Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([O:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:14])=[O:13])=[CH:7]2.[C:21]([Li])(C)(C)C.CN(C)C=O>CCOCC>[CH3:21][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([O:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:14])=[O:13])=[CH:7]2
Reactant: CC(C)(C)COS(=O)(=O)c1ccc2c(Br)cccc2c1
Reactant: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cccc2cc(S(=O)(=O)OCC(C)(C)C)ccc12
Reaction time: 1 h

Procedure:
To a cooled (-80° C.) solution of neopentyl 5-bromonaphthalene-2-sulfonate (300 mg; 0.84 mmol) in anhydrous ether (12 mL) is added tert-butyllithium (1.7M in ether) (1 mL; 1.7 mmol), immediately followed by a solution of dimethylformamide (125 mg; 1.7 mmol) in ether (2 mL). The external cooling bath is removed and stirring is allowed to proceed for 1 hour. The reaction mixture is quenched with water (10 mL), the two solution phases are separated and the aqueous phase is extracted with ether (2×10 mL). The combined organic phase is dried (MgSO4), filtered and concentrated under reduced pressure to afford crude neopentyl 5-methylnaphthalene-2-sulfonate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]([NH2:28])=[N:15][CH:16]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:18]=1)[CH3:11].I[C:30]1[CH:31]=[N:32][N:33]([CH:35]2[CH2:50][CH2:49][C:38]3([CH2:41][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:39]3)[CH2:37][CH2:36]2)[CH:34]=1>>[NH2:28][C:14]1[N:15]=[CH:16][C:17]([C:30]2[CH:31]=[N:32][N:33]([CH:35]3[CH2:50][CH2:49][C:38]4([CH2:41][N:40]([C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[CH2:39]4)[CH2:37][CH2:36]3)[CH:34]=2)=[CH:18][C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC2(CCC(n3cc(I)cn3)CC2)C1
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N)c1c(Cl)ccc(F)c1Cl
Product: C[C@@H](Oc1cc(-c2cnn(C3CCC4(CC3)CN(C(=O)OC(C)(C)C)C4)c2)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared as a off-white solid from (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine and tert-butyl 7-(4-iodo-1H-pyrazol-1-yl)-2-azaspiro[3.5]nonane-2-carboxylate under the conditions described in Step 6 of Example 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([F:9])=[C:7]([O:10][CH3:11])[CH:6]=[CH:5][C:4]=1I.[C:13]([C:15]1[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=1)#[CH:14].C(#N)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:8]([F:9])=[C:7]([O:10][CH3:11])[CH:6]=[CH:5][C:4]=1[C:14]#[C:13][C:15]1[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=1
Reactant: COc1ccc(I)c(OC)c1F
Reactant: C#Cc1cnn(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C#Cc2cnn(C)c2)c(OC)c1F
Reaction time: 1 h
Yield: 86 %

Procedure:
To a mixture of (0.95 mmol) of 2,4-dimethoxy-3-fluoro-iodo benzene, 0.122 g (1.15 mmol) of 4-ethynyl-1-methyl-1H-pyrazole, 0.028 g (0.04 mmol) of dichlorobis(triphenylphosphine)palladium (II) and 8 mg (0.042 mmol) of copper (I) iodide 4 mL of anhydrous acetonitrile and 2 mL of triethylamine were added under nitrogen atmosphere at room temperature. The resulting mixture was stirred for 1 hour, when TLC indicated a consumption of the iodobenzene. The solvent was evaporated under reduced pressure and the residue purified by flash column chromatography (silica gel; dichloromethane:ethyl acetate 9:1) to give the title compound in an 86% yield as creamy crystals. H1 NMR (CDCl3) 3.88 (s, 3H, Me); 3.89 (s, 3H, MeO); 4.05 (d, 3H, MeO, J=1.34 Hz); 6.62 (tr, 1H, CH, J=8.2 Hz); 7.12 (dd, 1H, CH, J=8.2 Hz, J=2.55 Hz); 7.53 (s, 1H, CH pyr); 7.62 s, 1H, CH pyr).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:17][C:18]1[CH:19]=[C:20]([N:24]=[C:25]=[O:26])[CH:21]=[CH:22][CH:23]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=2)=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2cccc(Cl)c2)cc1-c1c(Br)cnn1C
Yield: 92.2 %

Procedure:
To a stirred solution of 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.015 g, 0.051 mmol) in CH2Cl2 (1 mL) was added 3-chlorophenyl isocyanate (0.008 g, 7 μL, 0.054 mol, 1.05 equiv.). After the TLC showed the consumption of the starting material, it was isolated by preparative thin layer chromatography (TLC) (Eluent: EtOAc/Hexane=1/1) and Compound 20 (0.020 g, 0.047 mmol, 92%) was obtained as a solid film. LCMS m/z (%)=435 (M+H79Br, 68), 437 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.29 (s, 1H), 8.19 (s, 1H), 7.80 (t, J=1.9 Hz, 1H), 7.29 (dd, J=2.7, 9.0 Hz, 1H), 7.49 (s, 1H), 7.43 (d, J=2.7 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H), 7.14 (d, J=9.0 Hz, 1H), 7.00 (d, J=7.8 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13]3[N:17]([CH3:18])[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])=[N:15][N:14]=3)([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)[NH2:4].[F:29][C:30]1([F:37])[CH2:33][CH:32]([C:34](O)=O)[CH2:31]1.C(N1C=CN=C1)(N1C=CN=C1)=O>C(Cl)Cl>[F:29][C:30]1([F:37])[CH2:33][CH:32]([C:34]2[O:1][N:2]=[C:3]([C:5]34[CH2:12][CH2:11][C:8]([C:13]5[N:17]([CH3:18])[C:16]([C:19]6[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=6[C:25]([F:28])([F:27])[F:26])=[N:15][N:14]=5)([CH2:9][CH2:10]3)[CH2:7][CH2:6]4)[N:4]=2)[CH2:31]1
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(C(N)=NO)(CC1)CC2
Reactant: O=C(O)C1CC(F)(F)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(c3noc(C4CC(F)(F)C4)n3)(CC1)CC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N′-Hydroxy-4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]octane-1-carboximidamide (1-G) (120 mg, 0.305 mmol) was added to a pre-stirred solution of 3,3-difluorocyclobutanecarboxylic acid 2-D (166 mg, 1.22 mmol) and carbonyldiimidazole (198 mg, 1.22 mmol) in CH2Cl2 (8 ml). The resulting mixture was stirred at room temperature for 48 h, then concentrated. The solid was resuspended in toluene and refluxed under nitrogen atmosphere for 3 h. The product was purified by C-18 reverse phase HPLC eluting with 30-80% acetonitrile/water with 0.1% TFA to yield 2-E as a white powder. MS (ESI+)=494.2 (M+1); 1H NMR (500 MHz, CDCl3): δ 2.09 (6H, m), 2.31 (6H, m), 3.03-3.11 (4H, m), 3.57-3.61 (4H, m), 7.56 (1H, m), 7.71 (2H, m), 7.86 (1H, m) ppm. Shh-Light II Assay: IC50: 1.4 μM.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[C:20]2[CH:21]=[CH:22][NH:23][C:24](=[O:25])[C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[N:16][CH:17]=2)[N:12]=1.C(N(CC)CC)C.[CH3:33][C:34]([OH:38])([C:36]#[CH:37])[CH3:35]>CN(C=O)C.[Cu]I.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>[Cl:1][C:2]1[CH:7]=[C:6]([C:37]#[C:36][C:34]([OH:38])([CH3:35])[CH3:33])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[C:20]2[CH:21]=[CH:22][NH:23][C:24](=[O:25])[C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[N:16][CH:17]=2)[N:12]=1
Reactant: O=c1[nH]ccc2c(Nc3c(Cl)cc(I)cc3Cl)nc3ccncc3c12
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(O)C#Cc1cc(Cl)c(Nc2nc3ccncc3c3c(=O)[nH]ccc23)c(Cl)c1
Temperature: 80 °C

Procedure:
To a solution of 6-[(2,6-dichloro-4-iodophenyl)amino]pyrido[4,3-c]-1,6-naphthyridin-10(9H)-one (50 mg, 0.10 mmol) in DMF (4 mL) were added CuI (3.94 mg, 0.02 mmol), triethylamine (30 uL, 0.20 mmol), tetrakis(triphenylphosphine)palladium (0) (12 mg, 10.4 umol), and 2-methylbut-3-yn-2-ol (17.4 mg, 0.21 mmol). The mixture was degassed by bubbling nitrogen gas and heated to 80° C. overnight. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc. The organic layers were combined, dried with MgSO4, filtered, and concentrated under reduced pressure. Purification by column chromatography on silica gel (100% CH2Cl2 to 70% CH2Cl2/30% MeOH) afforded the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>CN(C=O)C.CC(=O)OCC>[OH:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:5]=1
Reactant: NCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CNCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
Prepared using General Procedure 13: To a stirred solution of 4-(aminomethyl)phenol (2.0 g, 16.2 mmol) in DMF (10 mL) was added TEA (4.53 mL, 32.5 mmol) followed by tert-butyl 2-bromoacetate (2.40 mL, 16.2 mmol) added drop-wise over 30 minutes. After stirring a further 1 h at room temperature, the reaction mixture was diluted with EA (100 mL) and washed with water (2×100 mL). The organics were isolated and pre-absorbed onto silica gel then purified by silica gel chromatography (EA/isohexanes) to afford 1.86 g (48%) tert-butyl 2-((4-hydroxybenzyl)amino)acetate INT-22 as a white powder. LCMS-ESI (m/z) calculated for C13H19NO3: 237 found 236 [M−H]−, tR=1.20 min (Method 10). 1H NMR (400 MHz, DMSO) δ 9.24 (s, 1H), 7.12-7.05 (m, 2H), 6.73-6.66 (m, 2H), 3.55 (s, 2H), 3.12 (s, 2H), 2.15 (s, 1H) 1.41 (s, 9H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[C:10]=1[C:11]#[N:12])=[O:7])(=[O:3])[CH3:2].C1CCCCC=1.C([OH:28])C>[C].[Pd]>[C:1]([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[C:10]=1[C:11]([NH2:12])=[O:28])=[O:7])(=[O:3])[CH3:2]
Reactant: CCO
Reactant: CC(=O)OCC(=O)Nc1cccc([N+](=O)[O-])c1C#N
Agent: [Pd]
Solvent: C1=CCCCC1
Product: CC(=O)OCC(=O)Nc1cccc(N)c1C(N)=O
Temperature: 25 °C

Procedure:
To a mixture of 2-(acetoxyacetylamino)-6-nitrobenzonitrile (5.7 g) and ethanol (50 ml) are added cyclohexene (10.5 ml) and 10% palladium-carbon (4.7 g). The mixture is refluxed for 20 minutes, and the reaction mixture is cooled to room temperature, and the solid materials are filtered off. The filtrate is distilled under reduced pressure. The residual crude crystals are recrystallized from ethanol to give the title compound (1.2 g) having the following physical properties.
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:18]1([C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][CH:26]=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([BH3-])#N>ClCCl.CO>[C:18]1([C:24]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:25][CH2:26][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=3)[CH2:6][CH2:5]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=CC=C(c1ccccc1)c1ccccc1
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1ccc(N2CCN(CC=C(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of ethyl 4-piperazin-1-ylbenzoate (1.36 g) and 3,3-diphenylacrylaldehyde (1.56 g) in dichloromethane (10 mL) and methanol (10 mL) was treated with polymer-supported cyanoborohydride (2.47 mmol/g, 6 g), shaken at room temperature for 24 hours, and filtered. The resin was washed with 1:1 dichloromethane/methanol (10 mL×3) and the combined filtrates were concentrated. The concentrate was purified by silica gel chromatography eluting with a gradient from 10%-50% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[C:13]([Cl:33])=[CH:14][C:15]([F:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=3)[CH:17]=1)[N:5]=2.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:33][C:13]1[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:38](=[O:37])[CH2:39][OH:40])=[N:10][C:9]3=[CH:8][CH:7]=2)=[CH:17][C:16]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=2)=[C:15]([F:32])[CH:14]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(N)sc4n3)c(Cl)cc2F)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)CO)sc4n3)c(Cl)cc2F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.4 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chloro-2-fluorophenyl}-3-(1-cyano-1-methylethyl)benzamide (100 mg, 0.207 mmol) produced in Example C52(v) in pyridine (2.0 mL) was added acetoxyacetyl chloride (48.9 μL, 0.455 mmol), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed with 5% aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (2.0 mL), sodium carbonate (100 mg, 0.943 mmol) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate (10 mL). The obtained suspension was washed with 5% aqueous ammonium chloride solution (10 mL), 5% aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→85/15), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to give the title compound (63.0 mg, 56%) as a colorless powder.
Reaction SMILES: [S:1](=[O:30])(=[O:29])([O:3][C:4]1[CH:21]=[CH:20][C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13]([C:22](=[O:28])[NH:23]CCCC)=[CH:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=1)[NH2:2].[Si](I)(C)(C)C>>[S:1](=[O:29])(=[O:30])([O:3][C:4]1[CH:21]=[CH:20][C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13]([C:22](=[O:28])[NH2:23])=[CH:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=1)[NH2:2]
Reactant: CCCCNC(=O)C1=CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C
Agent: C[Si](C)(C)I
Product: C[C@]12CC[C@@H]3c4ccc(OS(N)(=O)=O)cc4CC[C@H]3[C@@H]1CC=C2C(N)=O

Procedure:
Compound 11o was synthesized in a similar manner as 11a except that TMS-I was used in place of BBr3. Compound 11o was prepared from compound 12. EI-MS m/z 376 M+; 1H NMR (300 MHz, DMSO-d6) δ 0.88 (s, 3H, CH3), 6.44 (brs, 1H, 16-CH), 6.74 (brs, 2H, CONH2), 6.97 (s, 1H, ArH), 7.01 (d, 1H, J=9 Hz, ArH), 7.32 (d, 1H, J=9 Hz, ArH), 7.89 (s, 2H, SO2NH2).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[NH:15][C:16](=[O:18])[CH3:17])=[O:6].Cl>COCCOC>[C:16]([N:15]1[C:8]2[C:7](=[CH:12][CH:11]=[C:10]([O:13][CH3:14])[CH:9]=2)[C:5](=[O:6])[CH2:4]1)(=[O:18])[CH3:17]
Reactant: COc1ccc(C(=O)CCl)c(NC(C)=O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc2c(c1)N(C(C)=O)CC2=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77.2 %

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 3.97 g, 99.3 mmol) in DME (75 mL) was added an ice-cold solution of N-[2-(chloroacetyl)-5-methoxyphenyl]acetamide (12.00 g, 49.7 mmol) (Example 11) in DME (165 mL) at 0° C. The mixture was stirred under argon for 15 minutes, then 2 N HCl (75 mL) solution was added slowly. The mixture was extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to yield a solid. The crude material was purified on silica gel eluting with EtOAc/hexane (1:1) and then EtOAc to give a reddish solid (7.87 g, 77%) with minor impurities: LC/MS m/z 206 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, 1H), 7.59 (d, 1H), 6.80 (dd, 1H), 4.51 (s, 2H), 3.85 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C1C=CC=CN=1)C.[CH2:31]([N:38]=[C:39]=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>ClCCl.C(OCC)(=O)C>[CH2:31]([NH:38][C:39]([N:18]1[C:19]2[C:15](=[CH:14][C:13]([NH:12][S:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)(=[O:11])=[O:10])=[CH:21][CH:20]=2)[CH:16]=[CH:17]1)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C=NCc1ccccc1
Reactant: O=S(=O)(Nc1ccc2[nH]ccc2c1)c1cc(Cl)cc(Cl)c1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NCc1ccccc1)n1ccc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
130 mg 3,5-dichloro-N-(1H-indol-5-yl)-phenylsulphonamide are dissolved in 5 ml dichloromethane and 14 mg dimethylaminopyridine and 56 μl benzylisocyanate are added. The mixture is stirred overnight at ambient temperature, divided between 1 N HCl and ethyl acetate, the aqueous phase is extracted with ethyl acetate and the combined organic phases are dried with magnesium sulphate. The solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 10:1 to 1:3).
Reaction SMILES: [C:1]([C:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]3[N:16]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[C:17]([CH3:20])=[C:18]([CH3:19])[C:10]=23)[CH2:7][CH:8]=1)#[N:2].S(=O)(=O)(O)[OH:30]>C(Cl)Cl>[C:1]([C:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]3[N:16]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[C:17]([CH3:20])=[C:18]([CH3:19])[C:10]=23)[CH2:5][CH:4]=1)(=[O:30])[NH2:2]
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(N2CC=C(C#N)CC2)c2c(C)c(C)n(-c3ccc(Cl)cc3Cl)c2n1
Solvent: ClCCl
Product: Cc1cc(N2CC=C(C(N)=O)CC2)c2c(C)c(C)n(-c3ccc(Cl)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In methylene chloride (2.0 mL) was dissolved 4-(4-cyano-1,2,3,6-tetrahydropyridin-1-yl)-1-(2,4-dichlorophenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine (0.19 g), followed by adding thereto concentrated sulfuric acid (0.5 mL) under ice-cooling, and the resulting mixture was slowly heated to room temperature and then stirred overnight. The reaction mixture was separated with ethyl acetate and a saturated aqueous sodium hydrogencarbonate solution, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and the desiccating agent was filtered off, after which the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: chloroform-methanol=30:1) and the crystals precipitated were washed with ethyl acetate to obtain the title compound (0.10 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH2:41][CH2:42][N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1)[CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=2[CH2:17]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Reactant: O=C(CCl)N1CCCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCCC3)c(F)c2)C(C)C)c1
Yield: 76.1 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (19 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[CH3:13][C:14]1[N:19]=[C:18]([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)[CH:17]=[CH:16][CH:15]=1>>[CH3:12][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([NH:1][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][C:20]([C:18]4[CH:17]=[CH:16][CH:15]=[C:14]([CH3:13])[N:19]=4)=[CH:21][CH:22]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: Cc1cccc(-c2ccc(C(=O)O)cc2)n1
Reactant: Cc1ccc2ccc(N)cc2n1
Product: Cc1cccc(-c2ccc(C(=O)Nc3ccc4ccc(C)nc4c3)cc2)n1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-amino-2-methylquinoline (D66) (33 mg, 0.21 mmol) and 4-(6-methyl-2-pyridyl)benzoic acid (D29) (47 mg, 0.25 mmol) as an off-white solid. MS (ES): MH+ 354, M-H+ 352.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:18][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: NC1CCCCC1
Solvent: ClCCl
Product: O=S(=O)(NC1CCCCC1)c1ccc(Br)cc1
Yield: 26.2 %

Procedure:
According to general procedure C, 4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and cyclohexylamine (0.46 mL, 3.90 mmol) were stirred together in dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-cyclohexylbenzenesulfonamide (0.13 g) was provided after purification. MS (ESI) m/z 318. HPLC purity 100.0% at 210-370 nm, 10.0 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18]([C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])(=[O:20])=[O:19])[NH: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.Cl[CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:30]([O:29][CH2:28][N:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]1[S:18]([C:21]([F:25])([F:26])[CH:22]([F:24])[F:23])(=[O:20])=[O:19])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: ClCOCc1ccccc1
Reactant: O=S(=O)(c1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)C(F)(F)C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1nc(-c2ccccc2)c(-c2ccccc2)n1COCc1ccccc1)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 1.92 g (5 mmole) of 4,5-diphenyl-2-(1,1,2,2-tetrafluoroethylsulfonyl)imidazole, 1.6 g (10 mmole) of benzyl chloromethyl ether, 2.8 g (20 mmole) of potassium carbonate in 20 ml DMF was stirred at RT for six hours, then poured into ice water. The aqueous mixture was extracted three times with ether. The ether extracts were backwashed three times with water, then dried and concentrated. The residue was chromatographed on 150 g SilicAR CC-7, eluting with toluene to give, after recrystallization from hexane, 2.5 g (100%) of white product, mp 97.5°-98.5°.