Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:10][CH2:11][CH:12]=[CH2:13])(=[O:9])[CH2:2][C:3]([O:5][CH2:6][CH:7]=[CH2:8])=[O:4].[H-].[Na+].Cl[CH2:17][C:18]1[C:31]2[C:32]3=[C:33]4[C:28](=[CH:29][CH:30]=2)[CH:27]=[CH:26][CH:25]=[C:24]4[CH:23]=[CH:22][C:21]3=[CH:20][CH:19]=1>C1C=CC=CC=1>[C:18]1([CH2:17][C:2]([CH2:17][C:18]2[C:31]3[C:32]4=[C:33]5[C:28](=[CH:29][CH:30]=3)[CH:27]=[CH:26][CH:25]=[C:24]5[CH:23]=[CH:22][C:21]4=[CH:20][CH:19]=2)([C:3]([O:5][CH2:6][CH:7]=[CH2:8])=[O:4])[C:1]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])[C:31]2[C:32]3=[C:33]4[C:28](=[CH:29][CH:30]=2)[CH:27]=[CH:26][CH:25]=[C:24]4[CH:23]=[CH:22][C:21]3=[CH:20][CH:19]=1
Reactant: C=CCOC(=O)CC(=O)OCC=C
Reactant: ClCc1ccc2ccc3cccc4ccc1c2c34
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: C=CCOC(=O)C(Cc1ccc2ccc3cccc4ccc1c2c34)(Cc1ccc2ccc3cccc4ccc1c2c34)C(=O)OCC=C
Temperature: 25 °C

Procedure:
Diallyl malonate (0.36 g, 2.0 mmol) was added to a stirred suspension of NaH (2.5 mmol) in dry benzene (5 mL). After 30 minutes 1-chloromethylpyrene (0.5 g, 2.0 mmol) in benzene (20 mL) was added. The mixture was gently refluxed for 18 hours, cooled to room temperature and washed with saturated aqueous NaCl (2×5 mL). The organic layer was dried over MgSO4 and the solvent evaporated under reduced pressure to give the product, which was recrystallized from AcOEt/hexane to afford the desired product as white crystals, yield: 0.26 g, 42%, m.p. 178°-180° C. 1H NMR and 13C NMR were in accord with the desired product. Analysis (C43H32O4): calculated C:84.29, H:5.26; found: C:84.13, H:5.23.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4]([N:10]2[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11]2)[N:3]=1.C(Cl)Cl.[CH3:19][O:20][C:21](Cl)=[O:22]>C(N(CC)CC)C>[N:10]1([C:4]2[N:3]=[C:2]([NH:1][C:21]([O:20][CH3:19])=[O:22])[N+:7]([O-:8])=[C:6]([NH:9][C:21]([O:20][CH3:19])=[O:22])[CH:5]=2)[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]1
Reactant: Nc1cc(N2CC=CCC2)nc(N)[n+]1[O-]
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Nc1cc(N2CC=CCC2)nc(NC(=O)OC)[n+]1[O-]

Procedure:
45 G. of 2,4-diamino-6-[3,6-dihydro-1(2H)-pyridyl]pyrimidine-3-oxide are mixed in 600 ml. of methylene chloride with 90 ml. of triethylamine and cooled to 5° C. 90 Ml. of chloroformic acid methyl ester are added dropwise while stirring. The mixture is stirred at 5° C. for 30 minutes and at room temperature for 18 hours. Then, the mixture is treated with 100 ml. of methanol and subsequently extracted with 400 ml. of methylene chloride, washed with water, dried over sodium sulfate and evaporated under reduced pressure. Recrystallization of the residue from methanol yields dimethyl 6-[3,6-dihydro-1(2H)-pyridyl]-2,4-pyrimidinedicarbamate-3-oxide having a melting point of 202°-203° C.
Reaction SMILES: [OH:1][C:2]1([C:6]2[S:7][C:8]([C:11]3[CH:12]=[C:13]([NH:18][C:19]4[N:24]=[C:23]([O:25][CH:26]5[CH2:31][CH2:30][CH:29]([C:32]([O:34]CC)=[O:33])[CH2:28][CH2:27]5)[CH:22]=[CH:21][N:20]=4)[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:9][N:10]=2)[CH2:5][CH2:4][CH2:3]1.CO.[OH-].[Na+].Cl>O1CCCC1.O>[OH:1][C:2]1([C:6]2[S:7][C:8]([C:11]3[CH:12]=[C:13]([NH:18][C:19]4[N:24]=[C:23]([O:25][CH:26]5[CH2:31][CH2:30][CH:29]([C:32]([OH:34])=[O:33])[CH2:28][CH2:27]5)[CH:22]=[CH:21][N:20]=4)[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:9][N:10]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)C1CCC(Oc2ccnc(Nc3cc(C)cc(-c4cnc(C5(O)CCC5)s4)c3)n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(Nc2nccc(OC3CCC(C(=O)O)CC3)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of ethyl 4-{[2-({3-[2-(1-hydroxycyclobutyl)-1,3-thiazol-5-yl]-5-methylphenyl}-amino)pyrimidin-4-yl]oxy}cyclohexanecarboxylate (Example 94A-16, 40 mg, 0.08 mmol) in tetrahydrofuran (0.52 mL), water (0.13 mL), and methanol (0.13 mL) was added aqueous sodium hydroxide (1.0 M in H2O, 0.2 mL, 0.2 mmol). The mixture was stirred at room temperature until complete. The reaction was then quenched with aqueous hydrochloric acid (1.0 M in H2O, 0.22 mL, 0.22 mmol). The resulting mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 4-{[2-({3-[2-(1-hydroxycyclobutyl)-1,3-thiazol-5-yl]-5-methylphenyl}amino)pyrimidin-4-yl]oxy}cyclohexanecarboxylic acid (37 mg, 0.08 mmol, 99%) as a pale yellow solid. MS ESI: [M+H]+ m/z 480.8. 1H NMR (500 MHz, DMSO-d6) δ 12.12 (s, 1H), 9.52 (s, 1H), 8.19 (m, 1H), 7.97 (s, 1H), 7.88 (s, 1H), 7.73-7.39 (m, 2H), 7.08 (s, 1H), 6.63-6.41 (m, 1H), 6.36-6.15 (m, 1H), 5.38-4.87 (m, 2H), 2.57-2.50 (m, 1H), 2.40-2.26 (m, 4H), 2.19-2.06 (m, 1H), 1.97-1.79 (m, 3H), 1.79-1.68 (m, 2H), 1.67-1.58 (m, 1H), 1.51-1.36 (m, 1H), 1.30-0.74 (m, 2H). rhSyk activity=+++.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][C:24](=O)[CH3:25]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:24]([CH3:25])[CH2:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[Cl:15])=[CH:6][CH:7]=1
Reactant: CC(=O)CCc1ccccc1Cl
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccccc1Cl

Procedure:
Prepared according to the procedure described in Example 8, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 4-(2-chloro-phenyl)-butan-2-one.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][CH2:8][CH:9]([CH2:20][NH:21][C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[CH:10]([O:12][Si](C(C)(C)C)(C)C)[CH3:11])=[O:6])[CH:2]=[CH2:3].Cl>C(#N)C>[CH2:25]([O:24][C:22]([NH:21][CH2:20][CH:9]([CH2:8][NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:10]([OH:12])[CH3:11])=[O:23])[CH:26]=[CH2:27]
Reactant: C=CCOC(=O)NCC(CNC(=O)OCC=C)C(C)O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CC#N
Product: C=CCOC(=O)NCC(CNC(=O)OCC=C)C(C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.2 %

Procedure:
To a solution of 3.98 g of 1-allyloxycarbonylamino-2-(N-allyloxycarbonylaminomethyl)-3-t-butyldimethylsilyloxybutane in 20 ml of acetonitrile was added 2 ml of concentrated hydrochloric acid at 0° C. After stirring for 3 hours at room temperature, the mixture was extracted with chloroform and the organic layer was washed with saturated sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. Evaporation of the solvent followed by a column chromatography on silica gel (hexane:ethyl acetate=1:1) gave 2.88 g of 1-allyloxycarbonylamino-2-(N-allyloxycarbonylaminomethyl)butan-3-ol quantitatively.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:11]([NH:14][CH3:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)(O)=O.Br.[NH2:17][CH2:18][CH2:19][CH2:20][SH:21]>>[CH3:15][NH:14][C:11]1[CH:12]=[CH:13][C:5]2[CH:4]=[C:1]3[S:21][CH2:20][CH2:19][CH2:18][N:17]3[C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: CNc1ccc(CC(=O)O)c(C(=O)O)c1
Reactant: NCCCS
Agent: Br
Product: CNc1ccc2cc3n(c(=O)c2c1)CCCS3

Procedure:
By following the same procedure as in Example 29 using 2.3 g. of 2-carboxymethyl-5-methylaminobenzoic acid and 1.8 g. of 3-aminopropanethiol.hydrobromide, 300 mg. of 8-methylamino-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline was obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[CH3:9][C:10]1[N:11]=[CH:12][NH:13][C:14]=1[CH2:15][S:16][CH2:17][CH2:18][NH2:19].[CH3:20][N:21]=[C:22]=[S:23]>O>[CH3:20][NH:21][C:22]([NH:19][CH2:18][CH2:17][S:16][CH2:15][C:14]1[NH:13][CH:12]=[N:11][C:10]=1[CH3:9])=[S:23]
Reactant: CN=C=S
Reactant: Cc1nc[nH]c1CSCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CNC(=S)NCCSCc1[nH]cnc1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
i. Potassium carbonate (7.75 g.) was added to a solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride (14.6 g.) in water (120 ml.). The solution was stirred at room temperature for 15 minutes and methyl isothiocyanate (5.15 g.) was added. After heating under reflux for 30 minutes, the solution was slowly cooled to 5°. The product (13.1 g.) was collected and recrystallized from water to give N-methyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiourea, m.p. 150°-152°.
Reaction SMILES: [CH3:1][C:2]1[C:12](=[O:13])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:4](=[O:5])[CH:3]=1.[OH-:14].[Na+].OO>CO.O>[CH3:1][C:2]12[C:12](=[O:13])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4](=[O:5])[CH:3]1[O:14]2
Reactant: [OH-]
Reactant: CC1=CC(=O)c2ccccc2C1=O
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC12OC1C(=O)c1ccccc1C2=O
Reaction time: 0.17 h
Yield: 91.5 %

Procedure:
Menadione crystalline (1) (5 g, 29.04 mmol, 1 equivalent) and 2 M NaOH (7.26 mL, 14.52 mmol, 0.5 equivalents) are dissolved in a mixture of methanol/water 4:1 (50 mL) at 0-2° C. After stirring at this temperature for 10 minutes, 35% hydrogen peroxide is added (4.2 mL, 43.56 mmol, 1.5 equivalents). Work-up: after 30 minutes at 0° C. the product is extracted with ethyl ether. The organic phase is dried over Na2SO4 and evaporated under reduced pressure. A whitish powder is obtained (5 g, 26.57 mmol). Yield: 91.5%.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH:23]1([O:28][C:29]2[C:30]([O:52][CH3:53])=[CH:31][CH:32]=[C:33]3[C:38]=2[N:37]([CH2:39][CH2:40][OH:41])[C:36](=[O:42])[CH:35]=[C:34]3[NH:43][C:44]2[C:49]([Cl:50])=[CH:48][N:47]=[CH:46][C:45]=2[Cl:51])[CH2:27][CH2:26][CH2:25][CH2:24]1>C(Cl)Cl>[CH:23]1([O:28][C:29]2[C:30]([O:52][CH3:53])=[CH:31][CH:32]=[C:33]3[C:38]=2[N:37]([CH2:39][CH:40]=[O:41])[C:36](=[O:42])[CH:35]=[C:34]3[NH:43][C:44]2[C:45]([Cl:51])=[CH:46][N:47]=[CH:48][C:49]=2[Cl:50])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)n(CCO)c2c1OC1CCCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)n(CC=O)c2c1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dess-Martin periodinane (933 mg, 2.2 mmol) was added to a solution of 8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-1-(2-hydroxyethyl)-7-methoxyquinolin-2(1H)-one (500 mg, 1.08 mmol, Example 9) and CH2Cl2 (30 mL) at 0° C. After 30 min, the mixture was allowed to warm to rt. When the starting material was consumed, the reaction was diluted with dichloromethane (25 mL), washed with aq. NaOH (20 mL×2), and then washed with water (20 mL). The organic layer was dried, filtered, concentrated, and purified by silica gel chromatography (1:2→1:1; ethyl acetate:petroleum ether) to give 2-(8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxoquinolin-1(2H)-yl)acetaldehyde: MS (ESI): 462.2.
Reaction SMILES: [O-]CC.[Na+].C([O:7][C:8](=[O:39])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH2:30]Cl)=[O:27])=[CH:21][C:20]=2[CH2:32][S:33][CH2:34][C:35]([F:38])([F:37])[F:36])[CH:11]=1)C>CCO>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][C:8]([OH:7])=[O:39])=[CH:11][C:12]=1[O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][C:26]2=[O:27])=[CH:21][C:20]=1[CH2:32][S:33][CH2:34][C:35]([F:37])([F:36])[F:38]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)NCCCl)cc2CSCC(F)(F)F)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(CC(=O)O)cc1Oc1ccc(N2CCNC2=O)cc1CSCC(F)(F)F
Temperature: 65 °C
Reaction time: 8 h

Procedure:
Sodium ethoxide (20% wt/v; 2.27 mL, 0.187 mmol) was added to a solution of {3-[4-[3-(2-chloro-ethyl)-ureido]-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester (0.050 g, 0.094 mmol) in EtOH (5 mL). The reaction was stirred at 65° C. overnight, and then partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by preparative HPLC to give Compound 57.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(C)N
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 91 %

Procedure:
As described for example 61b, 6-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (83 mg, 0.25 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (85 mg, 91%) which was obtained as a white solid. MS: m/e=370.2 [M+H]+.
Reaction SMILES: [C:1]1([N:7]2[N:11]=[C:10]([OH:12])[CH:9]=[N+:8]2[O-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.[Zn]>[C:1]1([N:7]2[N:11]=[C:10]([OH:12])[CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [O-][n+]1cc(O)nn1-c1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Product: Oc1cnn(-c2ccccc2)n1

Procedure:
88.5 g of 2-phenyl-4-hydroxy-1,2,3-triazole-1-oxide of formula I (R = phenyl) is stirred in 1000 ml of glacial acetic acid, with ice cooling, with 75 g of zinc dust. After completion of the reaction, the filtrate is filtered off and concentrated by evaporation to dryness. The residue is stirred into water, filtered off under suction, washed with water and again filtered off under suction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[CH3:31][N:32]1[C:36]([CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]2[OH:43])=[CH:35][N:34]=[CH:33]1.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:43][C@H:38]2[CH2:39][CH2:40][CH2:41][CH2:42][C@@H:37]2[C:36]2[N:32]([CH3:31])[CH:33]=[N:34][CH:35]=2)=[CH:12][C:11]=1[F:18])(=[O:8])=[O:9]
Reactant: Cn1cncc1C1CCCCC1O
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3cncn3C)cc2F)c(OC)c1
Yield: 28.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide (120 mg, 0.273 mmol) prepared in Example 14b, 2-(1-methyl-1H-imidazol-5-yl)cyclohexanol (50 mg, 0.277 mmol) prepared in Example 49b, sodium hydride (63%; 40 mg, 1.05 mmol) and DMF (2.0 mL), to yield the title compound (46 mg, 28%) as a colorless oil.
Reaction SMILES: [CH3:1][C@H:2]([NH2:11])[C@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:12][O:13][C:14](=[O:31])[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26](I)=[CH:27][CH:28]=3)[CH:23]=[N:22]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)CCC>[Cu]I>[NH2:11][C@@H:2]([CH3:1])[C@@H:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[O:10][C:26]1[CH:25]=[C:24]2[C:29](=[CH:28][CH:27]=1)[N:21]([C:18]1[CH:19]=[CH:20][C:15]([C:14]([O:13][CH3:12])=[O:31])=[CH:16][CH:17]=1)[N:22]=[CH:23]2
Reactant: COC(=O)c1ccc(-n2ncc3cc(I)ccc32)cc1
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCC#N
Product: COC(=O)c1ccc(-n2ncc3cc(O[C@H](c4ccccc4)[C@H](C)N)ccc32)cc1
Yield: 16.4 %

Procedure:
(1R,2S)-Norephedrine (500 mg, 3.31 mmol), methyl-4-(5-iodoindazole-1-yl)-benzoate (1.28 g, 3.37 mmol), cesiumcarbonate (2.15 g, 6.61 mmol), copper (I)-iodide (314.9 mg, 1.65 mmol) and butyronitrile (2 mL) are stirred in a glass pressure tube at 120° C. for 20 h. The reaction mixture is filtered via a glass microfibre filter, the solvent evaporated and the residue purified by chromatography (silicagel, eluents: dichloromethane/methanol). 217.9 mg (16.4%) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:7]2.[H-].[Na+].ICCCN[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>CN(C)C=O>[C:28]([O:27][C:26]([CH:6]([NH2:7])[CH2:5][CH2:4][N:7]1[C:8]2[C:4](=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:11]=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:32])([CH3:29])([CH3:30])[CH3:31]
Reactant: CCOC(=O)c1cc2c(C(F)(F)F)cccc2[nH]1
Reactant: CC(C)(C)OC(=O)NCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C(F)(F)F)cccc2n1CCC(N)C(=O)OC(C)(C)C

Procedure:
The reaction was carried out in a manner similar to Reference Example 5 (25) except for using 2.60 g (10.11 mmol) of ethyl 4-trifluoromethyl-2-indolecarboxylate, 0.445 g (11.12 mmol) of 60% sodium hydride, 4.32 g (15.17 mmol) of tert-butyl N-(3-iodopropyl)-carbamate and 100 ml of dimethylformamide. Ethyl 1-(3-tert-butoxycarbonyl-aminopropyl)-4-trifluoromethyl-2-indolecarboxylate was thus obtained in an amount of 2.81 g (67.1%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9](=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20].O>O1CCCC1>[OH:18][CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[CH:20]1[CH2:24][CH2:23][O:22][C:19]1=[O:21]
Reactant: CCOC(C)=O
Reactant: COc1cccc(C=O)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C(O)C2CCOC2=O)c1
Reaction time: 0.5 h

Procedure:
To a solution of y-butyrolactone (3.0 g) in tetrahydrofuran (THF) (30 ml) was added lithium diisopropylamide (LDA) (28 ml, 1.5 M solution in cyclohexane) at −78° C. under N2, and then after 30 minutes, a solution of m-anisaldehyde (4.7 g) in THF (10 ml) was added in the solution. After being stirred for 2 hours at the same temperature, the solution was poured into the mixture of ethyl acetate and water. The organic layer was washed with 1N-HCl solution, sat. NaHCO3 and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 3-[hydroxy(3-methoxyphenyl)methyl)-2-oxotetrahydrofuran (7.4 g).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]>C(#N)C.O>[CH2:6]([O:7][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH2:4]
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Solvent: CC#N
Solvent: O
Product: C=CCOc1ccc(C(=O)O)cc1C(F)(F)F

Procedure:
The title compound was prepared from 4-fluoro-3-(trifluoromethyl)benzoic acid (1a) in >99% (5.65 g) yield. HPLC retention time on a C8(2) column (30×3.00 mm, 3 i) was 2.53 min with gradient 20-98% acetonitrile-H2O (0.1% TFA) in 4.0 min as mobile phase. 1H NMR (400 MHz, DMSO-d6) δ 13.10 (br s, 1H), 8.15 (dd, 1H, J=8.8 Hz, J=2.4 Hz), 8.08 (d, 1H, J=2.4 Hz), 7.35 (d, 1H, J=8.8 Hz), 5.95-6.80 (m, 1H), 5.38-5.45 (m, 1H), 5.26-5.32 (m, 1H), 4.77-4.82 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:21][CH2:22][CH2:23][O:24][CH3:25])[N:3]=1.[N+:26]([O-])([OH:28])=[O:27]>OS(O)(=O)=O>[Cl:1][C:2]1[C:20]([N+:26]([O-:28])=[O:27])=[CH:19][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:21][CH2:22][CH2:23][O:24][CH3:25])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: COCCOc1nc(Cl)ccc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: O=S(=O)(O)O
Product: COCCOc1nc(Cl)c([N+](=O)[O-])cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
The sub-title compound is prepared from 6-chloro-2-(2-methoxy-ethoxy)-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (2.20 g, 5.78 mmol), fuming HNO3 (5 mL) and conc. H2SO4 (10 mL) in analogy to example 1c.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:33]=[CH:32][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:29])=O)=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].[CH3:34][N:35]([CH3:41])[CH2:36][C:37]([NH2:40])([CH3:39])[CH3:38].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:11]1([N:10]2[C:6]3[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:33]=[CH:32][C:7]=3[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:29])[NH:40][C:37]([CH3:39])([CH3:38])[CH2:36][N:35]([CH3:41])[CH3:34])=[CH:23][C:22]=3[O:30][CH3:31])(=[O:19])=[O:20])[C:9]2=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CN(C)CC(C)(C)N
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)O)cc1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)NC(C)(C)CN(C)C)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.9 %

Procedure:
A mixture of 1 g of the compound obtained in EXAMPLE 13, 1 g of 2-dimethylamino -1,1- dimethylethylamine (synthesized according to J. Am. Chem. Soc., 1946, 68, 10-12), 1 g of BOP, 1 ml of DIPEA and 20 ml of DCM is stirred for 16 hours at RT. The reaction mixture is evaporated under vacuum, the residue is extracted with AcOEt, washed with a 1N solution of NaOH, extracted with a 6N solution of HCl, washed with AcOEt, the acidic aqueous phase is rendered alkaline by the addition of 2N NaOH, extracted with AcOEt and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/MeOH mixture (99/1; v/v) as the eluent to give 0.65 g of the expected product after crystallization from iso ether. M.p.=161° C.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14]Cl)=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1(=[O:23])=[O:22])([CH3:4])([CH3:3])[CH3:2].[C:24]1([SH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][S:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1(=[O:23])=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(NCCCCl)=C(c2ccccc2)S1(=O)=O
Reactant: Sc1ccccc1
Product: CC(C)(C)N1C(=O)C(NCCCSc2ccccc2)=C(c2ccccc2)S1(=O)=O
Yield: 65 %

Procedure:
The title compound was prepared as described for Example 12 from 2-tert-butyl-4-[(3-chloropropyl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide and thiophenol at 100° C. for 45 mins. The reaction mixture was filtered, evaporated to dryness and the residue was purified by silica gel column chromatography (Horizons Biotage) using 10-20% EtOAc in hexane as eluent to give the title compound (0.076 g, 65%). 1H NMR (500 MHz CDCl3): δ 7.52-7.48 (m, 2H), 7.46-7.38 (m, 3H), 7.32-7.18 (m, 5H), 5.32 (t, 1H), 3.02-2.96 (m, 2H), 2.70 (t, 2H), 1.74 (s, 9H), 1.68-1.60 (m, 2H); 13C NMR (125 MHz CDCl3): δ 159.8, 135.6, 135.1, 131.8, 129.4, 129.9, 129.3, 128.9, 126.7, 125.1, 107.5, 61.8, 42.8, 31.0, 28.9, 27.9; Mass Spectrum: M+H+ 431.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH3:17]O>>[CH3:17][O:11][C:10](=[O:12])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)COCc1ccccc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)COCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of benzyloxy-acetic acid (5 g, 30.12 mmol) in methanol (100 mL) was added SOCl2 (2.66 mL, 35.8 mmol) at 0° C. The mixture was stirred for 30 min at 0° C., finally at room temperature for 2.5 h. After completion of the reaction, the solvent was evaporated and the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The separated organic part was dried over sodium sulfate and concentrated under reduced pressure to get benzyloxy-acetic acid methyl ester (3) as a crude colorless oil (4.98 g).