Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[S:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].COC(C1ON=C(OC[C:36]2[C:37]([C:42]3C=CC=CN=3)=[N:38]OC=2C)C=1)=O.C(N)(C)C>>[CH:37]([NH:38][C:3]([C:5]1[S:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4])([CH3:42])[CH3:36]
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)no1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)ns1
Solvent: CC(C)N
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)NC(C)C)sn1
Yield: 77 %

Procedure:
As described for example 14e, 3-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-isothiazole-5-carboxylic acid methyl ester (120 mg, 0.34 mmol), instead of 3-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester, was converted, using isopropyl amine (24 mg, 0.41 mmol), to the title compound (99 mg, 77%) which was obtained as a white solid after purification by chromatography (silica, heptane:ethyl acetate=4:1 to 1:4). MS: m/e=377.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].C(N(CC)CC)C.[CH2:22]([N:29]=[C:30]=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>O1CCCC1>[CH2:22]([NH:29][C:30](=[O:31])[O:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][CH2:5][N:4]2[CH2:1][C:2]#[CH:3])=[CH:9][CH:10]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCN=C=O
Reactant: C#CCN1CCCc2ccc(O)cc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCN1CCCc2ccc(OC(=O)NCCCCCCC)cc21
Temperature: 35 °C

Procedure:
A mixture of 1-(prop-2-ynyl)-1,2,3,4-tetrahydroquinolin-7-ol (500 mg, 2.67 mM) and triethylamine (0.6 mL) in dry tetrahydrofuran (THF, 5 mL) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, heptyl isocyanate (644 mg/ml, 4 mM) was added at once and then the reaction mixture was further stirred for 48 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chlorophorm-hexane (1:19) to get 10b as creamish solid. Yield: 625 mg, 71.26%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH:28]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)=[O:28])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(SCCCCOc2ccc3c(c2)CCC(=O)N3)cc1OC
Reactant: OO
Product: COc1ccc(S(=O)CCCCOc2ccc3c(c2)CCC(=O)N3)cc1OC

Procedure:
Prepared analogous to Example 2 from 6-[4-(3,4-dimethoxyphenyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:17]([CH:18](O)[CH2:19][C:20]3[S:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][N:24]=3)=[C:16]([CH3:29])[O:15][N:14]=2)=[N:11][CH:12]=1>>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:17](/[CH:18]=[CH:19]/[C:20]3[S:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][N:24]=3)=[C:16]([CH3:29])[O:15][N:14]=2)=[N:11][CH:12]=1
Reactant: Cc1onc(-c2ccc(F)cn2)c1C(O)Cc1ncc(C(=O)O)s1
Agent: O=S(=O)(O)O
Product: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)O)s1
Temperature: 90 °C
Yield: 88.7 %

Procedure:
Concentrated sulfuric acid (29 mL) was added to 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-2-hydroxy-ethyl}-thiazole-5-carboxylic acid (1.71 g, 4.9 mmol) then the mixture was heated at 90° C. for 10 min. After cooling to room temperature the mixture was poured into ice (200 g) and the precipitate was filtered off and dried to give the title product (1.44 g, 89%) as a yellow solid. MS: m/e=330.0 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[C:6](=[O:7])[O:5][CH2:4][C:3]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:9]1=[O:18].Br[CH2:20][C:21]([C:23]1[C:24]([CH3:33])=[C:25]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:32])[O:27][CH2:26]2)=[O:22].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:33][C:24]1[C:23]([C:21](=[O:22])[CH2:20][N:15]2[CH2:16][CH2:17][C:10]3([C:9](=[O:18])[N:8]([C:3]4[CH2:4][O:5][C:6](=[O:7])[C:2]=4[CH3:1])[CH2:12][CH2:11]3)[CH2:13][CH2:14]2)=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][O:27][C:28]2=[O:32]
Reactant: Cc1c(C(=O)CBr)ccc2c1COC2=O
Reactant: CC1=C(N2CCC3(CCNCC3)C2=O)COC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1=C(N2CCC3(CCN(CC(=O)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O

Procedure:
2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (I-17) (2 g, 7.99 mmol), 5-(2-Bromo-acetyl)-4-methyl-3H-isobenzofuran-1-one (I-4B, method 2, step F) (2.150 g, 7.99 mmol) and N-ethyl-N-isopropylpropan-2-amine (3.48 mL, 19.98 mmol) in DCM (50 mL) were stirred overnight at rt. The mixture was washed with saturated ammonium chloride aqueous and brine, dried over MgSO4, and concentrated under reduced pressure. The crude material was used in the next step without further purification. 1H-NMR (500 MHz, CDCl3): δ ppm 7.83 (1H, d, J=7.8 Hz), 7.79 (1H. d, J=7.8 Hz), 5.34 (2H, s), 5.32 (2H, s), 5.26 (2H, s), 4.03 (2H, t, J=7.0 Hz), 3.71 (1H, m), 3.15 (1H, m), 2.94 (2H, m), 2.47 (2H, t, J=7.0 Hz), 2.42 (3H, s), 2.17 (2H, m), 2.07 (3H, s), 2.02 (2H, m), 1.58 (2H, m). LCMS 438.9 (M+1).
Reaction SMILES: [C:1]([N:5]1[CH:9]([NH2:10])[CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:7](=[O:18])[NH:6]1)([CH3:4])([CH3:3])[CH3:2].I[CH:20]([CH2:22][CH3:23])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]([N:5]1[CH:9]([NH2:10])[CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:7](=[O:18])[N:6]1[CH:20]([CH2:22][CH3:23])[CH3:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1C1C(=O)NN(C(C)(C)C)C1N
Reactant: CCC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCC(C)N1C(=O)C(c2ccccc2C)C(N)N1C(C)(C)C
Yield: 16 %

Procedure:
A mixture of 1.23 g of 1-tert-butyl-4-(2-methylphenyl)-5-amino-pyrazolin-3-one, 1.84 g of 2-iodobutane, 2.1 g of potassium carbonate and 20 ml of ethanol was heated under reflux for 10 hours. The solvent was distilled off under reduced pressure, then, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate anhydride, then, the solvent was distilled off under reduced pressure. The residue was analyzed by 1H-NMR on the ratio of N-alkyl compound to O-alkyl compound being 16 to 84 was applied to column chromatography to obtain 250 ml (yield: 16%) of 1-tert-butyl-2-sec-butyl-4-(2-methylphenyl)-5-aminopyrazolin-3-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].CC(C)([O-])C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH3:24])[CH:18]=1.O>CC(N(C)C)=O>[F:9][C:3]1[CH:4]=[C:5]([O:8][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: COc1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(Oc2ccc(N)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
A solution of 4-amino-3-fluorophenol (0.20 g, 1.6 mmol) in 4 mL of anhydrous DMA was treated with potassium tert-butoxide (0.24 g, 1.9 mmol). The resultant dark-red solution was stirred at RT for 1 hour in a capped vial. 4-Chloro-2-methoxypyridine (0.26 g, 1.6 mmol) was added and the reaction mixture was heated overnight at 100° C. Water (50 mL) was added and the solution was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried (Na2SO4), concentrated in vacuo and purified by silica gel column chromatography to obtain 2-fluoro-4-(2-methoxypyridin-4-yloxy)benzenamine (0.20 g, 58% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J=6.0 Hz, 1H), 6.95 (dd, J=2.8, 12.0 Hz, 1H), 6.82 (dd, J=8.4, 8.8 Hz, 1H), 6.73 (dd, J=2.0, 8.4 Hz, 1H), 6.54 (dd, J=2.4, 6.0 Hz, 1H), 6.10 (d, J=2.4 Hz, 1H), 5.17 (s, 1H), 3.81 (s, 3H); MS (ESI) m/z: 235.0 (M+H+).
Reaction SMILES: [CH2:1]([N:8]([CH2:24][C@H:25]([OH:46])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:30]([S:42]([CH3:45])(=[O:44])=[O:43])[CH:29]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:48]1[C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=2N=[N:49]1.Cl.C(N=C=NCCCN(C)C)C.C1(NN)C=CC=CC=1>ClCCl.C(#N)C.C(N(CC)CC)C>[CH2:1]([N:8]([CH2:24][C@H:25]([OH:46])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:30]([S:42]([CH3:45])(=[O:44])=[O:43])[CH:29]=1)[C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([NH:49][NH:48][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:51]=3)=[O:20])=[CH:22][CH:23]=2)[CH2:13][CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(C(=O)O)cc3)CC2)ccc1OCc1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS(=O)(=O)c1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(C(=O)NNc4ccccc4)cc3)CC2)ccc1OCc1ccccc1
Reaction time: 48 h

Procedure:
A solution of 0.3 g (0.441 mmol) of trans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-(methylsulfonyl)phenoxy]-2-hydroxypropyl}amino)cyclohexyl]benzoic acid (preparation 4), of 0.78 g (0.91 mmol) of 1-hydroxybenzotriazole, of 0.169 g (0.88 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, of 0.184 ml of triethylamine and of 0.095 g (0.88 mmol) of phenylhydrazine in a mixture of 4 ml of dichloromethane and 0.8 ml of acetonitrile is stirred for 48 hours. The solvents are evaporated under reduced pressure. Dichloromethane and water are added and the organic phase is washed three times with water. The organic phases are dried over magnesium sulfate and concentrated under reduced pressure. The product is obtained in the form of a white solid (0.166 g, 50%) after purification on silica gel (eluent: heptane/ethyl acetate 60/40 for 10 min, 60/40 to 40/60 in 10 min, then 40/60 for 20 min gradient). [M+H+]=734.7
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])(=[O:25])=[O:24])=[C:16]([CH3:35])[CH:15]=2)=[O:13])=[CH:7][CH:6]=1)C.[OH-].[K+]>C(O)C>[Cl:32][C:30]1[CH:29]=[CH:28][C:27]([O:33][CH3:34])=[C:26]([S:23]([N:20]2[C:21]3[C:17](=[C:16]([CH3:35])[CH:15]=[C:14]([C:12]([NH:11][C:8]4[CH:9]=[CH:10][C:5]([C:4]([OH:36])=[O:3])=[CH:6][CH:7]=4)=[O:13])[CH:22]=3)[CH2:18][CH2:19]2)(=[O:25])=[O:24])[CH:31]=1
Reactant: CCOC(=O)c1ccc(NC(=O)c2cc(C)c3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CC3)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2c(C)cc(C(=O)Nc3ccc(C(=O)O)cc3)cc21
Temperature: 50 °C
Yield: 79.3 %

Procedure:
A suspension of 4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-4-methyl-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid ethyl ester (185 mg, 0.350 mmol) in ethanol (2 mL) and 3 M aq. potassium hydroxide solution (0.35 mL, 1.05 mmol) was heated at 50° C. for 18 h, then volatile material was removed by distillation. The residue was taken up in water (2 mL) and brought to pH 1 by addition of 2 M aq. hydrochloric acid solution. The precipitate was collected by filtration and dried, producing 4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-4-methyl-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid (139 mg, 76%). Off-white solid, MS (ISP): m/e 499.1 (M−H).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[N:17][CH:18]=2)=[N:5]1)[CH3:3].[H-].[Na+].[CH3:22][N:23]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[N:25]=[C:24]1S(C)(=O)=O.O>CN(C=O)C>[CH3:3][CH:2]([N:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[CH:18]=[N:17][C:16]([O:19][C:24]3[N:23]([CH3:22])[C:27]4=[N:28][CH:29]=[CH:30][CH:31]=[C:26]4[N:25]=3)=[CH:15][CH:14]=2)=[N:5]1)[CH3:1]
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CC(C)n1nc(-c2ccc(O)nc2)c2ncccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1nc(-c2ccc(Oc3nc4cccnc4n3C)nc2)c2ncccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
To a stirred mixture of 5-[1-(1-Methylethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl]pyridin-2-ol (76 mg) in DMF (4 mL) was added NaH (60% in oil, 12.6 mg) at room temperature. The mixture was stirred at room temperature for 30 min and then 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (76 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane). The product was crystallized from AcOEt/hexane to give the title compound (23.0 mg).
Reaction SMILES: CN(C)C=O.[O:6]=[C:7]1[CH:16]=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]1[CH2:17][CH2:18][CH2:19][C:20]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Br[CH2:32][CH2:33][S:34][C:35]1[S:36][CH:37]=[CH:38][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[O:6]=[C:7]1[CH:16]=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]1[CH2:17][CH2:18][CH2:19][C:20]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:25][CH2:24][N:23]([CH2:32][CH2:33][S:34][C:35]2[S:36][CH:37]=[CH:38][CH:39]=2)[CH2:22][CH2:21]1
Reactant: CCOC(=O)C1(CCCn2c(=O)cnc3ccccc32)CCNCC1
Reactant: BrCCSc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CCCn2c(=O)cnc3ccccc32)CCN(CCSc2cccs2)CC1
Temperature: 52.5 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To 2 mL of an N,N-dimethylformamide solution containing 95 mg of ethyl 4-(3-(2-oxoquinoxalin-1(2H)-yl)propyl)piperidine-4-carboxylate, 69 mg of 2-(2-bromoethylthio)thiophene and 84 mg of potassium carbonate were added at room temperature, and stirred at 50-55° C. for 1 hour. Additional 35 mg of 2-(2-bromoethylthio)thiophene was added and stirred at 50-55° C. for 1 hour, then stirred at 60° C. for 1 hour. The mixture was cooled to the room temperature, ethyl acetate and water were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=20:1] to give 98 mg of ethyl 4-(3-(2-oxoquinoxalin-1(2H)-yl)propyl)-1-(2-(2-thienylthio)ethyl)piperidine-4-carboxylate as a light brown oil.
Reaction SMILES: [CH:1]1([S:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[C:10](O)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:21])=O>ClCCl>[CH:1]1([S:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[C:10]([Cl:21])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(C(=O)O)cc1SC1CCCC1
Solvent: ClCCl
Product: COc1ccc(C(=O)Cl)cc1SC1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-cyclopentylthio-4-methoxybenzoic acid (9 g; that is prepared as described in Reference Example 46) in dry dichloromethane (90 mL) under nitrogen is treated with oxalyl chloride (6.2 mL). After stirring at room temperature for 2 hours, the mixture is evaporated and dried under high vacuum, to give 3-cyclopentylthio-4-methoxybenzoyl chloride.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([O:7][CH2:8][CH2:9][CH:10]([NH:20]C(=O)OC(C)(C)C)[CH2:11][N:12]2[CH:17]3[CH2:18][CH2:19][CH:13]2[CH2:14][NH:15][CH2:16]3)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.[CH2:37]([N:41]=[C:42]=[O:43])[CH2:38][CH2:39][CH3:40]>CC#N>[NH2:20][CH:10]([CH2:9][CH2:8][O:7][C:6]1[CH:28]=[CH:29][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH2:11][N:12]1[CH:13]2[CH2:19][CH2:18][CH:17]1[CH2:16][N:15]([C:42]([NH:41][CH2:37][CH2:38][CH2:39][CH3:40])=[O:43])[CH2:14]2
Reactant: CCCCN=C=O
Reactant: CC(C)(C)OC(=O)NC(CCOc1ccc(C#N)cc1)CN1C2CCC1CNC2
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCNC(=O)N1CC2CCC(C1)N2CC(N)CCOc1ccc(C#N)cc1
Reaction time: 96 h

Procedure:
tert-Butyl 3-(4-cyanophenoxy)-1-(3,8-diazabicyclo[3.2.1]oct-8-ylmethyl)propylcarbamate (100.1 mg, 0.25 mmol; see Preparation M) was dissolved in MeCN (2.5 mL) and triethylamine (37.9 mg, 0.38 mmol). Butylisocyanate (29.7 mg, 0.3 mmol) was added and the reaction mixture was stirred at r.t for 4 days. The solvent was evaporated and the resulting residue dissolved in ethyl acetate (0.5 mL). Ethyl acetate saturated with HCl (2 mL) was added and the mixture was stirred for 6 h. The solvent was evaporated and the residue dissolved in MeCN (2 mL). The solution was added to ion-exchange solid phase extraction plug. The plug was then eluted with DCM/MeCN (4×2 mL of 4:1) (fraction 1) followed by DCM:MeOH:Et3N (4×2 mL of 8:1:1)(fraction 2). Evaporation of fraction 2 gave the title compound in quantitative yield.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[S:14])=[CH:4][CH:3]=1.[Cl:15][C:16]1[S:20][C:19]([C:21]([NH:23][CH2:24][C:25]2[N:26]=[CH:27][NH:28][CH:29]=2)=[O:22])=[CH:18][CH:17]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:15][C:16]1[S:20][C:19]([C:21]([NH:23][CH2:24][C:25]2[N:26]=[CH:27][N:28]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]4=[S:14])=[CH:4][CH:3]=3)[CH:29]=2)=[O:22])=[CH:18][CH:17]=1
Reactant: S=c1ccccn1-c1ccc(I)cc1
Reactant: O=C(NCc1c[nH]cn1)c1ccc(Cl)s1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: O=C(NCc1cn(-c2ccc(-n3ccccc3=S)cc2)cn1)c1ccc(Cl)s1
Temperature: 130 °C

Procedure:
A mixture of 1-(4-iodophenyl)pyridine-2(1H)-thione prepared above (65 mg, 0.21 mmol), 5-chloro-N-((1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 3-1 prepared in Example 11 (65 mg, 0.18 mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and K2CO3 (75 mg, 0.54 mmol) in DMSO (2 mL) was degassed with Ar before being charged with CuI (27 mg, 0.14 mmol). The mixture in a sealed tube was heated at 130° C. overnight. It was then purified by HPLC to give the title compound (15 mg). MS 427.0 and 429.0 (M+H, Cl pattern).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[CH3:15][O:16][C:17]([C:19]1[S:23][N:22]=[C:21](O)[CH:20]=1)=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:15][O:16][C:17]([C:19]1[S:23][N:22]=[C:21]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])[CH:20]=1)=[O:18]
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: COC(=O)c1cc(O)ns1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)ns1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (350 mg, 2.2 mmol) in THF (30 mL) was added 3-hydroxy-isothiazole-5-carboxylic acid methyl ester (416 mg, 2.2 mmol) and triphenylphosphine (692 mg, 2.4 mmol) at 0° C. under an argon atmosphere. Then diethyl azodicarboxylate (˜40% in toluene, 1.05 mL, 2.4 mmol) was added and the reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (silica, heptane:ethyl acetate=9:1 to 0:1) afforded the title compound (567 mg, 78%) as a colourless oil. MS: m/e=331.1 [M+H]+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2[C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)O1.Br[C:34]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:35]=1[CH2:36][CH2:37][N:38]([S:44]([NH:47][C:48]1[S:49][C:50]([F:53])=[CH:51][N:52]=1)(=[O:46])=[O:45])[CH2:39]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O>[F:53][C:50]1[S:49][C:48]([NH:47][S:44]([N:38]2[CH2:37][CH2:36][C:35]3[C:40](=[CH:41][CH:42]=[CH:43][C:34]=3[C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:18])[F:17])=[CH:11][C:10]=3[C:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:21][CH:20]=3)[CH2:39]2)(=[O:46])=[O:45])=[N:52][CH:51]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=S(=O)(Nc1ncc(F)s1)N1CCc2c(Br)cccc2C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2-c2cccc3c2CCN(S(=O)(=O)Nc2ncc(F)s2)C3)CC1
Yield: 25.9 %

Procedure:
A solution of Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 0.027 g, 0.038 mmol), tert-butyl 4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate K, 0.260 g, 0.574 mmol), 5-bromo-N-(5-fluorothiazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (Intermediate I, 0.150 g, 0.382 mmol), and potassium phosphate (0.325 g, 1.530 mmol) in 2.5 mL dioxane, 1 mL water was heated to 100° C. 2 hours. The reaction mixture was diluted with EtOAc and washed with 1 N citric acid solution. The organics were dried over MgSO4 and concentrated. Purification of the resulting residue by silica gel column chromatography (0 to 100% EtOAc/heptane) gave tert-butyl 4-(2-(2-(N-(5-fluorothiazol-2-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.063 g, 0.099 mmol). This material was taken up in 1 mL THF, was treated with HCl 4N in dioxane (1.912 ml, 7.65 mmol) and was allowed to stir at room temperature overnight. The reaction mixture was concentrated yielding N-(5-fluorothiazol-2-yl)-5-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride (0.063 g, 0.117 mmol). [M+H]+=538.8 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.82 (br. s., 2H), 7.73 (d, J=7.9 Hz, 1H), 7.60 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.30 (s, 1H), 7.25 (d, J=4.7 Hz, 2H), 7.02 (t, J=4.5 Hz, 1H), 5.71 (br. s., 1H), 4.29 (s, 2H), 3.62-3.68 (m, 1H), 3.53-3.59 (m, 2H), 3.37-3.44 (m, 1H), 3.18-3.28 (m, 2H), 2.85-3.07 (m, 2H), 2.06-2.20 (m, 1H), 1.92-2.02 (m, 1H)
Reaction SMILES: COCCOCC[N:8](CCOCCOC)CCOCCOC.Cl[C:24]1[N:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=[O:27].C(N)(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cu]Cl.C(OCC)(=O)C.O.C1(C)C(C)=CC=CC=1>[NH2:8][C:24]1[N:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=[O:27]
Reactant: COCCOCCN(CCOCCOC)CCOCCOC
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: Cl[Cu]
Agent: CC(N)=O
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1nc(Cl)ccc1C(=O)O
Temperature: 145 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
Tris(2-(2-methoxyethoxy)ethyl)amine (3.0 mL, 9.4 mmol) was added to a mixture of 2,6-dichloronicotinic acid (40 g (90% purity), 0.19 mol), acetamide (80 g, 1.4 mol), potassium carbonate (78 g, 0.56 mol), copper(I) chloride (0.93 g, 9.4 mmol) and xylene (80 mL), which was stirred overnight at 145° C. After cooling, copper(I) chloride (0.46 g, 4.6 mmol) was added to the reaction solution, which was stirred overnight at 145° C. After cooling the reaction solution to 105° C., water (100 mL) was added, the solution was stirred for 1 hour at the same temperature, and cooled down to room temperature. 5N hydrochloric acid (150 mL) was added, the solution was neutralized with a citric acid aqueous solution, then, ethyl acetate was added, and the solution was filtered through Celite pad. The organic layer was washed with brine, then, the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate), recrystallization by the ethyl acetate-hexane was carried out to obtain the title compound (1.4 g, 8.3 mmol, 4.5%) as white crystal.