Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].CO.S(OC)(O[CH3:22])(=O)=O>O>[CH3:22][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1
Reactant: COS(=O)(=O)OC
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
A mixture of 38 g of 4-phenylphenol, 9 g of sodium hydroxide, 200 ml of methanol and 20 ml of water was heated. 28 g of dimethyl sulfate was dropped in the mixture with stirring at 50° C. After one hour, 20 ml of 10N-sodium hydroxide was dropped in the solution and continued stirring for 2 hours. The crystals were obtained after the solution was cooled to room temperature. After washing with water and methanol for several times, 30 g of 4-methoxybiphenyl (O) was obtained. 154 g of (O) was dissolved with mixed solution of 200 ml of chloroform and 75 ml of carbon tetrachloride, and then 11 g of aluminum chloride powder was added to the solution. 14 g of octanic acid chloride was added to the solution with stirring after changing colour of the solution to greenish blue. 150 ml of ice-water and 5 ml of conc. hydrochloric acid was added, after refluxing 5 hours. The water layer was removed, then the organic layer was washed with 0.1N hydrochloric acid and dehydrated with magnesium sulfate anhydride, and then evaporated after filtration to obtain crude crystals of 4'-nonylcarbonyloxy-4-methoxybiphenyl (P). 13 g of (P), 1 g of 10% palladium-carbon, 130 ml of acetic acid were put into an autoclave and then gave the pressure to 25 kg/cm2 by using hydrogen. (P) was reduced by heating for 3 hours at 80° C. After substituting nitrogen for hydrogen, palladium-carbon was separated by filtrating the reacted solution. 4'-decyl-4-methoxybiphenyl (Q) was obtained after cooling and drying. 8 g of (Q), 90 ml of acetic acid 30 ml of hydrogen bromide water solution were mixed and refluxed for 5 hours to obtain crude crystals. After cooling, the crude crystals were washed with methanol to crystallize 5.5 g of 4-(4'-octylphenyl)phenol.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:4]=[C:5]([OH:35])[CH:6]=[CH:7][C:8]=2[N:9]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:23][CH:24]=2)[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1.[CH:36]([OH:39])([CH3:38])C>CO>[CH3:1][C:2]1[C:3]2[CH:4]=[C:5]([OH:35])[CH:6]=[CH:7][C:8]=2[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:21][CH:20]=2)[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1.[CH3:38][C:36]([OH:39])=[O:17]
Reactant: CC(C)O
Agent: Cc1c(-c2ccc(O)cc2)n(Cc2ccc(OCCN3CCCCCC3)cc2)c2ccc(O)cc12
Solvent: CO
Product: CC(=O)O
Temperature: 27.5 °C
Reaction time: 1 h

Procedure:
Crystalline bazedoxifene free base (5 g) is charged in methanol (100 mL) heated at reflux temperature to make a clear solution. The solution is filtered and cooled to 25-30° C. followed by addition of acetic acid (0.82 g). The reaction mixture is stirred for about 1 hour. In a separate flask, slurry of crystalline Form D of bazedoxifene acetate is prepared by providing seed of Form D (250 mg) in methanol (5 mL). The said seed slurry is added to the previous reaction mixture and further it is cooled to 10-15° C. in a period of 30 minutes followed by addition of isopropyl alcohol in a period of 2 hours. The reaction mixture is further cooled to 0-5° C. and maintained at same temperature for 30-45 minutes. The solid is collected by filtration and sequentially washed with isopropyl alcohol (5 mL) and methanol (5 mL), and dried under vacuum at about 90° C. to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:5]([CH2:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:6]=1[C:7]([N:9]([CH2:31][CH:32]([CH3:34])[CH3:33])[C@H:10]1[CH2:15][C@@H:14]([C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])[CH2:13][N:12]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:11]1)=[O:8].C([O-])(=O)C.[K+]>CO.[OH-].[Pd+2].[OH-].[C]>[CH3:40][O:39][CH2:38][CH2:37][CH2:36][CH2:35][N:5]1[C:6]([C:7]([N:9]([CH2:31][CH:32]([CH3:33])[CH3:34])[C@H:10]2[CH2:15][C@@H:14]([C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[O:17])[CH2:13][N:12]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:11]2)=[O:8])=[CH:2][N:3]=[C:4]1[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: COCCCCn1c(-c2ccccc2)nc(Cl)c1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)cnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.5 %

Procedure:
tert-Butyl(3S,5R)-3-[{[4-chloro-1-(4-methoxybutyl)-2-phenyl-1H-imidazol-5-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (200 mg), palladium(II) hydroxide-carbon (20 mg) and potassium acetate (30 mg) were suspended in methanol (10 ml), and the mixture was stirred under a hydrogen atmosphere (1 atom) at room temperature for 1 day. The palladium catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was suspended in water, and the suspension was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-80:20) was concentrated under reduced pressure to give the object product (90 mg).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].[C:14]([OH:23])(=[O:22])[C@@H:15]([C@H:17]([C:19]([OH:21])=[O:20])[OH:18])[OH:16]>C(#N)C.O.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>[C:19]([C@@H:17]([C@H:15]([C:14]([OH:23])=[O:22])[OH:16])[OH:18])([OH:21])=[O:20].[CH3:7][C:4]1[S:3][CH:2]=[N:6][N:5]=1
Reactant: Cc1nnc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: Cc1nncs1
Temperature: 100 °C
Reaction time: 17 h

Procedure:
A mixture of 5-(4-chlorophenyl)-2,5-ethano-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1H-2-benzoazepine (80 mg, 0.19 mmol) from Step B of Example 14, 2-bromo-5-methyl-1,3,4-thiadiazole (35 mg, 0.19 mmol) and potassium carbonate (81 mg, 0.58 mmol), in N,N-dimethylformamide (2 mL), was degassed with argon. Next, tetrakis(triphenylphosphine)palladium(0) (33 mg, 0.028 mmol) was added, the mixture was degassed again and heated to 100° C. After stirring for 17 h, the reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (25 mL), washed with water (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (90:9:1 methylene chloride/methanol/ammonium hydroxide). To the obtained material (6.3 mg, 0.016 mmol) in acetonitrile (1.5 mL) was added L-tartaric acid (2.5 mg, 0.016 mmol) in water (6 mL). The resultant solution was lyophilized to give 24544-chlorophenyl)-2,5-ethano-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)-5-methyl-1,3,4-thiadiazole, L-tartrate salt (11 mg, 11%, AUC HPLC 98.7%) as a white solid: 1H NMR (CD3OD, 500 MHz) δ 7.90 (s, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.47 (d, J=9.0 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 6.53 (d, J=8.5 Hz, 1H), 4.90 (s, 2H), 4.43 (s, 2H), 3.65-3.61 (m, 2H), 3.46-3.39 (m, 2H), 2.83-2.78 (m, 5H), 2.48-2.43 (m, 2H); ESI MS m/z 382 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C@:7]([C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]1)([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:8][CH2:9][CH3:10])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[NH2:1][CH2:4][CH2:5][O:6][C@:7]([C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:19]1)([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCC[C@](OCCN=[N+]=[N-])(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCC[C@](OCCN)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-1-(2-azidoethoxy)-1-(3-chlorophenyl)butyl)piperidine-1-carboxylate (790 mg, 1.81 mmol) in the mixture of THF/H2O (20:1, 10.5 mL) was added PPh3 (1.9 g, 7.25 mmol). The reaction mixture was stirred at rt overnight. The solvent was removed under reduced pressure to the residue, which was purified by column chromatography on silica gel to afford (R)-tert-butyl 3-((R)-1-(2-aminoethoxy)-1-(3-chlorophenyl)butyl)piperidine-1-carboxylate (410 mg, 55%). 1HNMR (CDCl3, 400 MHz) δ 7.31 (s, 1H), 7.24 (m, 2H), 7.15 (m, 1H), 4.31-3.52 (m, 3H), 3.27 (m, 2H), 2.93 (m, 1H), 2.41-2.22 (m, 3H), 2.15-1.95 (m, 3H), 1.85 (m, 4H), 1.57 (m, 1H), 1.44 (s, 9H), 1.38-1.10 (m, 2H), 0.95 (t, 31).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:24])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[N:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2.O[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[N:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2
Reactant: OCCc1ccncc1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCCc1ccncc1
Yield: 56.2 %

Procedure:
Using an analogous procedure to that described in Example 20, 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.2 g, 0.6 mmol), (prepared as described in Example 4), was reacted with 4-(2-hydroxyethyl)pyridine (0.11 g, 0.9 mmol), (Zhur. Obshchei. Khim. 1958, 28, 103-110), to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(2-(4-pyridyl)ethoxy)cinnoline (0.15 g, 57%).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:18])[CH:15](Br)[CH3:16])[CH3:3].[C:19]1([CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][NH2:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:18])[CH:15]([NH:27][CH2:26][CH:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:16])[CH3:3]
Reactant: CC(Br)C(=O)Nc1c(C(C)C)cccc1C(C)C
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(NCC(c1ccccc1)c1ccccc1)C(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A solution of (±)-N-[2,6-bis(1-Methylethyl)-phenyl]-2-bromopropanamide (2.0 g, 6.4 mmol), 2,2-diphenylethylamine (1.26 g, 6.41 mmol) and triethylamine (1.8 mL, 13 mmol) in acetonitrile (30 mL) was refluxed (96 hours), then cooled (25° C.). The resulting slurry was diluted with ethyl acetate (300 mL), washed with water (1×100 mL), with saturated aqueous sodium bicarbonate (1×100 mL), with brine (1×100 mL), then dried (MgSO4) and concentrated. Crystallization from ethyl acetate/hexane yielded 2.0 g (72.8%) of the title compound as a white solid, mp 206.5°-208.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl-].[CH3:28][O:29][C:30](=[O:35])[CH2:31][C:32](O)=[O:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[N:15]([C:32](=[O:33])[CH2:31][C:30]([O:29][CH3:28])=[O:35])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CC(=O)O
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CC(=O)N1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C2C(N3CCCC3)CCCC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under N2, 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (101 mg, 0.26 mmol) was dissolved in absolute CH2Cl2 (13 ml) and malonic acid monomethyl ester chloride (42 mg, 0.31 mmol) was added dropwise. The mixture was stirred at room temperature overnight and then evaporated in vacuo. The residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH3 9.5:0.5:0.05, l=15 cm, V=5 ml). A yellowish resin was obtained.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C>CCOC(C)=O>[OH:33][C:29]1[CH:28]=[C:27]([C:24]2[O:23][C:22]([C:9](=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:26][CH:25]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2cccc(O)c2)o1
Solvent: CCOC(C)=O
Product: O=C(CCCCCCc1ccccc1)c1ncc(-c2cccc(O)c2)o1
Yield: 24 %

Procedure:
The title compound was prepared from 3-(2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)phenol (29 mg, 0.062 mmol) following General Procedure D. Preparative thin layer chromatography (30% EtOAc) yielded the title compound as a white solid (5.2 mg, 27%): 1H NMR (CD3OD, 500 MHz) δ 7.74 (s, 1H), 7.38-7.37 (m, 2H), 7.32-7.29 (m, 3H), 7.24-7.23 (m, 2H), 7.21-7.20 (m, 1H), 6.95-6.94 (m, 1H), 3.14 (t, 2H, J=7.0 Hz), 2.69 (t, 2H, J=7.5 Hz), 1.85-1.79 (m, 2H), 1.75-1.69 (m, 2H), 1.54-1.42 (m, 4H); 13C NMR (CD3OD, 125 MHz) δ 188.5, 158.4, 157.4, 154.7, 142.9, 130.5, 128.4, 128.2, 128.2, 125.6, 123.9, 117.2, 116.5, 111.7, 38.7, 35.8, 31.5, 29.0, 29.0, 23.9; MALDI-FTMS m/z 350.1752 (M+H+, C22H24NO3, requires 350.1751).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[C:11]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:10][CH:9]=[CH:8][N:7]=2)[CH2:2]1.Cl[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:15]1[CH2:16][CH2:17][CH:12]([C:11]2[C:6]([O:5][CH:3]3[CH2:2][N:1]([C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)[CH2:4]3)=[N:7][CH:8]=[CH:9][CH:10]=2)[CH2:13][CH2:14]1
Reactant: Clc1ccc2ccccc2n1
Reactant: c1cnc(OC2CNC2)c(C2CCOCC2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1cnc(OC2CN(c3ccc4ccccc4n3)C2)c(C2CCOCC2)c1
Temperature: 130 °C
Yield: 4 %

Procedure:
A mixture of 2-(azetidin-3-yloxy)-3-(tetrahydro-2H-pyran-4-yl)pyridine (see PREPARATION P27.1; 100 mg, 0.45 mmol), 2-chloroquinoline (73 mg, 0.45 mmol), Pd2(dba)3 (56 mg, 0.062 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (40 mg, 0.06 mmol), KI (40 mg, 0.13 mmol) and sodium tert-butoxide (t-BuONa) (110 mg, 1.2 mmol) was dissolved in toluene (5 mL). The reaction mixture was heated in a microwave at 130° C. for 4 hours. The solvent was evaporated and the crude product was purified by silica gel column chromatography to give the product (6.7 mg, 0.018 mmol, yield 10%). [M+1] 363. IC50 (uM) 0.331.
Reaction SMILES: OC1C2C(=CC=CC=2)C(NS(C2SC=CC=2)(=O)=O)=CC=1SCC(OCC)=O.[CH:28]1([NH:31][C:32](=[O:56])[CH2:33][CH2:34][S:35][C:36]2[C:37](=[O:55])[C:38]3[C:43]([C:44](=[N:46][S:47]([C:50]4[S:51][CH:52]=[CH:53][CH:54]=4)(=[O:49])=[O:48])[CH:45]=2)=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:30][CH2:29]1>>[CH:28]1([NH:31][C:32](=[O:56])[CH2:33][CH2:34][S:35][C:36]2[CH:45]=[C:44]([NH:46][S:47]([C:50]3[S:51][CH:52]=[CH:53][CH:54]=3)(=[O:48])=[O:49])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]=2[OH:55])[CH2:29][CH2:30]1
Reactant: O=C(CCSC1=CC(=NS(=O)(=O)c2cccs2)c2ccccc2C1=O)NC1CC1
Agent: CCOC(=O)CSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Product: O=C(CCSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O)NC1CC1

Procedure:
5.2.51 N-cyclopropyl-3-(1-hydroxy-4-(thiophene-2-sulfonamido)naphthalen-2-ylthio)propanamide (14h) was prepared according to the procedure for 9a except using 13h affording 8.8 mg (89%) title compound, m.p.: ° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([OH:17])=O)[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:25][C:26]([F:40])([F:39])[C:27]1[C:28]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:29][CH:30]=[CH:31][CH:32]=1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:36]3[CH2:37][CH2:38][N:33]([C:28]4[C:27]([C:26]([F:40])([F:25])[F:39])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:34][CH2:35]3)=[O:17])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1
Product: O=C(C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1)N1CCN(c2ncccc2C(F)(F)F)CC1

Procedure:
In analogy to example 1, (RS)-1-benzenesulfonyl-3-cyclohexyl-2-oxo-imidazolidine-4-carboxylic acid was coupled with 1-[3-(trifluoromethyl)pyrid-2-yl]piperazine to give the title compound as a colorless solid. MS: 565.8 ([M+H]+)
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[N:11]([CH2:19][CH3:20])[CH:10]=[C:9]([C:21](O)=[O:22])[C:8]2=[O:24])(=[O:3])[CH3:2].S(Cl)([Cl:27])=O>CN(C)C=O.C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[N:11]([CH2:19][CH3:20])[CH:10]=[C:9]([C:21]([Cl:27])=[O:22])[C:8]2=[O:24])(=[O:3])[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(OC(C)=O)c(OC(C)=O)cc21
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCn1cc(C(=O)Cl)c(=O)c2cc(OC(C)=O)c(OC(C)=O)cc21

Procedure:
A mixture of 6,7-diacetoxy-1-ethyl-1,4-dihydro-4-oxoquinoline-3-caroxylic acid (60 mg), thionyl chloride (40 μL), and dimethylformamide (one drop) was heated under reflux for 3 hours in benzene (40 mL), and then the solvent was evaporated. To the residue was added benzene (20 mL). Benzene was evaporated and the residue was vacuum dried to give 6,7-diacetoxy-1-ethyl-1,4-dihydro-4-oxoquinoline-3-carbonyl chloride.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][CH:8]=[C:7]([O:13][CH3:14])[CH:6]=2.[C:15]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)([OH:17])=[O:16].C([O-])([O-])=O.[K+].[K+].O>COCCOCCO.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCOC(C)=O>[CH3:14][O:13][C:7]1[CH:6]=[C:5]2[C:10]([C:11]([CH3:12])=[C:2]([C:21]3[CH:22]=[CH:23][C:18]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=3)[N:3]=[CH:4]2)=[CH:9][CH:8]=1
Reactant: COc1ccc2c(C)c(Cl)ncc2c1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOCCO
Solvent: CCOC(C)=O
Product: COc1ccc2c(C)c(-c3ccc(C(=O)O)cc3)ncc2c1
Temperature: 120 °C
Yield: 12.8 %

Procedure:
To a mixture of 3-chloro-7-methoxy-4-methylisoquinoline (Intermediate 15) (470 mg, 2.27 mmol), 4-carboxyphenylboronic acid (451 mg, 2.72 mmol) and K2CO3 (627 mg, 4.54 mmol) in DEGME/H2O (7 mL/1 mL) was added Pd(dppf)Cl2 (40.8 mg, 0.050 mmol) under N2 atmosphere. Then the mixture was heated to 120° C. for 16 hours. H2O (30 mL) was added, and the resulting mixture was extracted with EtOAc (15 mL×2). The aqueous layer was neutralized with 1N aqueous HCl to pH=7, extracted with EtOAc (20 mL×3). The combined organic layers were washed with H2O (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated. Purification by silica gel column (PE/EtOAc=20/1 to 1/1, then EtOAc) gave 4-(7-methoxy-4-methylisoquinolin-3-yl)benzoic acid (85.0 mg, yield 13%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].[CH3:25][O:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31](Cl)=[N:30][CH:29]=1>>[CH3:25][O:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31]([O:9][CH2:8][C:6]2[CH:5]=[CH:4][C:3]([CH:10]([CH3:24])[C:11]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=3)([OH:16])[C:12]([F:15])([F:14])[F:13])=[C:2]([Cl:1])[CH:7]=2)=[N:30][CH:29]=1
Reactant: CC(c1ccc(CO)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(Cl)nc1
Product: COC(=O)c1ccc(OCc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)nc1

Procedure:
The title compound was prepared in analogy to Example 93, step 7 from 3-(2-chloro-4-hydroxymethyl-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (obtained in Example 120, step 1) by alkylation with methyl-6-chloronicotinate [CAS Reg. No. 73781-91-6]. MS (m/e)=515.1 [MH+].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Br[CH:10]([CH3:17])[C:11](=O)[C:12]([F:15])([F:14])[F:13]>COCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH3:17])=[C:11]([C:12]([F:15])([F:14])[F:13])[N:8]=2)[N:7]=1
Reactant: CC(Br)C(=O)C(F)(F)F
Reactant: Nc1ccc(Cl)nn1
Solvent: COCCOC
Product: Cc1c(C(F)(F)F)nc2ccc(Cl)nn12
Temperature: 25 °C

Procedure:
A solution of 6-chloro-3-aminopyridazine x34 (3.16 g, 1 eq, 24.2 mmol) and 3-bromo-1,1,1-trifluorobutan-2-one (5 g, 1 eq, 24.4 mmol) in 1,2-dimethoxyethane (100 ml) is refluxed during 17 hours. After cooling to room temperature and filtration, the solvent is removed under reduced pressure and the crude mixture is purified by preparative chromatography on silicagel (CH2Cl2/MeOH/NH4OH: 98/2/0.2 (v/v/v)) leading to 6-chloro-3-methyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazine x35.
Reaction SMILES: [CH:1]1([C:5]2[C:12]([C:13]3[NH:17][C:16]([O:18][CH2:19]C)=[N:15][N:14]=3)=[CH:11][C:8]([C:9]#[N:10])=[C:7]([CH3:21])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.CO>CCO>[CH:1]1([C:5]2[C:12]([C:13]3[NH:17][C:16]([O:18][CH3:19])=[N:15][N:14]=3)=[CH:11][C:8]([C:9]#[N:10])=[C:7]([CH3:21])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCOc1nnc(-c2cc(C#N)c(C)cc2C2CCC2)[nH]1
Solvent: CO
Solvent: CCO
Product: COc1nnc(-c2cc(C#N)c(C)cc2C2CCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzonitrile (compound 219.7), except MeOH was used as the solvent instead of EtOH. m/z (ES+) 269 (M+H)+. 1H NMR (400 MHz, Chloroform-d) δ 10.96 (br, 1H), 7.82 (s, 1H), 7.35 (s, 1H), 4.11 (s, 3H), 4.15-4.05 (m, 1H), 2.59 (s, 3H), 2.31-2.16 (m, 2H), 2.14-1.89 (m, 3H), 1.87-1.71 (m, 1H).
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:26])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:8][CH:7]=1)([CH3:3])[CH3:2].[CH3:27]C1ON=C(C2C=CC=CC=2)C=1COC1C=CC(C(NC2CCOCC2)=O)=CN=1>>[CH:1]([N:4]([CH3:27])[C:5](=[O:26])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:8][CH:7]=1)([CH3:3])[CH3:2]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC(C)C)cn1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N(C)C(C)C)cn1
Yield: 33 %

Procedure:
As described for example 50, N-isopropyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide (200 mg, 0.6 mmol), instead of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide, was converted to the title compound (69 mg, 33%) which was obtained as a colourless gum. MS: m/e=366.3 [M+H]+.