Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=1)[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.[F:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:14]=2)[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])(=[O:41])=[O:40])=[CH:35][CH:34]=1
Reactant: COC(=O)CCC(CCCCN)c1cccc(-c2cccnc2)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(F)cc1)c1cccc(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 0.144 g (0.44 mmol) methyl 8-amino-4-[m-(3-pyridyl)-phenyl]-octanoate in 2 ml methylene chloride is added a catalytic amount (0.02 g) 4-dimethylaminopyridine followed by 0.08 ml (0.57 mmol) triethylamine and 0.098 g (0.5 mmol) p-fluorophenylsulfonyl chloride. The mixture is stirred at room temperature for 18 h, diluted with methylene chloride, washed with saturated sodium bicarbonate solution, water and brine, dried, filtered and evaporated to give a greenish oil which is purified by chromatography using 3:2 ethyl acetate/hexane as eluent to obtain methyl 8-(p-fluorophenylsulfonamido)-4-[m-(3-pyridyl)-phenyl]-octanoate as an oil; NMR (CDCl3): delta 3.63 (s,3H), 2.9 (q,2H), 8.95 (d,1H), 8.67 (dd,2H).
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[S:19](Cl)(=[O:21])=[O:20].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O>[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[S:19]([O:4][CH2:3][C:2]([F:8])([F:1])[CH:5]([F:7])[F:6])(=[O:20])=[O:21]
Reactant: OCC(F)(F)C(F)F
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(OCC(F)(F)C(F)F)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.2 %

Procedure:
A mixture of 52.8 parts of 2,2,3,3-tetrafluoro-1-propanol, 117.8 parts of 2-naphthalenesulfonyl chloride, 294 parts of pyridine and 2.0 parts of N,N-dimethyl-4-pyridinamine was stirred for 48 hours at room temperature. The reaction mixture was diluted with water and the whole was left to crystallize. The product was filtered off, washed with water and recrystallized from 2-propanol, yielding 98.2 parts (76.2%) of 2,2,3,3-tetrafluoropropyl 2-naphthalenesulfonate; mp. 89.6° C. (interm. 27).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[N:17]=[C:16]2[O:18][C:19]([CH3:31])([CH3:30])[CH2:20][CH:21]([NH:22]C(OC(C)(C)C)=O)[C:15]2=[CH:14][C:13]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:5]([O:7][CH3:8])=[O:6].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][CH:21]1[C:15]2[C:16](=[N:17][C:12]([C:11]3[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=3[Cl:1])=[C:13]([C:32]3[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=3)[CH:14]=2)[O:18][C:19]([CH3:31])([CH3:30])[CH2:20]1
Reactant: COC(=O)c1ccc(-c2nc3c(cc2-c2ccc(Cl)cc2)C(NC(=O)OC(C)(C)C)CC(C)(C)O3)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(-c2nc3c(cc2-c2ccc(Cl)cc2)C(N)CC(C)(C)O3)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 315 (200 mg, 0.36 mmol) in 5.0 mL of CH2Cl2 was added 500 μL of TFA. After stirring at rt for 16 h, the reaction mixture was concentrated. The amine TFA salt was taken onto next step without further purification.
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[S:7][N:6]=1)(=O)=O.[CH2:16]([OH:20])[C:17]#[C:18][CH3:19].[H-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[CH:10]1([C:8]2[S:7][N:6]=[C:5]([O:20][CH2:16][C:17]#[C:18][CH3:19])[N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC#CCO
Reactant: CS(=O)(=O)c1nsc(C2CCCCC2)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1nsc(C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
200 mg of 3-methylsulfonyl-5-cyclohexyl-1,2,4-thiadiazole and 63 mg of 2-butyn-1-ol were dissolved in 2 g of N,N-dimethylformamide, 39 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 30 minutes under ice-cooling and for 1 hour at room temperature. Then, the reaction mixture was added to saturated brine, and extracted with t-butyl methyl ether. The organic layer was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography to give 79 mg of 5-cyclohexyl-3-(2-butynyloxy)-1,2,4-thiadiazole (hereinafter referred to as the present invention compound (1)).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]([S:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:12]=1[CH:23]=O>C1(O)CCCCC1>[Cl:10][C:11]1[C:12]2[CH:23]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[S:17][C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: COC(=O)CSc1ncnc(Cl)c1C=O
Solvent: OC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2c(Cl)ncnc2s1
Temperature: 120 °C
Yield: 53.9 %

Procedure:
DIPEA (2.1 mL) was added to methyl [(6chloro-5-formylpyrimidin-4-yl)thio]acetate (intermediate 9) (2.9 g) in cyclohexanol (50 mL) under an inert atmosphere. The reaction mixture was heated at 120° C. for 90 minutes. The solvent was evaporated and the product purified by flash chromatography on silica eluting with hexane:diethyl ether (4:1) to afford the title compound as a pale yellow solid (1.45 g, 53%);
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[CH:7][C:8]3[CH:22]=[N:21][CH:20]=[N:19][C:9]=3[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=O)[C:11]=3[N:5]2[CH2:4][N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:36][C:37]([CH:39]1[CH2:41][CH2:40]1)=[NH:38].C(O)(=O)C>CN(C=O)C>[CH:39]1([C:37]2[N:38]=[C:16]([C:12]3[C:11]4[N:5]5[CH2:4][N:3]=[C:2]([CH3:1])[C:6]5=[CH:7][C:8]5[CH:22]=[N:21][CH:20]=[N:19][C:9]=5[C:10]=4[CH:15]=[CH:14][CH:13]=3)[O:18][N:36]=2)[CH2:41][CH2:40]1
Reactant: CC1=NCN2C1=Cc1cncnc1-c1cccc(C(=O)O)c12
Reactant: N=C(NO)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1=NCN2C1=Cc1cncnc1-c1cccc(-c3nc(C4CC4)no3)c12
Temperature: 85 °C
Yield: 59 %

Procedure:
To a suspension of 6-methyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid (1.0 g, 3.4 mmol) in DMF (15 mL) was added 1,1′-carbonyldiimidazole (0.61 g, 3.76 mmol) followed by N-hydroxy-cyclopropanecarboxamidine and the resulting solution was heated at 85° C. for 1.5 h. Then acetic acid (3.4 mL) was added and the resulting mixture heated at 130° C. for 40 min. After cooling, the mixture was evaporated and dissolved n DCM (15 mL). This DCM extract was washed with sodium hydrogen carbonate (saturated solution, 40 mL) and then the aqueous phase was washed with DCM (20 mL). The combined DCM layers were then dried over MgSO4 and evaporated. The residue was recrystallized from ethyl acetate: hexane to afford the product (720 mg, 59%) as white crystals, mp 216-218° C., m/z 356 (M).
Reaction SMILES: COC1C=CC([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=CC=1.C(Br)CC>CC(C)=O>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[O:13][CH2:12][CH2:11][CH2:10][NH2:9]
Reactant: COc1ccc(NCCCOc2ccc3ccccc3c2)cc1
Solvent: CC(C)=O
Solvent: CCCBr
Product: NCCCOc1ccc2ccccc2c1

Procedure:
A mixture of N-(4-methoxyphenyl)-[3-(naphthalen-2-yloxy)propyl]amine (0.5 gm, 0.002 mole) and propyl bromide (0.54ml, 0.003 mole) was taken in dry acetone (40 ml). It was refluxed for 12 hrs and the progress of reaction checked by TLC. Reaction mixture was filtered and the filtrate was concentrated to get oily compound which was further crystallized by benzene hexane mixture to get N-(4-methoxyphenyl)-N-propyl[3-(naphthalen-2-yloxy)propylamine, yellow solid, m.p. 127° C., (yield 0.67 gm, 95.7%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:15]3[N:14]=[CH:13][C:12]4[N:18]([CH3:35])[C:19](=[N:32][C:33]#[N:34])[N:20]([C:21]5[CH:22]=[N:23][C:24]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])=[CH:25][CH:26]=5)[C:11]=4[C:10]=3[CH:9]=2)=[CH:4][C:3]=1[C:36]([F:39])([F:38])[F:37].[C:40]([O-:43])(=O)[CH3:41].[K+]>C(OC(=O)C(CCC)CCC)(=O)C(CCC)CCC.O>[C:33]([N:32]=[C:19]1[N:18]([CH3:35])[C:12]2[CH:13]=[N:14][C:15]3[CH:16]=[CH:17][C:8]([C:5]4[CH:4]=[C:3]([C:36]([F:38])([F:37])[F:39])[C:2]([NH:1][C:40](=[O:43])[CH:41]([CH2:6][CH2:5][CH3:8])[CH2:2][CH2:3][CH3:4])=[N:7][CH:6]=4)=[CH:9][C:10]=3[C:11]=2[N:20]1[C:21]1[CH:22]=[N:23][C:24]([C:27]([C:30]#[N:31])([CH3:28])[CH3:29])=[CH:25][CH:26]=1)#[N:34]
Reactant: CC(=O)[O-]
Reactant: Cn1c(=NC#N)n(-c2ccc(C(C)(C)C#N)nc2)c2c3cc(-c4cnc(N)c(C(F)(F)F)c4)ccc3ncc21
Agent: CCCC(CCC)C(=O)OC(=O)C(CCC)CCC
Agent: [K+]
Solvent: O
Product: CCCC(CCC)C(=O)Nc1ncc(-c2ccc3ncc4c(c3c2)n(-c2ccc(C(C)(C)C#N)nc2)c(=NC#N)n4C)cc1C(F)(F)F
Reaction time: 2 h

Procedure:
N-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (Example 5, 0.379 mmol) was stirred in valproic anhydride (5 mL). Potassium acetate (0.379 mmol) was added to it and the reaction was carried out at 110-115° C. for 2 h. The reaction mixture was cooled, diluted with water and extracted with ethyl acetate. Organic layer was concentrated, dried using anhydrous sodium sulfate and purified on silica gel column to obtain the title compound. 1H NMR (300 MHz, DMSO-d6): δ 10.21 (s, 1H), 9.32 (s, 1H), 9.08 (s, 1H), 8.63 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.28 (d, J=5.1 Hz, 1H), 8.18-8.15 (m, 1H), 8.01 (d, J=5.1 Hz, 1H), 7.06 (s, 1H), 3.94 (s, 3H), 1.77 (s, 3H), 1.56 (m, 2H), 1.35 (s, 6H), 1.23 (s, 1H), 0.91 (s, 6H); MS (m/z): 654.4 (M+1)+.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:18](O)=O)=[N:9][O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:21]/[N:22]=[C:23](/[C:25]1[CH:42]=[CH:41][C:28]([CH2:29][N:30]2[CH2:33][CH:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31]2)=[CH:27][CH:26]=1)\[NH2:24].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:1]1([C:7]2[C:8]([C:18]3[O:21][N:22]=[C:23]([C:25]4[CH:26]=[CH:27][C:28]([CH2:29][N:30]5[CH2:31][CH:32]([C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[CH2:33]5)=[CH:41][CH:42]=4)[N:24]=3)=[N:9][O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Reactant: O=C(O)c1noc(-c2ccccc2)c1-c1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4noc(-c5ccccc5)c4-c4ccccc4)n3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
A mixture of 4,5-diphenylisoxazole-3-carboxylic acid (26.5 mg, 0.1 mmol), (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate, Int.1, (30.5 mg, 0.100 mmol), HOBT (16.85 mg, 0.110 mmol) and EDC (21.09 mg, 0.110 mmol) in DMF (1 mL) was stirred at rt for 18 hr. The reaction mixture was warmed to 60° C. for 2 hr and 70° C. for 2 hr. After cooling to rt overnight, the reaction mixture was partitioned between EtOAc (30 ml) and saturated sodium bicarbonate solution (30 ml). The organic layer was washed with water (2×30 ml) and brine (20 ml). After drying (MgSO4) and filtration, the organic layer was concentrated to a yellow solid that was chromatographed on a 4 gm Isco silica gel cartridge, eluting with a 0-60% EtOAc/Hex gradient. The pure fractions were concentrated to afford tert-butyl 1-(4-(5-(4,5-diphenylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (37 mg, 0.069 mmol, 69.2% yield) as a white solid. HPLC retention time=1.90 minutes (YMC Combi 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1 TFA a 2 minute gradient.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:10])[C:4]=2[CH:3]=[CH:2]1.[CH:11]([N-]C(C)C)(C)C.[Li+].IC.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:11][CH:8]1[C:9](=[O:10])[C:4]2[CH:3]=[CH:2][S:1][C:5]=2[CH2:6][CH2:7]1
Reactant: O=C1CCCc2sccc21
Reactant: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1CCc2sccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a solution of 6,7-dihydro-1-benzothiophen-4(5H)-one (1.63 g) in tetrahydrofuran (90 ml) at −78° C. under N2 was added lithium diisopropyl amide (5.89 ml, 2 M). After 30 min, iodomethane (0.732 ml) was added and the reaction was allowed to warm to ambient temperature. After 2 h, the reaction mixture was poured into saturated sodium bicarbonate (100 ml), extracted methylene chloride (3×100 ml), dried MgSO4, filtered and concentrated. MPLC was run on a biotage 40M column with 4-6% ethyl acetate/heptane to provide the title compound as an oil (560 mg, 32%): 1H NMR (300 MHz, CDCl3) δ) 7.41, 7.08, 3.15-2.99, 2.61-2.53, 2.33-2.25, 2.06-1.92, 1.28; HRMS (FAB) calcd for C9H10OS+H 167.0531, found 167.0527.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.Cl.[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([OH:27])[C:21]=1[OH:28].CCN(CC)CC>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([OH:27])[C:21]=1[OH:28]
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: NCc1ccc(O)c(O)c1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2C1=CNCc1ccc(O)c(O)c1O
Yield: 28.9 %

Procedure:
To a mixture of 6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (200 mg, 0.71 mmol) and 4-aminomethyl-benzene-1,2,3-triol hydrochloride salt (139.6 mg, 1 mmol) in N,N-dimethylformamide (DMF) (10 mL) is added Et3N (0.25 mL, 1.83 mmol). The resulting precipitate is filtered to give 83 mg (28.9%) of the title compound as a dark brown solid. (ESI) m/z 403.0 (M−H)−1. 1H NMR (DMSO-d6) δ 4.53 (d, 2H, J=6 Hz), 6.29 (d, 1H, J=8 Hz), 6.55 (d, 1H, J=8 Hz), 7.28 (d, 1H, J=8 Hz), 7.85 (d, 1H, J=8 Hz), 8.05 (s, 1H), 8.39 (s, 1H), 8.67 (d, 1H, J=12 Hz), 8.80 (s, 1H), 9.18 (s, 1H), 10.63-10.68 (m, 1H), 11.05 (s, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][N:14]([CH3:21])[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:18]2[CH2:19][CH2:20][CH:15]([N:14]([CH3:21])[CH3:13])[CH2:16][CH2:17]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN(C)C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCC(N(C)C)CC2)ccc1[N+](=O)[O-]

Procedure:
A solution of 4-fluoro-2-methoxy-1-nitrobenzene (1.711 g, 10 mmol), N,N-dimethylpiperidin-4-amine (1.410 g, 11.00 mmol) and N-ethyl-N-isopropylpropan-2-amine (3.48 mL, 20.00 mmol) in anhydrous N,N-dimethylformamide (25 mL) was stirred at 70° C. overnight. The mixture was concentrated and the residue was mixed with water (60 mL), adjusted to pH 12, then extracted with CH2Cl2. The crude product was purified on a silica gel column eluting with 7.5% methanol in CH2Cl2 saturated with NH3 to provide the title compound. (ESI+) m/e 280.1 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.[CH3:19][O:20][C:21](=[O:42])[CH2:22][CH:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][C:32](C3C=CC(Br)=CN=3)=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[CH3:19][O:20][C:21](=[O:42])[CH2:22][CH:23]1[CH2:24][CH2:25][CH:26]([C:29]2[CH:30]=[CH:31][C:32]([C:2]3[CH:7]=[N:6][C:5]([NH:8][C:9]4[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=4)=[CH:4][N:3]=3)=[CH:33][CH:34]=2)[CH2:27][CH2:28]1
Reactant: FC(F)(F)c1ccc(Nc2cnc(Br)cn2)cn1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(Br)cn3)cc2)CC1
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: COCCOC
Product: COC(=O)CC1CCC(c2ccc(-c3cnc(Nc4ccc(C(F)(F)F)nc4)cn3)cc2)CC1
Temperature: 130 °C

Procedure:
A solution of (5-Bromopyrazin-2-yl)-(6-trifluoromethyl-pyridin-3-yl)-amine (0.072 g) and {4-[4-(5-bromo-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (0.087 g) in 2 Ml DME was charged with 2 M sodium carbonate (1 Ml) and Pd(PPh3)4 (0.027 g, 0.1 equiv). The biphasic mixture was sparged with nitrogen for 3 min, then stirred at 130° C. under microwave heating for 30 min. The reaction was partitioned between EtOAc and water, and the organic extracts were dried over magnesium sulphate and concentrated in vacuo. Purification by silica gel chromatography (33% EtOAc in hexanes) afforded the title compound: (M+H)+471.2.
Reaction SMILES: C(Cl)([Cl:3])=O.[CH3:5][N:6]([CH3:13])[CH2:7][CH2:8][S:9]([O-])(=[O:11])=[O:10].[Na+].CN(C=O)C>C(Cl)Cl>[CH3:5][N:6]([CH3:13])[CH2:7][CH2:8][S:9]([Cl:3])(=[O:11])=[O:10]
Reactant: CN(C)CCS(=O)(=O)[O-]
Reactant: O=C(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)CCS(=O)(=O)Cl

Procedure:
Phosgene (12 ml, 1M in toluene) was added to a solution of the subtitle product of step i) in DCM (20 ml) and DMF (2.5 ml) and stirred for 3 h before concentrating in vacuo to afford the subtitle compound as an oil that was used directly in the next step. 1H NMR δ(CD3OD) 3.30 (2H, m), 2.80 (2H, m) and 2.31 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([CH:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][C:29]=4[Cl:31])[C:24](=[O:32])[O:23]3)=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([CH:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][C:29]=4[Cl:31])[C:24](=[O:32])[O:23]3)=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34]
Reactant: COCN(c1cc(Cl)cnc1C1OC(=O)c2cccc(Cl)c21)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C1OC(c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c2c(Cl)cccc21
Temperature: 25 °C
Yield: 57.2 %

Procedure:
A mixture of 4-chloro-N-[5-chloro-2-(7-chloro-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzene-sulfonamide (77 mg, 0.13 mmol) in 4M HCl in dioxane (3 mL) and water (1 mL) was heated at reflux for 3 h. The reaction mixture was then cooled to room temperature, evaporated to dryness and neutralized with saturated aqueous NaHCO3 solution to pH 2-3. The aqueous layer was extracted with EtOAc (2×25 mL), dried (Na2SO4), and concentrated. The obtained residue was purified by flash chromatography on silica gel (50% EtOAc-hexanes) to afford 4-chloro-N-[5-chloro-2-(7-chloro-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (40 mg) as a white solid in 56% yield. MS m/z: 537 (M+H), 559 (M+Na).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[O:5][CH2:4][CH2:3]1.[Li].Cl[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=1>O1CCCC1.CCCCCC>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=3)[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCO2
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCO3)nc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Reaction vessels used in this procedure were flame dried under vacuum and all operations were carried out in an oxygen-free, argon or nitrogen atmosphere. To a solution of 509.4 mg (2.74 mmol) of 4,4-dimethyl-6-ethynylchroman in 4 ml of dry tetrahydrofuran at 0° C. was added dropwise 1.72 ml of 1.6M (2.75 mmol) of n-buryl lithium in hexane. Stirring was commenced at 0° C. for 30 minutes and at room temperature for 15 minutes, after which the solution was cooled again to 0° C. and then treated with a solution of 380 mg (2.79 mmol) of fused zinc chloride in 5 ml of dry tetrahydrofuran using a double ended needle. The resulting solution was stirred at 0° C. for 1 hour and then at room temperature for 15 minutes. A solution of 628.6 mg (2.74 mmol) of ethyl 6-chloronicotinate in 4 ml of dry tetrahydrofuran was transferred by double ended needle into a suspension of 380 mg (0.33 mmol) of tetrakistriphenylphosphine palladium in 5 ml dry tetrahydrofuran and mixture stirred at room temperature for 15 minutes and then treated by double ended needle with the solution of alkynylzinc prepared above. The mixture was stirred at room temperature for 20 hours and then quenched with ice and 30 ml of 3N hydrogen chloride. The mixture was extracted with (MgSO4). Solvent was removed in vacuo and the residue further 3×75 ml ether and ether extracts were combined and washed successively with saturated NaHCO3 and saturated NaCl and then dried purified by flash chromatography (silica; 10% ethyl acetate in hexane) to give the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[C:38]([O:42][C:43](=[O:51])[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43](=[O:51])[NH:44][CH:45]1[CH2:50][CH2:49][N:48]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:47][CH2:46]1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: CC(C)(C)OC(=O)NC1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and piperidin-4-yl-carbamic acid t-butyl ester according to conditions described in general procedure C. Mp: 214-216° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.33-1.41 (m, 14 H), 2.47-3.41 (m, 4H), 3.25-3.28 (m, 4H), 3.75-3.78 (m, 4 H), 4.20 (s, 1 H), 6.20 (d, J=5.5 Hz, 1H), 6.77-6.79 (m, 1 H), 7.00-7.05 (m, 1H), 7.18-7.26 (m, 1H), 7.38-7.63 (m, 5H), 7.85 (d, J=9.2 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 8.26 (d, J=5.5 Hz, 1H), 10.47 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[C:8]([OH:10])[CH:9]=1)([O-])=O.BrC1C=CC([N+]([O-])=O)=CC=1O>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:11]([F:12])([F:13])[F:14])=[C:8]([OH:10])[CH:9]=1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)c(O)c1
Agent: [Ni]
Agent: O=[N+]([O-])c1ccc(Br)c(O)c1
Solvent: CO
Product: Nc1ccc(C(F)(F)F)c(O)c1
Reaction time: 4 h
Yield: 11 %

Procedure:
To a solution of 5-nitro-2-(trifluoromethyl)phenol and 2-bromo-5-nitrophenol (10 g, crude) in MeOH (60 mL) was added Raney Ni (2 g) under an atmosphere of nitrogen. The mixture was stirred under hydrogen atmosphere (1 atm) at r. t. for 4 h. The catalyst was filtered off through the celite pad and the filtrate was evaporated under vacuum. The crude product was purified by preparative HPLC to obtain 5-amino-2-(trifluoromethyl)phenol (1.7 g, 11% yield for 3 steps). 1H-NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 7.04 (d, J=8.8 Hz, 1H), 6.10 (s, 1H), 6.01 (d, J=8.4 Hz, 1H), 5.58 (br s, 2H).