Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[C:5]2[C:21]([O:23][C:24](=[O:25])[C:3](=[C:4]23)[CH:2]=1)=O.[CH2:26]([NH2:35])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CN1CCCC1=O>[CH2:26]([N:35]1[C:21](=[O:23])[C:5]2[C:4]3[C:19]4[C:8](=[CH:7][CH:6]=2)[C:9]2[C:20]5[C:13]([CH:12]=[CH:11][CH:10]=2)=[CH:14][CH:15]=[CH:16][C:17]=5[C:18]=4[CH:1]=[CH:2][C:3]=3[C:24]1=[O:25])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCN
Reactant: O=C1OC(=O)c2ccc3c4cccc5cccc(c6ccc1c2c63)c54
Solvent: CN1CCCC1=O
Product: CCCCCCCCCN1C(=O)c2ccc3c4cccc5cccc(c6ccc(c2c36)C1=O)c54
Temperature: 175 °C

Procedure:
A mixture of 5 g (15.5 mmol) of perylene-3,4-dicarboxylic anhydride (prepared in accordance with Liebigs Ann. 1995, 1229–1244), 2.44 g (17 mmol) of n-nonylamine and 75 ml of N-methylpyrrolidone (NMP) was heated at 175° C. under nitrogen for 1.5 h. After cooling to room temperature, the resulting precipitate was filtered off, washed with methanol and dried under reduced pressure at 80° C. This gave 5.5 g (79%) of the desired product in the form of dark red crystals having a melting point of 201° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.FC(F)(F)S(O[C:18]1[CH2:27][CH2:26][C:21]2([O:25][CH2:24][CH2:23][O:22]2)[CH2:20][CH:19]=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:18]2[CH2:27][CH2:26][C:21]3([O:25][CH2:24][CH2:23][O:22]3)[CH2:20][CH:19]=2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(OC1=CCC2(CC1)OCCO2)C(F)(F)F
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(C2=CCC3(CC2)OCCO3)cc1
Temperature: 50 °C

Procedure:
A flask was charged with (4-methoxyphenyl)boronic acid (515 mg, 3.39 mmol), 1,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (780 mg, 2.71 mmol), 1,1′-bis(di-t-butylphosphino)ferrocene palladium dichloride (35 mg, 0.054 mmol), 1M K2CO3 (10 mL, 10 mmol), and THF (10 mL). The reaction was degassed with N2 and heated to 50° C. for 16 hours. The reaction was cooled to room temperature and diluted with EtOAc (100 mL). The mixture was washed with water (2×25 mL) and brine (2×25 mL), and the organic layer was dried (Na2SO4), filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (5 to 40% EtOAc/hexanes) afforded 8-(4-methoxyphenyl)-1,4-dioxaspiro[4.5]dec-7-ene. Rf=0.20 (25% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3): δ 7.31-7.34 (m, 2H), 6.82-6.85 (m, 2H), 5.90 (m, 1H), 4.02 (s, 4H), 3.80 (s, 3H), 2.62-2.66 (m, 2H), 2.45-2.46 (m, 2H), 1.92 (t, J=6.5 Hz, 2H).
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:6][CH:5]=1.[CH2:29]([NH2:31])[CH3:30]>>[CH2:29]([NH:31][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:20])([F:18])[F:19])=[N:6][CH:5]=1)[CH3:30]
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Reactant: CCN
Product: CCNC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Yield: 72 %

Procedure:
As described for example 137, 6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.25 mmol) was converted, using ethylamine instead of methylamine, to the title compound (75 mg, 72%) which was obtained as a white solid. MS: m/e=410.4 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH2:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C:12]2=[O:30])[S:5]([CH3:8])(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[CH3:37][O:38][CH2:39][CH2:40][NH2:41]>C(#N)C>[CH3:37][O:38][CH2:39][CH2:40][NH:41][CH2:2][CH2:3][N:4]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH2:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C:12]2=[O:30])[S:5]([CH3:8])(=[O:7])=[O:6]
Reactant: COCCN
Reactant: CS(=O)(=O)N(CCBr)c1ccc2c(c1)C(=O)N(CC(=O)OCc1ccccc1)C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCNCCN(c1ccc2c(c1)C(=O)N(CC(=O)OCc1ccccc1)C2=O)S(C)(=O)=O
Temperature: 130 °C
Yield: 52 %

Procedure:
To a solution of benzyl 2-(5-(N-(2-bromoethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (0.300 g, 0.606 mmol) in acetonitrile (6 ml), K2CO3 (0.126 g, 0.908 mmol) and 2-methoxyethanamine (0.079 ml, 0.908 mmol) were added, and the resulting mixture was heated under MW irradiation for 1 hour at 130° C. The insoluble inorganic salts were filtered off and the filtrate was evaporated to dryness. The crude was purified by flash chromatography on silica gel column (DCM:MeOH=95:5) affording benzyl 2-(5-(N-(2-(2-methoxyethylamino)ethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (0.154 g, 0.315 mmol, 52.0% yield, MS/ESI+ 490.0 [MH]+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].F[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1>CN(C=O)C>[CH2:14]([O:13][C:11](=[O:12])[CH:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)[CH3:15]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: Fc1ccnc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(c1ccc([N+](=O)[O-])cc1)c1ccnc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
To a solution of ethyl (4-nitrophenyl)acetate (760 mg, 3.6 mmol) in DMF (10 mL) was added 60% sodium hydride (145 mg, 3.6 mmol). The deep purple reaction mixture was stirred at rt for 30 min, then 4-fluoro-2-trifluoromethyl-pyridine (500 mg, 3.0 mmol) was added. After heating at 70° C. for 2 h, the mixture was poured onto ice water and extracted with ethyl acetate. The organic layers were washed with water and brine, then dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography, eluting with 10-30% ethyl acetate in hexanes, to give (4-nitro-phenyl)-(2-trifluoromethyl-pyridin-4-yl)-acetic acid ethyl ester as a viscous yellow oil (440 mg, 41%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:7]=[N:8][N:9]([CH2:12][C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=2[OH:20])[C:10]=1[CH3:11])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[CH2:57]([CH:59]([CH2:62][CH3:63])[CH2:60]O)[CH3:58]>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:7]=[N:8][N:9]([CH2:12][C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:60][CH:59]([CH2:62][CH3:63])[CH2:57][CH3:58])[C:10]=1[CH3:11])[CH3:2]
Reactant: CCC(CC)CO
Reactant: CCOC(=O)Cc1cnn(Cc2cc(Br)ccc2O)c1C
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cnn(Cc2cc(Br)ccc2OCC(CC)CC)c1C
Reaction time: 0.33 h

Procedure:
A solution of [1-(5-Bromo-2-hydroxy-benzyl)-5-methyl-1H-pyrazol-4-yl]-acetic acid ethyl ester, 2, (0.18 g g 0.51 mmol), triphenylphosphine (0.26 g, 1.02 mmol), di-tert-butylazodicarboxylate (0.23 g, 1.02 mmol) and 2-ethylbutan-1-ol (0.116 ml, 1.02 mmol) in a mixture of THF (1 mL) and toluene (2 ml) was at 120° C. on microwave for 20 min. The volatiles were removed in vacuo. The crude product was purified on silica to yield {1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-4-yl}-acetic acid ethyl ester, 3.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:20]([OH:22])=O)[C:5]2[CH2:6][CH2:7][N:8]([CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[C:9](=[O:12])[C:10]=2[CH:11]=1.Cl.[NH2:24][C@@H:25]([CH2:43][C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[C:46]([F:51])[CH:45]=1)[C@H:26]([OH:42])[CH2:27][NH:28][C:29]1([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)[CH2:31][CH2:30]1.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C.O.C(N(CC)CC)C>[F:50][C:48]1[CH:49]=[C:44]([CH:45]=[C:46]([F:51])[CH:47]=1)[CH2:43][C@H:25]([NH:24][C:20]([C:4]1[C:5]2[CH2:6][CH2:7][N:8]([CH:13]([CH2:14][CH2:15][CH3:16])[CH2:17][CH2:18][CH3:19])[C:9](=[O:12])[C:10]=2[CH:11]=[C:2]([CH3:1])[CH:3]=1)=[O:22])[C@H:26]([OH:42])[CH2:27][NH:28][C:29]1([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=2)[CH2:31][CH2:30]1
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1
Reactant: CCCC(CCC)N1CCc2c(C(=O)O)cc(C)cc2C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(CCC)N1CCc2c(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNC3(c4cccc(C(F)(F)F)c4)CC3)cc(C)cc2C1=O
Reaction time: 15 h

Procedure:
Added to a solution of 33 mg of 7-methyl-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid in 0.5 cm3 of anhydrous dimethylformamide are 0.05 cm3 of triethylamine and 51 mg of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)butan-2-ol hydrochloride (2:1), then 17 mg of 1-hydroxy-7-azabenzotriazole and 24 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The solution is kept stirring for 15 h at a temperature close to 20° C. 20 cm3 of water and 30 cm3 of ethyl acetate are added to the reaction medium. After decanting, the organic phase is washed with 20 cm3 of a saturated aqueous solution of ammonium chloride, five lots of 20 cm3 of water, then 20 cm3 of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (5 kPa). The residue is dissolved in 2 cm3 of dichloromethane then purified by flash chromatography over silica (column: 15 g; spherical silica of BP-SUP type, particle size: 20-40 μm; eluent: 60% heptane/40% ethyl acetate). After concentrating the fractions under reduced pressure, 68 mg of N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-7-methyl-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide are obtained in the form of a colorless oil.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][N:27]=1>>[Cl:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][N:27]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1
Reactant: Cc1ccnc(Br)c1
Product: Cc1ccnc(C(=O)c2cn(-c3cccc(-c4cccnc4Cl)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12l and 2-bromo-4-methylpyridine
Reaction SMILES: O[CH2:2][NH:3][C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)([O-:14])=[O:13]>S(=O)(=O)(O)O>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][C:17]=1[CH2:2][NH:3][C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C(NCO)c1ccccc1
Agent: O=S(=O)(O)O
Product: Cc1ccc([N+](=O)[O-])cc1CNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 63 h
Yield: 43 %

Procedure:
N-hydroxymethyl benzamide (7.55 g; 0.05 mol) is added to a solution of p-nitrotoluene (0.85 g; 0.05 mol) in concentrated sulfuric acid (60 ml). The reaction mixture is stirred for 63 hours at room temperature and then poured onto ice. A colorless precipitate is obtained which is isolated and recrystallized repeatedly from aqueous ethanol to give 4.0 g (i.e., 30% yield) of product. Increasing the reaction time to 7 days gives a 43% yield of product compound. This product has the following characteristics: melting point of 134° to 137° C.; i.r. 3300, 1635, 1655 cm-1 (sh); mass. spec. m/e 270.
Reaction SMILES: [NH3:1].[C:2]([O:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[C:26]([C:27](ON3C(=O)CCC3=O)=[O:28])=[C:25]([CH2:37][OH:38])[N:24]=[C:23]2[CH2:39][CH2:40][CH2:41][CH3:42])=[CH:17][CH:16]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3]>O1CCCC1>[C:2]([O:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]2[C:26]([C:27]([NH2:1])=[O:28])=[C:25]([CH2:37][OH:38])[N:24]=[C:23]2[CH2:39][CH2:40][CH2:41][CH3:42])=[CH:19][CH:20]=1)=[O:8])([CH3:3])([CH3:5])[CH3:4]
Reactant: CCCCc1nc(CO)c(C(=O)ON2C(=O)CCC2=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: N
Solvent: C1CCOC1
Product: CCCCc1nc(CO)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
0.5 ml of concentrated aqueous ammonia was added to a solution of 0.60 g of succinimido 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-hydroxymethylimidazole-5-carboxylate [prepared as described in step (a) above] in 6 ml of tetrahydrofuran, and the title compound started to separate immediately. The solvent was removed by distillation under reduced pressure, and the resulting residue was washed with diethyl ether and with water, to afford 0.38 g of the title compound as a powder, melting at 222°-224° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[N:11]=[N:10][NH:9]1.[CH2:14]([N:16]([CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[C:17](Cl)=[O:18])[CH3:15]>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH2:14]([N:16]([CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[C:17]([N:11]1[C:12](=[O:13])[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:9]=[N:10]1)=[O:18])[CH3:15]
Reactant: O=c1nn[nH]n1-c1ccccc1Cl
Reactant: CCN(C(=O)Cl)C1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CCN(C(=O)n1nnn(-c2ccccc2Cl)c1=O)C1CCOCC1

Procedure:
3.7 g (19 mmol) of 1-(2-chlorophenyl)-1,2-dihydro-5H-tetrazol-5-one, 3.6 g (19 mmol) of N-ethyl-N-(tetrahydro-2H-pyran-4-yl)carbamoyl chloride and 2.6 g (21 mmol) of 4-dimethylaminopyridine in 150 ml of toluene were heated under reflux for 5 hours. The organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent hexane/ethyl acetate 2:1). Yield 5.5 g. 1H NMR (270 MHz, in CDCl3): δ=1.20-1.40 (m, 3H), 1.80-2.05 (m, 4H), 3.30-3.60 (m, 4H), 3.70-4.50 (m, 3H), 7.40-7.60 (m, 4H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]=O)=[CH:15][CH:16]=3)[N:11]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:10]=2)=[CH:3][CH:2]=1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][C:29]1=[O:37].N1CCCCC1>CO>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]=[C:30]4[C:31]5[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=5)[NH:28][C:29]4=[O:37])=[CH:15][CH:16]=3)[N:11]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:10]=2)=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1nc(CCc2ccncc2)c2ccc(C=O)cc21
Reactant: O=C1Cc2ccccc2N1
Solvent: CO
Solvent: C1CCNCC1
Product: C[Si](C)(C)CCOCn1nc(CCc2ccncc2)c2ccc(C=C3C(=O)Nc4ccccc43)cc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 80.8 %

Procedure:
A solution of 3-(2-(pyridin-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (54 mg, 0.142 mmol), oxindole (19 mg, 0.142 mmol) in MeOH (2.0 mL) was treated with piperidine (1.5 uL, 0.0142 mmol) and the reaction heated to 60° C. and stirred for 4 hours at which time the solvent was removed and the residue purified by column chromatography (silica gel, 96:4 CH2Cl2/MeOH) to give the title compound (57 mg, 80%) as a yellow film. MS ESI 497.2 [M+H]+, calcd for [C29H32N4O2Si+H]+ 497.24.
Reaction SMILES: C([Cl:4])(=O)C.[CH3:5][O:6][CH2:7][CH2:8][C@@H:9]1[N:14]([CH3:15])[CH2:13][CH2:12][N:11]([C:16]2[C:25]3[CH:24]=[C:23]([CH:26]([CH3:28])[CH3:27])[S:22][C:21]=3[NH:20][C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=2)[CH2:10]1>C(O)C>[ClH:4].[ClH:4].[CH3:5][O:6][CH2:7][CH2:8][C@@H:9]1[N:14]([CH3:15])[CH2:13][CH2:12][N:11]([C:16]2[C:25]3[CH:24]=[C:23]([CH:26]([CH3:28])[CH3:27])[S:22][C:21]=3[NH:20][C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=2)[CH2:10]1
Reactant: CC(=O)Cl
Agent: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(C)C)cc32)CCN1C
Solvent: CCO
Product: Cl

Procedure:
Add a solution of acetyl chloride (0.13 mL, 1.76 mmol) in absolute ethanol to a solution of (S)-10-[3-(2-methoxy-ethyl)-4-methyl-piperazin-1-yl]-2-isopropyl-4H-3-thia-4,9-diaza-benzo[f]azulene (0.14 g, 0.35 mmol) in absolute ethanol and stir. Concentrate under reduced pressure to give the title compound (0.16 g, 94%): mass spectrum (APCI, m/e): 399 (M+1); exact mass spectrum (ES+, m/e, C22H30N4OS.2HCl): calc. 399.2218 (M+1-2HCl), found 399.2226.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([OH:13])=[O:12].S(Cl)(Cl)=O.O.[CH3:19]O>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([O:13][CH3:19])=[O:12]
Reactant: CO
Reactant: O=C(O)Cc1c(F)cc(F)cc1F
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)Cc1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2,4,6-trifluorobenzeneacetic acid (5.00 g, 26.3 mmol) in methanol (25 mL) was stirred at ambient temperature, and thionyl chloride (6 mL, ˜3 eq.) was added dropwise, causing the temperature of the reaction mixture to reach 60° C. The reaction mixture was allowed to cool to ambient temperature and was stirred for 3 h. Water (25 mL) was added with ice cooling. The mixture was extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with water (2×), with saturated aqueous sodium bicarbonate solution and with brine, and dried over MgSO4. Concentration provided the title product as a clear oil (5.38 g).
Reaction SMILES: [H-].[Na+].[F:3][CH:4](P(=O)(OCC)OCC)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)[CH:6]=1.O=[C:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1>CCCCC.C1COCC1>[F:3][C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][N:13]=2)[CH:6]=1)=[C:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1
Reactant: CCOP(=O)(OCC)C(F)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=C(F)c2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
NaH (166 mg, 6.92 mmol) under a N2 atmosphere was washed with n-pentane and dried blowing N2 gas. THF (5 mL) was added and the mixture was cooled to 0° C. Diethyl fluoro(3-(5-(trifluoromethyl)pyridin-2-yloxy)phenyl)methylphosphonate (940 mg, 2.3 mmol) was added as a solution in THF dropwise and the mixture was stirred for 30 min. tert-Butyl 4-oxopiperidine-1-carboxylate as a solution in THF was added dropwise and the reaction was stirred for 1 h. Excess NaH was quenched with water at 0° C. and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated to dryness. The residue was purified by column chromatography to give the pure title compound (600 mg). 1H NMR (500 MHz, CDCl3): δ 1.4 (s, 9H), 2.0 (m, 2H), 2.4 (m, 2H), 3.4 (m, 2H), 3.5 (m, 2H), 7.0 (d, 1H, J=8.5 Hz), 7.1-7.2 (m, 4H), 7.4 (t, 1H, J=8 Hz), 7.9 (d, 1H, J=8.5 Hz), 8.4 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1ccc(CC2CCNCC2)cc1

Procedure:
A mixture of 2 g of 4-(4-chloro-benzyl)-piperidine-1-carboxylic acid tert-butyl ester, dioxane (1.5 mL), and 3N hydrochloric acid (1.0 mL, 4equiv.) was heated at reflux for 3.5 hours. The cooled mixture was made basic with saturated sodium carbonate solution and extracted with chloroform (3×10 mL). The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. The crude product (1.2 g) was an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([NH:32][S@:33]([C:35]([CH3:38])([CH3:37])[CH3:36])=[O:34])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.CO.[Li+].[OH-]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([NH:32][S@:33]([C:35]([CH3:38])([CH3:37])[CH3:36])=[O:34])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:31]=[CH:30][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(N2CCC([C@@H](N[S@@](=O)C(C)(C)C)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)[S@](=O)N[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-(4-((R)-(4′-chlorobiphenyl-2-yl)((S)-1,1-dimethylethylsulfinamido)methyl)piperidin-1-yl)benzoate (INTERMEDIATE 128, 0.40 g, 0.62 mmol) in THF (4.3 ml) was added MeOH (1.4 ml) and a solution of LiOH (0.09 g, 4.44 mmol) in water (1.4 ml). The reaction mixture was stirred at 40° C. overnight. The reaction mixture was cooled to rt, concentrated under reduced pressure, and the residue suspended in water. The suspension was cooled to 0° C., acidified to pH ˜2 using 1N HCl aq., filtered, and the filtercake dried in a vacuum oven to provide the title compound (0.38 g, yield: almost quantitative).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[CH3:21])=O.[NH2:22][C:23]([NH2:25])=[S:24]>CCO>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([C:3]2[N:22]=[C:23]([NH2:25])[S:24][CH:2]=2)=[C:6]([CH3:21])[CH:7]=1
Reactant: COc1cccc(Oc2cc(C)c(C(=O)CBr)c(C)c2)c1
Reactant: NC(N)=S
Solvent: CCO
Product: COc1cccc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)c1
Yield: 65.9 %

Procedure:
A mixture of 2-bromo-1-(4-(3-methoxyphenoxy)-2,6-dimethylphenyl)ethanone (6.98 g, 20.0 mmol) and thiourea (1.52 g, 20.0 mmol) in 95% EtOH (28.5 mL) was heated at reflux for 5.0 h. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (1.0 mL), and extracted with ethyl acetate (100 ml). The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 4-(4-(3-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-amine (4.30 g) as deep-brown oil, which was used directly for the next step without further purification.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.S(Cl)(Cl)(=O)=O>C(OC(C)C)(C)C.O>[C:22]([C:21]1[CH:25]=[CH:26][C:18]([NH:17][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])=[CH:19][CH:20]=1)([OH:24])=[O:23]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: O=S(=O)(Cl)Cl
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C(=O)O)cc2)cc1
Yield: 82.4 %

Procedure:
A mixture of 190.5 g (1 mole) of 4-toluenesulfonyl chloride in 300 ml of i-propyl ether is added dropwise at 20°-30° C. to one of 252 g (3 mole) of sodium bi-carbonate and 139.1 g (1 mole) of 4-aminobenzoic acid in 2.5 l of water. The mixture is stirred vigorously for 2-4 hours, until the sulfonyl chloride has been consumed. The aqueous solution is separated off and then adjusted to pH 1 with concentrated hydrochloric acid, and the precipitate is taken up in propyl acetate. The extract is washed 2× with 2N hydrochloric acid and 1× with water, dried over sodium sulfate and evaporated. 240 g (82.5% of theory) of N-(4-carboxyphenyl)-4-toluenesulfonamide are obtained.