Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][CH:8]([CH2:10][CH2:11][CH2:12][C@H:13]([C:15]1[C@:32]2([CH3:33])[C@H:18]([C@H:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22](=[CH:23][C:24](=[O:34])[CH2:25][CH2:26]2)[CH2:21][CH2:20]3)[CH2:17][CH:16]=1)[CH3:14])[CH3:9].IC>CC(O)(C)C.C1COCC1>[CH3:9][CH:8]([CH2:10][CH2:11][CH2:12][C@H:13]([C:15]1[C@:32]2([CH3:33])[C@H:18]([C@H:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22]([CH2:23][C:24](=[O:34])[CH2:25][CH2:26]2)=[CH:21][CH2:20]3)[CH2:17][CH:16]=1)[CH3:14])[CH3:7]
Reactant: CC(C)CCC[C@@H](C)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)C1=CC[C@H]2[C@@H]3CC=C4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.33 h
Yield: 35.9 %

Procedure:
To a stirred suspension of KOtBu (900 mg, 8.2 mmol) in tBuOH (25 mL) at 45° C. was added cholesta-4,16-dien-3-one (620 mg, 1.6 mmol) in THF (5 mL) and the whole stirred for 20 minutes. Iodomethane (1 ml) was added and the reaction stirred a further 12 hours., concentrated to one half the original volume and poured into 20 mL ice water. Extraction with ethyl acetate, drying over magnesium sulphate and concentration gave a residue which was purified by flash chromatography to give the title compound (220 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[C:12]([NH:19][C@H:20]([C:22]3[N:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=3)[CH3:21])[N:11]=2)[CH:5]=1)[CH3:2].[CH2:29](O)C.C(OCC)(=O)C>[Cl-].[Na+].O.[Pd]>[CH2:1]([O:3][C:4]1[NH:8][N:7]=[C:6]([N:9]2[C:10]3=[N:11][C:12]([NH:19][C@H:20]([C:22]4[N:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=4)[CH3:21])=[CH:13][CH:14]=[C:15]3[N:16]=[CH:29]2)[CH:5]=1)[CH3:2]
Reactant: CCO
Reactant: CCOc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ccc2[N+](=O)[O-])n[nH]1
Agent: [Pd]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1cc(-n2cnc3ccc(N[C@@H](C)c4ncc(F)cn4)nc32)n[nH]1
Temperature: 25 °C

Procedure:
N2-(5-Ethoxy-1H-pyrazol-3-yl)-N6-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-3-nitropyridine-2,6-diamine (Intermediate 28, 0.3 g) was dissolved into ethanol (20 mL) with Pd—C (90 mg) and a hydrogen inlet. The mixture was stirred at room temperature until no starting material was detected with TLC or LCMS. Formylamidine acetate (0.5 g) was added to the filtrate after the filtration of resulting mixture. The mixture was stirred at 85° C. for 4 hours. Ethyl acetate (40 mL) was added into the resulting mixture, and brine (10 mL×3) was used to wash the organic layer. The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Ethyl acetate/MeOH) to afford 0.034 g of the title compound. MS (electrospray): 369 (M+1) for C17H17FN8O. 1H NMR (300 MHz, CD3OD) δ ppm 8.70 (s, 2H) 8.30 (s, 1H) 7.80 (d, 1H) 6.80 (d, 1H) 6.30 (s, 1H) 5.40 (m, 1H) 4.30 (q, 2H) 1.70 (d, 3H) 1.55 (t, 3H).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[N:16]1[CH:17]=[CH:18][N:19]=[CH:20][C:15]=1[N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cnccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cnccn2)CC1
Temperature: 60 °C
Yield: 59.2 %

Procedure:
A 500-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with DMSO (250 mL), tert-butyl piperazine-1-carboxylate (15.8 g, 85.0 mmol), 2-chloropyrazine (9.7 g, 85.0 mmol), and Cs2CO3 (55.3 g, 170 mmol). The mixture was heated at 60° C. for 3 days. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 5:1 petroleum ether/ethyl acetate to afford 189a (13.3 g, 60%) as a yellow solid. MS: [M+H]+ 265.3
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7](O)[N:6]=[CH:5]2.P(Cl)(Cl)([Cl:17])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([Cl:17])[N:6]=[CH:5]2
Reactant: COc1cc2nc(O)ncc2cc1Br
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2nc(Cl)ncc2cc1Br
Temperature: 25 °C
Yield: 75 %

Procedure:
To a solution of 6-bromo-7-methoxyquinazolin-2-ol (3.0 g, 11.8 mmol) in phosphoryl trichloride (30 mL) was refluxed at 130° C. for 5 h. LCMS showed the reaction was completed. The reaction was cooled to RT, and most of phosphoryl trichloride was evaporated. The residue was dropwise added to ice water (100 mL), and the resulting precipitate was collected via filtration to give the title compound as a yellow solid (2.4 g, 75%). MS (ES+) C9H6BrClN2O requires: 272, 274. found: 273, 275 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2=[N:11][CH:12]=[CH:13][C:14](Cl)=[C:9]2[NH:8][C:7]=1[CH3:16])=[O:5])[CH3:2].[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][C:27]=2[C:14]2[CH:13]=[CH:12][N:11]=[C:10]3[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([CH3:16])[NH:8][C:9]=23)[CH2:18][CH2:19]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ccnc12
Reactant: COc1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(OC)ccc3OCC3CC3)ccnc12

Procedure:
Starting from ethyl-7-chloro-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (example A3) and 2-(2-cyclopropylmethoxy-5-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c6) the title compound is obtained as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15]([CH2:24]O)=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].S(Cl)([Cl:28])=O>CC#N>[Cl:28][CH2:24][C:15]1[N:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:12]([C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)([CH3:11])[CH3:10])=[CH:13][N:14]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(CO)n1-c1ccc(F)cc1
Solvent: CC#N
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(CCl)n1-c1ccc(F)cc1
Reaction time: 3 h

Procedure:
To a solution of (5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)methanol (402 mg, 1.06 mmol) in CH3CN (6 mL) at 0° C. was added thionyl chloride. After stirring 3 h, the solution was concentrated under reduced pressure, and azeotroped with DCM (3×) to give 2-(chloromethyl)-5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole as a yellow solid (420 mg) that was used directly for the next step without purification.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH:20]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=3)[C:21]([O:23]CC3C=CC=CC=3)=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1>C1COCC1.[Pd]>[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH:20]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=3)[C:21]([OH:23])=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: COc1ccc(C(Oc2ccc3c(N)nccc3c2)C(=O)OCc2ccccc2)cc1OC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(Oc2ccc3c(N)nccc3c2)C(=O)O)cc1OC
Reaction time: 16 h
Yield: 110 %

Procedure:
137F (130 mg, 0.29 mmol) was dissolved in THF (8 mL). To this solution was added 10% Pd/C (cat.), and the mixture was hydrogenated at 50 psi for 16 h. The reaction was filtered and concentrated to provide 2-(1-aminoisoquinolin-6-yloxy)-2-(3,4-dimethoxyphenyl)acetic acid (113 mg, 10%). LC-MS: 355.19 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][CH:8]=2)=[O:4].Br[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]=[C:5]([C:3]([OH:2])=[O:4])[N:6]2[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1cccc2ccccc12
Reactant: COC(=O)c1cc2c(OC)cccc2[nH]1
Product: COc1cccc2c1cc(C(=O)O)n2Cc1cccc2ccccc12

Procedure:
Using general procedure B, 4-methoxy-1H-indole-2-carboxylic acid methyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a pale yellow solid. MS: 330.1 ([M−H]−).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].F[C:25]1[C:26]([N+:31]([O-:33])=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=1>C1COCC1>[N+:31]([C:26]1[C:25]([O:13][C:9]2[CH:8]=[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[CH:12]=[CH:11][CH:10]=2)=[CH:30][CH:29]=[CH:28][N:27]=1)([O-:33])=[O:32]
Reactant: Oc1cccc(N2CCOCC2)c1
Reactant: O=[N+]([O-])c1ncccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ncccc1Oc1cccc(N2CCOCC2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73.1 %

Procedure:
In a 125 mL round-bottom flask, 3-morpholinophenol (0.91 g, 5.07 mmol) was dissolved in THF (40 mL). Solution was cooled to 0° C. and NaHMDS (5.07 mL, 5.07 mmol) (1M in THF) was added slowly. The mixture was agitated for 15 minutes and solution of 3-fluoro-2-nitropyridine (0.60 g, 4.22 mmol) in THF (5 mL) was added slowly. After agitating for 2 hours the solvent was evaporated and the residue dissolved in 100 mL of CH2Cl2 and washed with diluted sodium bicarbonate solution twice, dried over magnesium sulfate, filtered and evaporated. Crude material was purified by chromatography on silica gel, eluted with 25% ethyl acetate/Hexane to give the title compound (0.93 g, 72%) was obtained as thick red oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH2:13][CH:14]([OH:18])[CH2:15][CH2:16][CH3:17])=[CH:7][CH:6]=1.[C:20]([C:28]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:29]=1[C:30](O)=[O:31])(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:2][O:3][C:4](=[O:19])[C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:12]2[C:13]([C:14](=[O:18])[CH2:15][CH2:16][CH3:17])=[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:28]3[C:29](=[CH:33][CH:34]=[C:35]([Cl:37])[CH:36]=3)[C:30]2=[O:31])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CCCC(O)CNCc1ccc(C(=O)OC)cc1
Agent: Cl
Product: CCCC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(C(=O)OC)cc1

Procedure:
In the same manner as in Example 458, Step 2, the title compound was synthesized from 4-[(2-hydroxypentylamino)methyl]benzoic acid methyl ester hydrochloride and 2-benzoyl-4-chlorobenzoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:35][CH2:36][C:37]([CH3:40])([OH:39])[CH3:38].O>CS(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([NH:35][CH2:36][C:37]([OH:39])([CH3:40])[CH3:38])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Reactant: CC(C)(O)CN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(O)CNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)OC(C)(C)C)sc3c2)cc1
Yield: 83.1 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-tert-butoxycarbonylaminobenzo-thiazol-6-yl ester (intermediate 15) (300 mg, 0.707 mmol), cesium carbonate (230 mg, 0.707 mmol) and 1-amino-2-methylpropan-2-ol (126 mg, 1.414 mmol) in 5 ml of dimethyl sulfoxide is stirred at 80° C. for 72 hours. Water is added to the reaction medium, and the mixture is extracted 3 times with ethyl acetate. The organic phase is washed with saturated sodium chloride solution and then dried over magnesium sulfate and finally evaporated to dryness to give 290 mg of 4-(2-hydroxy-2-methylpropylamino)benzenesulfonic acid 2-tert-butoxycarbonylaminobenzo-thiazol-6-yl ester in a yield of 83%.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=O)=[CH:5][CH:4]=1.[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12]C([O-])=O>N1CCCCC1.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[CH:12][C:11]([O:17][CH2:18][CH3:19])=[O:16])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: COc1ccc(C=O)cn1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CCOC(=O)C=Cc1ccc(OC)nc1
Yield: 79.2 %

Procedure:
A mixture of 6-methoxypyridine-3-carboxaldehyde (2.34 g), monoethyl malonate (4.51 g), pyridine (12 ml) and piperidine (6 drops) was heated under reflux for 5 hours and was evaporated to an oil. This oil was partitioned between ether and dilute aqueous ammonia. The ether layer was washed with water and evaporated to an oil which crystallised on standing to give ethyl 3-(6-methoxy-3-pyridyl)acrylate (2.8 g, 79%) m.p. 49°-52°.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]([OH:28])=O)[CH:24]=4)[NH:19][CH:18]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.[C:36]([NH2:40])([CH3:39])([CH3:38])[CH3:37].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:36]([NH:40][C:26]([C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9]1)=[O:28])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc2[nH]cc(CCCCN3CCN(c4ccccc4)CC3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)NC(=O)c1ccc2[nH]cc(CCCCN3CCN(c4ccccc4)CC3)c2c1

Procedure:
A solution of 3.74 g of 3-[4-(4-phenylpiperazino)butyl]indole-5-carboxylic acid in 500 ml of DMF is treated with 1.01 g of N-methylmorpholine. A solution of one equivalent of tert-butylamine in 5 ml of DMF, 1.35 g of 1-hydroxybenzotriazole and a solution of 1.92 g of N-(3-dimethylaminopropyl-N'-ethylcarbodiimide hydrochloride in 20 ml of DMF are added with stirring. The mixture is stirred for 16 hours at 20° and the filtrate is evaporated. After working up in a conventional manner, 3-[4-(4-phenylpiperazino)butyl]indole-5-carboxylic acid N-tert-butylamide is obtained.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:22])=[C:16]([S:18](Cl)(=[O:20])=[O:19])[CH:17]=1.C([O-])(O)=O.[Na+]>C(OCC)C>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:22])=[C:16]([S:18]([O:5][C:4]2[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=2)(=[O:20])=[O:19])[CH:17]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2cc(F)ccc2C)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100.6 %

Procedure:
To a solution of 1.00 g (8.05 mmol) of orcinol monohydrate and 1.63 g (7.38 mmol) of 5-fluoro-2-methylbenzenesulfonyl chloride in 20 mL of diethyl ether was added 20 mL of saturated aqueous NaHCO3 and the biphasic mixture stirred vigorously at ambient temperature for 3 days. The layers were separated and the aqueous layer extracted with 2×30 mL of ethyl acetate. The combined organic layers were washed with 50 mL of brine, dried (Na2SO4) and concentrated to give 2.2 g of an orange syrup. Crystallization from dichloromethane-hexane (two crops) afforded 1.24 g (54%) of the title compound as a light orange powder: 1H-NMR (300 MHz; CDCl3) δ 7.57 (dd, 1H, J=8.2, 2.8 Hz), 7.36 (dd, 1H, J=8.6, 5.2 Hz), 7.22 (td, 1H, J=8.4, 2.8 Hz), 6.52 (m, 1H), 6.39 (m, 1H), 6.30 (t, 1H, J=2.2 Hz), 2.69 (s, 3H) and 2.21 (s, 3H).
Reaction SMILES: C(C1SC=C([N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])C=1)=O.[CH:24]([C:26]1[S:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25]>>[CH:24]([C:26]1[S:30][C:29]([N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[CH:28][CH:27]=1)=[O:25]
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1csc(C=O)c1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc(C=O)s1
Yield: 47 %

Procedure:
Following the same procedure as described for compound 11 (step 1, scheme 2, example 1c) except using 5-formyl-2-thiopheneboronic acid (1.80 g, 11.5 mmol) instead of 5-formylthiophen-3-ylboronic acid to afford 19 (935 mg, 47%) as an orange solid. LRMS (ESI): calc. 342.1; found 343.2 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([C:17]([OH:19])=O)[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:35][CH2:36][C:37]([NH2:39])=[O:38].N1C=CC=CC=1>CN1CCCC1=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:11](=[CH:15][CH:16]=2)[C:12](=[O:14])[N:35]([CH2:36][C:37]([NH2:39])=[O:38])[C:17]3=[O:19])=[CH:20][CH:21]=1
Reactant: NCC(N)=O
Reactant: O=C(O)c1ccc(OCc2ccc(F)cc2)cc1C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Solvent: O
Product: NC(=O)CN1C(=O)c2ccc(OCc3ccc(F)cc3)cc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.5 %

Procedure:
A mixture of 4-(4-fluoro-benzyloxy)-phthalic acid (185 mg, 0.64 mmol) and carbonyldiimidazole (109 mg, 0.67 mmol) in 1-methyl-2-pyrrolidinone (4 mL) was stirred at room temperature for 10 min and then heated at 50° C. for 15 min. To this mixture was added glycinamide hydrochloride (78 mg, 0.71 mmol) and pyridine (50 mg, 0.63 mmol) and the resulting mixture heated at 175 or 200° C. with microwave radiation (Smith reactor) for 10 min. After cooling to room temperature, the mixture was diluted with water and the resulting precipitate was filtered off and purified by chromatography (SiO2, CH2Cl2:2N NH3/MeOH 9:1) to afford the title compound (146 mg, 69%) as a white solid. MS: m/e=329.3. (M+H+).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([CH3:15])=[C:11]([CH:14]=1)[C:12]#[N:13].[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.Cl>O1CCCC1>[C:12]([C:11]1[CH:14]=[C:7]([B:16]([OH:21])[OH:17])[CH:8]=[CH:9][C:10]=1[CH3:15])#[N:13]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1ccc(Br)cc1C#N
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(B(O)O)cc1C#N
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
17.5 ml of n-butyllithium solution (1.6M in hexane) are added dropwise to a solution of 5 g of 5-bromo-2-methylbenzonitrile in 80 ml of dry tetrahydrofuran at −78° C. After stirring at this temperature for 35 minutes, 7.3 ml of triisopropyl borate are added. After one hour, 50 ml of 1N HCl are added to the reaction mixture at −78° C., and the mixture is warmed to room temperature. The phases are separated and the aqueous phase is extracted three more times with 100 ml of diethyl ether each time. The combined organic phases are dried with sodium sulphate, and the solvent is concentrated to 5 ml. The residue is mixed with 150 ml of pentane. The precipitate which has separated out is filtered off with suction and washed twice with pentane. Drying under high vacuum results in 2.85 g of the title compond as a pale yellow solid. Rt=2.98.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[C:24]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[CH2:11]([C:3]1[C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][O:6][C:2]=1[NH:1][S:30]([C:27]1[CH:26]=[CH:25][C:24]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:29][CH:28]=1)(=[O:32])=[O:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CCCCCCCCCCCCCc1c(C(F)(F)F)noc1N
Product: CCCCCCCCCCCCCc1c(C(F)(F)F)noc1NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Yield: 81 %

Procedure:
N-(4-Tridecyl-3-trifluoromethyl-5-isoxazolyl)-4-biphenylsulfonamide was prepared, in the same manner as described in Example 90b, from 5-amino-4-tridecyl-3-trifluoromethyl-isoxazole and 4-biphenylsulfonyl chloride in 81% yield. Purification was achieved by recrystallization from methanol/water to give an off white solid, m.p. 115°-116° C.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6](=[N:8]C(=O)C(F)(F)F)[N:5]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[N:4]=1)[CH3:2].[ClH:52]>O1CCOCC1.O>[ClH:52].[CH2:1]([C:3]1[S:7][C:6](=[NH:8])[N:5]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:29][N:30]=[N:31][N:32]=3)=[CH:20][CH:21]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c(=NC(=O)C(F)(F)F)s1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=N)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-ethyl-2-trifluoroacetylimino-3-[2'-(1-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1,3,4-thiadiazoline (700 mg) in 1,4-dioxane (10 ml) was added 12N hydrochloric acid (2ml), and they were stirred at room temperature for 18 hours. The solvent was distilled off from the reaction mixture. The residue so obtained was dispersed in water, collected by filtration and then dried, whereby 250 mg of the title compound was obtained.
Reaction SMILES: [CH3:1]CN(C(C)C)C(C)C.[Cl:10][C:11]1[C:16]([CH:17]=[O:18])=[C:15](Cl)[N:14]=[CH:13][N:12]=1.C[CH:21]([SH:25])[C:22]([O-:24])=[O:23]>C(Cl)Cl>[Cl:10][C:11]1[N:12]=[CH:13][N:14]=[C:15]([S:25][CH2:21][C:22]([O:24][CH3:1])=[O:23])[C:16]=1[CH:17]=[O:18]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(S)C(=O)[O-]
Reactant: O=Cc1c(Cl)ncnc1Cl
Solvent: ClCCl
Product: COC(=O)CSc1ncnc(Cl)c1C=O
Temperature: -10 °C

Procedure:
DIPEA (4.1 mL) was added to a solution of 4,6-dichloropyrimidine-5-carbaldehyde (intermediate 8) (4.2 g) in DCM (85 mL) under an inert atmosphere. The solution was cooled to −10° C. and methylthioglycolate (2.1 mL) in DCM (40 mL) was added dropwise over 30 minutes. The reaction mixture was allowed to warm to ambient temperature over 2 hours, washed with water (4×50 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound as an orange oil which later solidified (5.4 g, 92%);
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH2:7]Br)=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[CH3:13][S-:14].[Na+].O>O1CCCC1>[Br:1][C:2]1[O:6][C:5]([CH2:7][S:14][CH3:13])=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1
Reactant: C[S-]
Reactant: COC(=O)c1cc(Br)oc1CBr
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)oc1CSC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of methyl 5-bromo-2-(bromomethyl)furan-3-carboxylate (8.9 g) in tetrahydrofuran (50 mL) was added sodium methanethiolate (2.5 g) at 0° C., and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 10% ethyl acetate/hexane) to give the title compound (6.7 g, 84%) as an oil.