-(3-{4-[({2-[(3-{ethyl[trans-4-(methoxycarbonyl)cyclohexyl]sulfamoyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}propyl)benzoate as a yellow amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].[OH-].[Na+].[Cl:14][C:15]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.Cl>O.CCO>[Cl:14][C:15]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:16]=1/[CH:17]=[CH:9]/[C:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([CH3:11])[CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(O)c(C)c1
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=O)/C=C/c2cccc(Cl)c2Cl)ccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.4 %

Procedure:
To a mixture of 1-(4-hydroxy-3-methylphenyl)ethanone (0.7 g, 4.66 mmol) (ICC, Indofine Chemical Company Inc.) and NaOH (0.36 g, 9.1 mmol) in 10 mL of 200 proof EtOH was added 2,3-dichlorobenzaldehyde (0.8 g, 4.66 mmol) (ACROS). The reaction mixture was stirred at rt for 18 h. Upon completion by LC/MS, 5 mL of H2O was added and the reaction mixture was acidified with conc. HCl to pH 5-6. The resulting precipitate was filtered, washed with water and dried to yield (E)-3-(2,3-dichlorophenyl)-1-(4-hydroxy-3-methylphenyl)prop-2-en-1-one, (0.45 g, 31%). MS (EI) for C16H12C2O2, 308.3 (MH+).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH:9][C:10]3[CH:15]=[C:14]([Cl:16])[N:13]=[C:12](Cl)[N:11]=3)[NH:7][N:8]=2)[CH2:3][CH2:2]1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[SH:28].C(N(CC)CC)C>C(O)(C)(C)C>[Cl:16][C:14]1[N:13]=[C:12]([S:28][C:19]2[CH:20]=[CH:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)[N:11]=[C:10]([NH:9][C:6]2[NH:7][N:8]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[CH:5]=2)[CH:15]=1
Reactant: Sc1ccc2ccccc2c1
Reactant: Clc1cc(Nc2cc(C3CC3)n[nH]2)nc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: Clc1cc(Nc2cc(C3CC3)n[nH]2)nc(Sc2ccc3ccccc3c2)n1
Temperature: 25 °C

Procedure:
To a solution of (5-cyclopropyl-2H-pyrazol-3-yl)-(2,6-dichloropyrimidin-4-yl)-amine (211 mg, 0.781 mmol) and 2-naphthalenethiol (125-mg, 0.781 mmol) in tert-butanol (5 mL) was added triethylamine (174 μL, 1.25 mmol) and the resulting mixture was heated at reflux for 15 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and aqueous NaHCO3. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, Hexane/AcOEt gradient) to afford (6-chloro-2-(naphthalen-2-ylsulfanyl)-pyrimidin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([N:8]([CH3:18])[C:9]2[N:14]=[CH:13][N:12]=[C:11]3[NH:15][N:16]=[CH:17][C:10]=23)[CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:40][C:41]1[CH:42]=[C:43]([NH:48][CH2:49][C:50](O)=[O:51])[CH:44]=[C:45]([Cl:47])[CH:46]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O.C(OCC)(=O)C>[NH:15]1[C:11]2=[N:12][CH:13]=[N:14][C:9]([N:8]([CH:3]3[CH2:4][CH2:5][CH2:6][CH2:7][N:1]([C:50](=[O:51])[CH2:49][NH:48][C:43]4[CH:42]=[C:41]([Cl:40])[CH:46]=[C:45]([Cl:47])[CH:44]=4)[CH2:2]3)[CH3:18])=[C:10]2[CH:17]=[N:16]1
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Reactant: CN(c1ncnc2[nH]ncc12)C1CCCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ncnc2[nH]ncc12)C1CCCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(azepan-3-yl)-N-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (350 mg, 1.4 mmol) in DMF (7 mL) was added EDCI (409 mg, 2.1 mmol), HOBt (287 mg, 2.1 mmol), 2-(3,5-dichlorophenylamino)acetic acid (312 mg, 1.4 mmol) and DIEA (0.5 mL, 2.8 mmol) at 0° C. The reaction mixture was stirred at rt overnight and diluted with water and ethyl acetate (3:1, 400 mL). The organic layer was dried over Na2SO4 and evaporated in vacuo to give the crude compound that purified by column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford (325 mg 51%) the titled compound. 1H NMR (DMSO-d6, 400 MHz): δ 13.50 and 13.44 (2s, 1H), 8.25-8.19 (m, 2H), 6.74 (s, 1H), 6.68 (s, 1H), 6.62 (s, 1H), 6.36 (bs, 1H), 4.21-3.71 (m, 5H), 3.42-3.01 (m, 2H), 3.31 (s, 3H), 1.93-1.65 (m, 6H). LC-MS: m/z [M+1]=448.