Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[C:10]([NH2:16])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:6]=2[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:35])=[CH:20][N:19]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[Na]>O.CC(O)C>[Cl:35][C:21]1[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:16][C:10]2[C:7]3[CH2:8][CH2:9][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]=3[C:13]([O:14][CH3:15])=[CH:12][CH:11]=2)=[N:19][CH:20]=1
Reactant: CCN1CCc2c(N)ccc(OC)c2CC1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: [Na]
Solvent: CC(C)O
Solvent: O
Product: CCN1CCc2c(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc(OC)c2CC1
Temperature: 120 °C

Procedure:
3-Ethyl-9-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-ylamine (50.01 mg, 0.2270 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (67.4 mg, 0.227 mmol) and 10-camphorsulfonic acid (79.1 mg, 0.340 mmol) were charged to 2 ml IPA in a microwave tube. The reaction was heated to at 120° C. for 40 minutes. Pour reaction into water (50 ml) and saturated sodium bicarb (90 ml) and extract 3 times with 25 ml portions of methylene chloride. Dry combined organic over magnesium sulfate, filter and evaporate to a brown oil (102 mg). The crude reaction was purified on silica gel (12 g Isco column) using a gradient of 0-10% methanol in methylene chloride and then isocratic 20% methanol in methylene chloride to yield 2-[5-Chloro-2-(3-ethyl-9-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a beige foam. 1H-NMR (CDCl3) δ 11.10 (br s, 1H), 8.42 (br s, 1H), 8.02 (s, 1H), 7.40 (d, J=7.6 Hz, 1H), 7.15 (d, J=8.6 Hz, 1H), 6.95 (m, 1H), 6.77 (d, J=8.6 Hz, 1H), 6.43 (s, 1H), 3.89 (s, 3H), 3.12 (br s, 1H), 3.03 (d, J=4.8 Hz, 3H), 2.93 (br s, 1H), 2.60-2.41 (m, 6H), 1.00 (m, 3H).
Reaction SMILES: C([S:9][CH2:10][CH:11]([CH3:26])[C:12]([N:14]1[CH2:22][CH:21]2[N:17]([CH2:18][CH2:19][CH2:20]2)[CH2:16][CH:15]1[C:23]([OH:25])=[O:24])=[O:13])(=O)C1C=CC=CC=1>CO>[SH:9][CH2:10][CH:11]([CH3:26])[C:12]([N:14]1[CH2:22][CH:21]2[N:17]([CH2:18][CH2:19][CH2:20]2)[CH2:16][CH:15]1[C:23]([OH:25])=[O:24])=[O:13]
Reactant: CC(CSC(=O)c1ccccc1)C(=O)N1CC2CCCN2CC1C(=O)O
Solvent: CO
Product: CC(CS)C(=O)N1CC2CCCN2CC1C(=O)O
Reaction time: 6 h

Procedure:
By allowing a solution of (-)4-(3-benzoylthio-2-methylpropionyl)-1,4-diazabicyclo[4.3.0]nonane-3-carboxylic acid in ammoniacal methanol to stand at 25° C. for 4-8 hours the title compound is obtained.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].C([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([OH:16])[CH:8]=1)=O.C(=O)([O-])O.[Na+]>O>[C:11]([C:10]1[CH:14]=[CH:15][C:7]([CH2:1][NH2:2])=[CH:8][C:9]=1[OH:16])([OH:13])=[O:12]
Reactant: O=Cc1ccc(C(=O)O)c(O)c1
Reactant: [BH3-]C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NCc1ccc(C(=O)O)c(O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium cyanoborohydride (32 mg; 0.5 mmol) was added to a mixture of PAMAM 4.0 (EDA) (69 mg; 0.01 mmol), 4-formyl-2-hydroxybenzoic acid (83 mg; 0.5 mmol), and sodium hydrogen carbonate (42 mg; 0.5 mmol) in water (4 ml). The inhomogeneous orange mixture was stirred for four hours at room temperature, during which time it became homogeneous. The orange solution was then concentrated and the residue purified by gel filtration (Sephadex LH20; water) to give PAMAM 4.0 (EDA) terminated with ca. 32 4-carboxy-3-hydroxybenzylamine groups (91 mg). 1H and 13C nmr (D2O) shows mostly mono alkylation but with some signs of dialkylation of the terminal amino groups, both spectra show broad peaks. 13C nmr (D2O): δ37.0; 41.1; 50.9; 53.4; 55.5; 55.8; 61.5; 120.9; 122.2; 122.4; 132.3; 132.7; 135.0; 135.8; 163.5; 163.7; 169.0; 178.6; 179.3. 1H nmr (D2O): δ2.20; 2.35; 2.60; 3.15; 3.30; 3.55; 4.25; 6.68; 7.12; 7.55.
Reaction SMILES: [C:1](=[O:5])([O:3][CH3:4])[NH2:2].O=[C:7]([CH2:11][CH2:12][PH:13]([CH2:15][OH:16])=[O:14])[C:8]([OH:10])=[O:9].C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:4][O:3][C:1]([NH:2]/[C:7](=[CH:11]\[CH2:12][PH:13]([CH2:15][OH:16])=[O:14])/[C:8]([OH:10])=[O:9])=[O:5]
Reactant: COC(N)=O
Reactant: O=C(O)C(=O)CC[PH](=O)CO
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)N/C(=C\C[PH](=O)CO)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
5.835 g of methyl carbamate and 10.000 g of 2-oxo-4-(hydroxymethylphosphinyl)-butanoic acid were added to 17 mL of acetic acid to be suspended. After being dissolved by heating, 68 mL of toluene was added thereto and then the solution was refluxed with vigorous stirring. The internal temperature of the reaction solution was from 106 to 108 deg. C. Four hours later, dissipation of almost all the raw materials was confirmed by HPLC measurement. At this point, the area ratio of Z form to E form was 94:6. After removing about 42 mL of the solvent under a reduced pressure, followed by adding 23 mL of acetic acid, and then the resultant was stirred for 1 hour at 80 deg. C. The precipitate which was obtained by cooling the solution gradually to room temperature and stirring over-night, was filtered and then the filtrate was washed with acetic acid. After being washed with acetone, dried for 5 hours from 40 to 50 deg. C. under a reduced pressure, 9.931 g of the objective compound was obtained (75.4% yield, Z:E=99.6:0.4).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:11]1[C:16]2[N:17]=[C:18]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[O:19][C:15]=2[C:14]([F:25])=[C:13]([C:26]([O:28]CC)=[CH2:27])[C:12]=1[CH3:31])#[N:10]>O1CCCC1.O>[Br:1][CH2:28][C:26]([C:13]1[C:12]([CH3:31])=[C:11]([C:9]#[N:10])[C:16]2[N:17]=[C:18]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[O:19][C:15]=2[C:14]=1[F:25])=[O:27]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCC)c1c(C)c(C#N)c2nc(C(=O)N(C)C)oc2c1F
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)CBr)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Reaction time: 0.33 h

Procedure:
Next, at room temperature, N-bromosuccinimide (2.10 g, 11.8 mmol) was added to a tetrahydrofuran/water (178 ml/11 ml) mixed solution of the obtained 4-cyano-6-[1-(ethoxy)ethenyl]-7-fluoro-N,N,5-trimethyl-1,3-benzoxazole-2-carboxamide (3.56 g, 11.2 mmol), and stirred for 20 minutes. The solvent was evaporated away under reduced pressure, and the resulting residue was dissolved in ethyl acetate, and the solution was washed with water.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12](C(O)=O)[O:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N1C2C(=CC=CC=2)C=CC=1>[CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[CH:12][O:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(=O)c(OCc2ccccc2)co1
Solvent: c1ccc2ncccc2c1
Product: O=c1ccocc1OCc1ccccc1
Temperature: 25 °C

Procedure:
5-(Benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (68.9 g, 280 mmol) was added to 300 mL of quinoline at 235° C. and the mixture was heated at reflux for 30 min. The mixture was cooled to room temperature and concentrated to give a residue which was purified by silica gel chromatography to give 3-(benzyloxy)-4H-pyran-4-one, 1H-NMR (CDCl3, 400 MHz) δ 7.64 (dd, J=5.6, 0.8 Hz, 1H), 7.53 (d, J=0.4 Hz, 1H), 7.39-7.28 (m, 5H), 6.40(d, J=5.6 Hz, 1H), 5.06 (s, 2H). MS (M+H)+ 203.0.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[OH:18])[N:14]=[CH:13][CH:12]=[C:11]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2.Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:14]=[CH:13][CH:12]=[C:11]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
N,N-Dimethylformamide (1.5 ml) was added to 6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (50 mg), ethyl bromoacetate (75 mg), and potassium carbonate (62 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (31 mg, yield 49%).
Reaction SMILES: C[O:2][C:3](=[O:25])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:21](=[CH:22][CH:23]=1)[O:20][C:11]1([CH2:16][CH2:15][CH2:14][N:13]([CH:17]([CH3:19])[CH3:18])[CH2:12]1)[CH2:10][C:9]2=[O:24].[OH-].[Na+]>>[CH:17]([N:13]1[CH2:14][CH2:15][CH2:16][C:11]2([CH2:10][C:9](=[O:24])[C:8]3[C:21](=[CH:22][CH:23]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:25])=[O:2])[CH:7]=3)[O:20]2)[CH2:12]1)([CH3:19])[CH3:18]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(C)C)C1)O2
Agent: [Na+]
Agent: [OH-]
Product: CC(C)N1CCCC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1

Procedure:
(±)-(E)-3-[1′-Isopropyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester (234 mg, 0.681 mmol) was treated with 1 M NaOH according to the procedure described in Example 16 STEP B to give (±)-(E)-3-[1′-isopropyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid. The acid was treated with NH2OTHP according to the procedure described in Example 16, Step C, giving (±)-(E)-3-[1′-isopropyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide. Removal of the THP protecting group following the procedure described in Example 16, Step C, gave (±)-(E)-3-[1′-isopropyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-hydroxy-acrylamide hydrochloride as yellow powder (210 mg, 81% over three steps)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15](=[O:45])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[C:24]([NH:27][C:28]([CH:30]4[CH2:34][CH2:33][CH2:32][N:31]4[C:35]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[O:36])=[O:29])[S:25][CH:26]=3)=[CH:18][CH:17]=2)[CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:38]([O:37][C:35]([N:31]1[CH2:32][CH2:33][CH2:34][CH:30]1[C:28](=[O:29])[NH:27][C:24]1[S:25][CH:26]=[C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:15](=[O:45])[NH:14][CH:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[CH:17][CH:18]=2)[N:23]=1)=[O:36])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(NC(=O)c2ccc(-c3csc(NC(=O)C4CCCN4C(=O)OCc4ccccc4)n3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CCCNC1)c1ccc(-c2csc(NC(=O)C3CCCN3C(=O)OCc3ccccc3)n2)cc1
Temperature: 25 °C

Procedure:
3-(4-{2-[(1-Benzyloxycarbonyl-pyrrolidine-2-carbonyl)-amino]-thiazol-4-yl}-benzoylamino)-piperidine-1-carboxylic acid tert butyl ester (Compound 5336, Example 336, 100 mg, 0.16 mmol) was dissolved in 4 mL of 1:1 solution of CH2Cl2/TFA and stirred for 1.5 at room temperature. Reaction mixture was evaporated under reduced pressure to give pure desired product. MS: 534.2(M+H+); H1 NMR (MeOH-d4): δ(ppm) (HCl salt)12.47 (s, 1H), 9.52 (s, 1H), 8.64 (s, 1H), 7.95 (m, 5H), 7.50 (br s, 2H), 7.08 (d, 2H), 5.03 (m, 2H), 4.49 (m, 1H), 4.12 (m, 1H), 3.68-2.96 (m, 6H), 2.28 (m, 1H), 1.90 (m, 8H).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].Cl>C(Cl)(Cl)Cl.CC(O)C>[C:1]1([CH2:7][CH2:8][N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])C=Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: O=[N+]([O-])CCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
2-Phenylnitroethene (5.12 g, 34.3 mmol, from step 15a) was dissolved in CHCl3 /i-PrOH (410:85 mL) and SiO2 (51.4 g) was added. NaBH4 (5.2 g, 137 mmol) was added in portions, and the mixture was stirred for 90 minutes at room temperature. HCl (0.5N, 100, mL) was added, and the mixture was stirred for 30 minutes. The layers were separated, and the aqueous phase was extracted with methylene chloride. The organic layers were combine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel (eluting with ether:hexanes 1:30) to give the title compound as an oil (3.89 g, 75%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:28]S(C2C=CC(C)=CC=2)(=O)=O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:16][CH2:17][C:10]=12.[OH-].[Na+]>S(=O)(=O)(O)O>[NH:15]1[C:11]2=[N:12][CH:13]=[CH:14][C:9]([O:8][C:7]3[CH:6]=[CH:5][C:4]([NH2:28])=[CH:3][C:2]=3[F:1])=[C:10]2[CH2:17][CH2:16]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccnc4c3CCN4S(=O)(=O)c3ccc(C)cc3)c(F)c2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(Oc2ccnc3c2CCN3)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.09 mmol) of N-[3-fluoro-4-({1-[(4-methylphenyl)sulfonyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}oxy)phenyl]-4-methylphenylsulfonamide (from example XLV) are dissolved in 1.00 ml of sulfuric acid (95%) and stirred at RT overnight. With ice-cooling, the reaction solution is neutralized with 20% strength aqueous sodium hydroxide solution, and the mixture is extracted three times with ethyl acetate. The organic phase is dried over anhydrous magnesium sulfate and concentrated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][NH2:32])[C:6]=2[CH:33]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][NH:32][C:34](=[O:36])[CH3:35])[C:6]=2[CH:33]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(CCN)c3cc(Cl)ccc32)cn1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NCCC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)nc2)c2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 7-chloro-5-(2-aminoethyl)-1-[6-(2-methylbenzoyl-amino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.42 g) in pyridine (10 ml) is added acetic anhydride (0.13 ml), and the mixture is stirred at 80° C. for 2 hours, and then stirred at room temperature overnight. Water is added to the reaction solution, and the mixture is extracted with dichloromethane. The extract is washed successively with diluted hydrochloric acid, water, and aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-acetylamino-ethyl)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (91 mg) as white powder.
Reaction SMILES: CON(C)[C:4](=[O:23])[C:5]1[CH:10]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:8]=[C:7]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:6]=1.[CH3:25][Mg]Br.Cl>C1COCC1.O>[N:17]1([C:7]2[CH:6]=[C:5]([C:4](=[O:23])[CH3:25])[CH:10]=[C:9]([S:11]([F:12])([F:16])([F:15])([F:13])[F:14])[CH:8]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1cc(N2CCOCC2)cc(S(F)(F)(F)(F)F)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cc(N2CCOCC2)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Methoxy-N-methyl-3-morpholin-4-yl-5-(pentafluorosulfanyl)benzamide (2.38 g) was dissolved in THF (50 ml), methylmagnesium bromide (4.22 ml, 3 M in ether) was added dropwise at 0° C. and then the mixture was stirred at RT for 2 h. Then 1N hydrochloric acid (100 ml) was added, and the mixture was diluted with water and extracted by shaking three times with EA. Thereafter, the combined EA phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified using silica gel (80 g cartridge, n-heptane/EA gradient of 0-70% within 40 min). 1.1 g of the title compound were obtained.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([O:18][CH2:19][CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.[F:21][C:22]([F:36])([C:27]1[NH:31][C:30]2[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=2[N:28]=1)[C:23]([F:26])([F:25])[F:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:19]([O:18][CH:12]([CH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:28]2[C:29]3[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=3[N:31]=[C:27]2[C:22]([F:21])([F:36])[C:23]([F:26])([F:25])[F:24])=[CH:6][CH:7]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:20]
Reactant: CCOC(=O)C(Cc1ccc(OCCBr)cc1)OCC
Reactant: FC(F)(F)C(F)(F)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCCn2c(C(F)(F)C(F)(F)F)nc3ccccc32)cc1)OCC

Procedure:
This compound was prepared from ethyl 3-[4-(2-bromoethoxy)phenyl]-2-ethoxypropanoate (371 mg, 1 mmol), 2-(pentafluoroethyl)-1H-benzimidazole (259 mg, 1.1 mmol), K2CO3 (552 mg, 4 mmol) and DMF (5 ml) using the procedure described in Step B of Example 1. Yield 420 mg (84%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)=[O:22]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]([C:17]2[S:16][CH:20]=[CH:19][CH:18]=2)=[O:22])=[CH:24][CH:25]=1
Reactant: O=C(c1ccc(O)cc1)c1cccs1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Product: COc1cc2nccc(Oc3ccc(C(=O)c4cccs4)cc3)c2cc1OC
Temperature: 160 °C
Reaction time: 0.67 h
Yield: 17.4 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (112 mg) and 4-hydroxyphenyl 2-thienyl ketone (102 mg) obtained in Example 39 were mixed and stirred at 160° C. for 40 minutes. The reaction mixture was purified in the same manner as described in Example 24 to obtain 34 mg of the title compound (yield: 17%).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:13]3[O:12][N:11]=[C:10]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:9]=3[CH:8]=[CH:7][C:6]=2[OH:20])[CH2:3][CH2:2]1.[Br:21][CH2:22][CH2:23][CH2:24]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH:1]1([CH2:4][C:5]2[C:13]3[O:12][N:11]=[C:10]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:9]=3[CH:8]=[CH:7][C:6]=2[O:20][CH2:24][CH2:23][CH2:22][Br:21])[CH2:2][CH2:3]1
Reactant: BrCCCBr
Reactant: Oc1ccc2c(-c3ccccc3)noc2c1CC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: BrCCCOc1ccc2c(-c3ccccc3)noc2c1CC1CC1

Procedure:
A solution of 7-cyclopropylmethyl-3-phenyl-6-hydroxybenz-[4,5]-isoxazole (0.25 grams) in 2-butanone (3.0 mL) was treated with 1,3-dibromopropane (0.48 mL) and potassium carbonate (0.50 grams). The mixture was refluxed for 4 hours. The reaction mixture was partitioned between isopropyl acetate and pH 4 buffer. The organic was washed once with water, then dried over magnesium sulfate. The organic was filtered and evaporated to an oil which was flitered through a silica gel plug using methylene chloride and hexane (1:2) to give 7-cyclopropylmethyl-3-phenyl-6-(3-bromopropyloxy)benz-[4,5]-isoxazole. A solution of 3-chloro-4-hydroxyphenylacetic acid methyl ester (42.0 mg) in DMF (1.0 mL) was treated with potassium carbonate (26 mg) and this mixture was stirred for 0.5 hours. Then 7-cyclopropylmethyl-3-phenyl-6-(3-bromopropyloxy)benz-[4,5]-isoxazole was added and the mixture was stirred over night. The reaction mixture was partitioned between ethyl acetate and 1 M HCl solution. The organic was dried over sodium sulfate and filtered. The solvent was removed in vacuo and the residue was chromatographed on silica gel using methlene chloride and hexane (1:1) to give an oil. A solution of methyl 3-chloro-4-(3-(3-phenyl-7-cyclopropylmethyl-6-benz-[4,5]-isoxazoloxy)-butyloxy)phenylacetic acid (0.04 grams) in methanol (1.5 mL) was treated with a solution of lithium hydroxide in water (1.01 M; 0.1 mL). The reaction was refluxed 1 hour. The reaction mixture was partitioned between isopropyl acetate and 0.1N HCl. The organic was dried over magnesium sulfate, filtered and concentrated to a solid. The solid was suspended in methylene chloride/cyclohexane (1:1; 2 mL). The mixture was refluxed briefly and cooled to 0° C. The title compound was isolated by filtration.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH2:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[O:14]>>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:13](=[O:14])[CH2:12][CH2:11][CH2:10][S:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(S)cc1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Product: Cc1ccc(SCCCC(=O)c2ccc(F)cc2)cc1
Yield: 100 %

Procedure:
The title compound (58.0 g, 100%) was prepared from 4-thiocresol and 4-chloro-4'-fluorobutyrophenone as described in Example 2 as an oil; IR(neat): C=O @ 1700 cm-1 ; NMR(DMSO-d6, TMS): δ 1.8-1.95(m,2H, CH2), 2.26(s,3H,ArCH3), 2.98(t,2H,CH2 --CO), 3.16(t,2H,S--CH2), 7.1-8.1(m,8H, aromatic); mass spectrum m/e 288.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([S:30](C)(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:34]>O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([NH2:34])(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2Oc2ccc(F)cc2)cc1
Solvent: O
Product: NS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2Oc2ccc(F)cc2)cc1

Procedure:
The product from Example 109 was converted to the title sulfonamide according to the method of Example 384 (yield: 110 mg, 45.7%). mp 224-226° C. 1H NMR (300 MHz, CDCl3) δ 4.86 (br s, 2H), 6.89-7.03 (m, 4H), 7.19-7.30 (m, 1H), 7.45-7.52 (m, 1H), 7.56-7.66 (m, 1H), 7.79 (d, J=9 Hz, 2H), 8.04 (d, J=9 Hz, 1H), 8.08 (s, 1H). MS (DCI/NH3) m/z 474 (M+H)+, 491 (M+NH4)+. Anal. calc. for C22H14F3N3O4S.0.25 H2O: C, 55.32; H, 2.93; N, 8.80. Found: C, 55.26; H, 3.11; N, 8.58.
Reaction SMILES: [N:1]12[CH2:8][C:5]([C:9](N(OC)C)=[O:10])([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[CH3:15][Li]>CCOCC>[C:9]([C:5]12[CH2:8][N:1]([CH2:7][CH2:6]1)[CH2:2][CH2:3][CH2:4]2)(=[O:10])[CH3:15]
Reactant: CON(C)C(=O)C12CCCN(CC1)C2
Reactant: [Li]C
Solvent: CCOCC
Product: CC(=O)C12CCCN(CC1)C2
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of (±) 1-azabicyclo[3.2.1]oct-5-yl-N-methyl-N-methoxycarboxamide (D3) (22.0 g; 0.11 mole) in dry ether (500 ml) was cooled to -30° C. under nitrogen and treated dropwise with methyl lithium (80.0 ml of a 1.4 M solution in diethyl ether; 0.11 mole). The rate of addition was controlled to ensure that the temperature of the reaction remained below 0° C. After stirring for 1 h at -10° C. the reaction was quenched by the addition of excess glacial acetic acid, while maintaining the temperature below -10° C. The ether solution was washed with a saturated solution of potassium carbonate. After extraction of the aqueous phase with chloroform (3×200 ml) the combined organic layers were dried over sodium sulphate and concentrated in vacuo.
Reaction SMILES: [OH:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35].[CH2:36](Br)[CH:37]=[CH2:38]>>[CH2:38]([O:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35])[CH:37]=[CH2:36]
Reactant: COc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1O
Reactant: C=CCBr
Product: C=CCOc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1OC

Procedure:
prepared by reaction of 2-[1-(4-hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with allyl bromide