Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](I)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C([Li])CCC.[Si:19]([C:26]1[O:27][C:28]2[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:29]=2[C:30]=1[CH:31]=[O:32])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCCC1.C1(C)C=CC=CC=1>[Si:19]([C:26]1[O:27][C:28]2[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:29]=2[C:30]=1[C:31](=[O:32])[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21]
Reactant: COc1ccc2c(C=O)c([Si](C)(C)C(C)(C)C)oc2c1
Reactant: COc1cc(I)cc(OC)c1OC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c([Si](C)(C)C(C)(C)C)oc2c1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of 3,4,5-trimethoxy-iodobenzene (377 mg, 1.27 mmol) in dry tetrahydrofuran (1 mL) at −78° C. under nitrogen was added n-butyllithium (795 μL, 1.59 mmol, 2M solution in cyclohexane) and the reaction mixture was stirred at this temperature for 40 minutes. After this time a solution of 2-t-butyldimethylsilyl-3-formyl-6-methoxy-benzofuran (310 mg, 1.07 mmol) in dry tetrahydrofuran (1 mL) was added to the reaction dropwise via syringe pipette. The reaction mixture was stirred at −60° C. for 20 minutes and then allowed to warm to 0° C., stirred for 10 minutes, quenched with saturated ammonium chloride solution (2 mL) and diluted with ethyl acetate (20 mL). The organic layer was washed with water (10 mL), dried over magnesium sulphate and the solvent was removed under vacuum to give a residue that was co-distilled with toluene. The crude product (908 mg) was dissolved in dry tetrahydrofuran (10 mL) and treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (900 mg, 1.59 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours (tlc) and then loaded onto silica (10 g) and purified by flash chromatography (silica gel, eluent=hexane/diethyl ether/triethylamine, 90:9:1) to afford the title compound as a light yellow paste that crystallised on standing; (232 mg, 48%); 1H NMR (300 MHz, CDCl3) δ 7.14(s, 2H, benzoyl Hs), 7.05(d, 1H, J=2.45 Hz), 6.77(dd, 1H, J=8.76, 2.17 Hz), 6.56(d, 1H, J=8.38 Hz), 3.94(s, 3H, OMe), 3.85(s, 6H, 2×OMe), 3.78(s, 3H, OMe), 1.00(s, 9H), 0.28(s, 6H); 13C NMR (75 MHz, CDCl3) δ 190.51(CO), 164.77, 158.23, 158.12, 152.64, 142.35, 133.19, 131.37, 123.19, 121.04, 119.63, 112.26, 107.03, 104.96, 95.00, 60.47, 55.81, 55.60, 55.13, 26.43, 17.29, −6.09.
Reaction SMILES: Br[C:2]1[C:3]([CH3:33])=[CH:4][C:5]([O:29][CH:30]([CH3:32])[CH3:31])=[C:6]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[C:12]([CH3:28])=[CH:11][N:10]=2)[CH:7]=1.[C:34]([Si:36]([CH3:39])([CH3:38])[CH3:37])#[CH:35].C(N(CC)C(C)C)(C)C>O1CCOCC1.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.[Cu]I>[CH:30]([O:29][C:5]1[CH:4]=[C:3]([CH3:33])[C:2]([C:35]#[C:34][Si:36]([CH3:39])([CH3:38])[CH3:37])=[CH:7][C:6]=1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[C:12]([CH3:28])=[CH:11][N:10]=1)([CH3:32])[CH3:31]
Reactant: Cc1cc(OC(C)C)c(Nc2ncc(C)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)cc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: N#Cc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OC(C)C)c(Nc2ncc(C)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)cc1C#C[Si](C)(C)C
Temperature: 22 °C
Reaction time: 20 h

Procedure:
A mixture of N2-(5-Bromo-2-isopropoxy-4-methyl-phenyl)-5-methyl-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine (Example 5, Step 4, 110 mg, 0.21 mmol), ethynyl-trimethyl-silane (0.14 mL), N,N-diisopropyl ethylamine (0.10 mL), PdCl2(PhCN)2 (12 mg), tBu3PHBF4 (17 mg), and CuI (4 mg) in 1 mL 1,4-dioxane is stirred at 22° C. for 20 hrs followed by heating at 60° C. for an additional 2 hrs. The reaction mixture is filtered through a small Celite plug and concentrated. The residue is purified over a 4 g SiO2 column (ISCO) using a gradient of 0 to 20% ethyl acetate in hexanes as eluent, affording N2-(2-Isopropoxy-4-methyl-5-trimethylsilanylethynyl-phenyl)-5-methyl-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine as a yellow viscous oil.
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:42]=O)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:18][C:17]=2[N:31]([CH3:41])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)(=[O:34])=[O:33])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:44]([N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)(=[O:46])[CH3:45].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=O)([O-])O.[Na+]>ClCCCl>[C:44]([N:47]1[CH2:52][CH2:51][N:50]([CH2:42][CH:9]([S:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:10][NH:11][C:12]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][C:19]([O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:18][C:17]=3[N:31]([CH3:41])[S:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)(=[O:33])=[O:34])=[O:13])[CH2:49][CH2:48]1)(=[O:46])[CH3:45]
Reactant: CN(c1cc(OCCCS(C)(=O)=O)cc2cc(C(=O)NCC(C=O)SCc3ccccc3)[nH]c12)S(=O)(=O)c1ccccn1
Reactant: CC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Solvent: ClCCCl
Product: CC(=O)N1CCN(CC(CNC(=O)c2cc3cc(OCCCS(C)(=O)=O)cc(N(C)S(=O)(=O)c4ccccn4)c3[nH]2)SCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.2 %

Procedure:
A mixture of N-[2-(benzylthio)-3-oxopropyl]-7-[methyl(pyridin-2-ylsulfonyl)amino]-5-[3-(methylsulfonyl)propoxy]-1H-indole-2-carboxamide (0.35 g), N-acetylpiperazine (0.14 g) and 1,2-dichloroethane (8 mL) was stirred at room temperature for 10 min. Sodium triacetoxyborohydride (345 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hr. The reaction solution was acidified with aqueous citric acid solution, basified with aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:methanol=10:0-9:1) to give the title compound (0.35 g, yield: 85%) as a colorless amorphous solid. MS: 756 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Nc1ncc(-c2ccc(F)cc2)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 9 h
Yield: 74.7 %

Procedure:
To a suspension of 2-amino-5-bromo-3-nitropyridine (2.2 g, 10.1 mmol) in dimethoxyethane (20 mL) were added 4-fluorophenylboronic acid (4.83 g, 13.1 mmol), tetrakis(triphenylphosphine)palladium (580 mg, 0.50 mmol) and 2N aqueous sodium carbonate solution (10 mL). The mixture was stirred at 80° C. for 9 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate to give a precipitate, which was collected by filtration, washed with ethyl acetate and then dried to give the title compound (1.76 g, 76%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.CO[C:12](=[O:32])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:14]=1[C:28]([O:30]C)=O.Cl.[NH2:34][CH:35]1[CH2:41][CH2:40][C:39](=[O:42])[NH:38][C:36]1=[O:37].O>CN(C=O)C>[C:24]([O:23][C:21](=[O:22])[NH:20][CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]2[C:14]=1[C:28](=[O:30])[N:34]([CH:35]1[CH2:41][CH2:40][C:39](=[O:42])[NH:38][C:36]1=[O:37])[C:12]2=[O:32])([CH3:25])([CH3:26])[CH3:27]
Reactant: COC(=O)c1cccc(CNC(=O)OC(C)(C)C)c1C(=O)OC
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 120 °C

Procedure:
Diisopropylethylamine (3.20 g, 25 mmol) was added to a stirred suspension of methyl-3-[(t-butoxycarbonylamino)methyl]-2-(methoxycarbonyl)benzoate (8.00 g, 25 mmol) and aminoglutarimide hydrochloride (4.07 g, 25 mmol) in DMF (60 ml). The mixture was heated to 120° C. for 24 hours and then cooled to room temperature. The mixture was poured into cold water (300 ml) and extracted with ethyl acetate (4×100 ml each). The combined ethyl acetate extracts were washed with water (2×50 ml), brine (50 ml) and dried. Solvent was removed in vacuo and the product purified by flash chromatography (dichloromethane/ethyl acetate 8 to 2) to yield 4.66 g of recovered starting material and 3.31 g (82%) of the product as a white solid: mp 180-182° C.; 1H NMR (CDCl3) δ 8.51 (s, 1H), 7.81-7.67 (m, 3H), 5.54 (b, 1H), 5.03-4.96 (dd, J=5.2 and 11.2 Hz, 1H), 4.66 (d, J=6.3 Hz, 2H), 2.95-2.74 (m, 3H), 2.18-2.14 (m, 1H), 1.43 (s, 9H); 13C NMR (CDCl3) δ 170.99, 168.08, 167.95, 167.07, 155.86, 139.17, 135.00, 134.61, 132,15, 128.22, 122.82, 79.81, 49.21, 40.53, 31.33, 28.32, 22.58; Anal. Calcd for C19H21N3O6: C, 58.91; H, 5.46; N, 10.85. Found: C, 59.08; H, 5.51; N, 10.69.
Reaction SMILES: [H][H].[BH4-].[Na+].CC(C)=O.[Cl:9][C:10]1[CH:15]=[C:14](/[C:16](/[CH3:21])=[CH:17]/[C:18](=[O:20])[CH3:19])[CH:13]=[CH:12][C:11]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C.O.O.O.O.C([O-])(=O)C.[Ni+2].C([O-])(=O)C.B#[Ni]>[Cl:9][C:10]1[CH:15]=[C:14]([CH:16]([CH3:21])[CH2:17][C:18](=[O:20])[CH3:19])[CH:13]=[CH:12][C:11]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: [H][H]
Reactant: CC(=O)/C=C(\C)c1ccc(-c2ccccc2)c(Cl)c1
Agent: B#[Ni]
Agent: [Ni+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCO
Solvent: CC(C)=O
Product: CC(=O)CC(C)c1ccc(-c2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
17.3 Gm (0.0695 mol) of nickel(II)acetate tetrahydrate, dissolved in 600 ml of 95% ethanol, were reduced in a hydrogenation apparatus in a hydrogen atmosphere with 70 ml of a 1 M sodium borohydride solution to black, colloidal nickel boride (P-2-catalyst). To remove any unreacted borohydride which may be present, 16 gm (0.276 mol) of acetone were first added, and then the mixture was shaken at room temperature for 1 hour and, after addition of 35.0 gm (0.129 mol) of (E)-4-(2-chloro-4-biphenylyl)-3-pentene-2-one, hydrogenated at a hydrogen pressure of 5 atmospheres until hydrogen absorption had ceased. The catalyst was filtered off, the filtrate was evaporated in vacuo, and the residue was distributed between the water and ethyl acetate. The organic layer was dried over sodium sulfate and evaporated, and the residue was distilled in a high vacuum. 28.0 Gm (80% of theory) of colorless crystals were obtained which, after recrystallization from methanol, melted 54°-55°C.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([NH2:16])[C:9]=2[CH3:17])[CH2:5][C:4](=[O:18])[C:3]=1[C:19](=[O:22])[CH2:20][CH3:21].N1C=CC=CC=1.[C:29](Cl)(=[O:31])[CH3:30].O>ClCCl>[OH:18][C:4]1[CH2:5][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([NH:16][C:29](=[O:31])[CH3:30])[C:9]=2[CH3:17])[CH2:7][C:2](=[O:1])[C:3]=1[C:19](=[O:22])[CH2:20][CH3:21]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(N)c2C)CC1=O
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(NC(C)=O)c2C)CC1=O
Yield: 33.9 %

Procedure:
A solution of 3-hydroxy-5-(3-amino-2,4,6-trimethylphenyl)-2-propionylcyclohex-2-en-1-one (2.6 g; 8.6 mmole) and pyridine (0.7 g; 9 mmole) in dichloromethane (100 ml) was treated with acetyl chloride (0.69 g; 9 mmole) at 20° C. with stirring. After 1.5 hours the mixture was poured into water (100 ml) and shaken. The organic layer was separated and dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure using a rotary evaporator. The product was purified by chromatograpy over silica gel (eluent 1% methanol in dichloromethane) to give 3-hydroxy-5-(3-acetamido-2,4,6-trimethylphenyl)-2-propionylcyclohex-2-en-1-one (1.0 g, 34%) as a pale orange semi-crystalline solid. Proton magnetic resonance spectrum (CDCl3, δ in ppm): 1.20 (3H, t); 2.18 (3H, s); 2.20 (3H, s); 2.27 (3H, s); 2.35 (3H, s); 2.4-4.0 (7H, m) 6.6 (1H, bs); 6.88 (1H, s); 18.20 (1H, s).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([Cl:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:16][CH2:17][C:18]#[CH:19])[CH:6]=1)(=[O:3])[CH3:2]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.CCCCCC>[C:1]([NH:4][C:5]1[C:14]([Cl:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]2[C:6]=1[CH:19]=[CH:18][CH2:17][O:16]2)(=[O:3])[CH3:2]
Reactant: C#CCOc1cc(NC(C)=O)c(Cl)cc1C(=O)OC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: COC(=O)c1cc(Cl)c(NC(C)=O)c2c1OCC=C2
Temperature: 65 °C
Yield: 64.8 %

Procedure:
A stirred solution of methyl 4-acetylamino-5-chloro-2-(prop-2-ynyloxy)benzoate (25 grams, 88.8 mmol, obtained in above step) in dowtherm A (127 mL) was heated to 220° C. for 3 hours. The reaction mixture was cooled to 60-70° C. and dumped in hexane. The solids precipitated were filtered and washed with hexane to obtain methyl 5-acetylamino-6-chloro-2H-chromene-8-carboxylate (16.2 grams).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[OH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20]([O:22][CH3:23])=[O:21])=[CH:14]2>>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20]([O:22][CH3:23])=[O:21])=[CH:14]2
Reactant: COC(=O)c1cc2cc(O)ccc2[nH]1
Reactant: ClCc1ccccn1
Agent: Cl
Product: COC(=O)c1cc2cc(OCc3ccccn3)ccc2[nH]1
Yield: 18.1 %

Procedure:
2-Chloromethylpyridine hydrochloride (515 mg) and methyl 5-hydroxy-1H-indole-2-carboxylate (600 mg) were processed in the same manner as in Production Example 1-1 to obtain the entitled compound (160 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]1=[N:4][C:5](=[O:22])[S:6]/[C:7]/1=[CH:8]\[CH:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1.[ClH:23].C(OCC)(=O)C>O1CCCC1.CO>[ClH:23].[ClH:23].[CH3:1][NH:2][C:3]1=[N:4][C:5](=[O:22])[S:6]/[C:7]/1=[CH:8]\[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: CNC1=NC(=O)S/C1=C\C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CNC1=NC(=O)S/C1=C\C1CCNCC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-{(Z)-[4-(methylamino)-2-oxo-1,3-thiazol-5(2H)-ylidene]methyl}piperidine-1-carboxylate (1.27 g) in tetrahydrofuran/methanol (6 mL/6 mL) was added 4M hydrogen chloride/ethyl acetate solution (5.85 mL), and the reaction mixture was stirred at 80° C. for 2 hr. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate to give the title compound (1.02 g).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:6]=[N:7][CH:8]=1.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1COCC1>[O:26]=[C:24]1[C:23]2[C:22](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21](=[O:31])[N:25]1[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:6]=[N:7][CH:8]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cn1c(-c2cncc(CO)c2)c(C#N)c2ccccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(-c2cncc(CN3C(=O)c4ccccc4C3=O)c2)c(C#N)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(5-hydroxymethyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 220, 190 mg, 0.72 mmol) in THF (5 mL) are added sequentially phthalimide (116 mg, 0.79 mmol), 1,1′-(azodicarbonyl)dipiperidine (346 mg, 1.37 mmol) and tributylphosphine (277 mg, 1.37 mmol). The mixture is stirred at room temperature overnight. The mixture is then concentrated in vacuo and the residue is purified by silica gel flash chromatography (heptane-ethyl acetate, 1:0 to 0:1) to give 2-[5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrile. MS (ESI) m/z 393.02 (M+H)+.
Reaction SMILES: [NH4+].[NH4+].C([O:5][C:6]([CH2:8][O:9][C:10]1[CH:19]=[C:18]([S:20]([OH:23])(=[O:22])=[O:21])[CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][C:14]([NH:24][C:25]([NH:27][C:28]1[CH:37]=[C:36]3[C:31]([C:32]([OH:42])=[CH:33][C:34]([S:38]([O-:41])(=[O:40])=[O:39])=[CH:35]3)=[CH:30][CH:29]=1)=[O:26])=[CH:15]2)=[O:7])C.C([O:45][C:46]([CH2:48][O:49][C:50]1[CH:59]=[C:58]([S:60]([OH:63])(=[O:62])=[O:61])[CH:57]=[C:56]2[C:51]=1[CH:52]=[CH:53][C:54]([NH:64][C:65]([NH:67][C:68]1[CH:77]=[C:76]3[C:71]([C:72]([OH:82])=[CH:73][C:74]([S:78]([O-:81])(=[O:80])=[O:79])=[CH:75]3)=[CH:70][CH:69]=1)=[O:66])=[CH:55]2)=[O:47])C.[OH-].[Na+:84].Cl>>[Na+:84].[Na+:84].[OH:42][C:32]1[CH:33]=[C:34]([S:38]([OH:41])(=[O:40])=[O:39])[CH:35]=[C:36]2[C:31]=1[CH:30]=[CH:29][C:28]([NH:27][C:25]([NH:24][C:14]1[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=1)[C:10]([O:9][CH2:8][C:6]([O-:7])=[O:5])=[CH:19][C:18]([S:20]([OH:23])(=[O:22])=[O:21])=[CH:17]3)=[O:26])=[CH:37]2.[OH:82][C:72]1[CH:73]=[C:74]([S:78]([OH:81])(=[O:80])=[O:79])[CH:75]=[C:76]2[C:71]=1[CH:70]=[CH:69][C:68]([NH:67][C:65]([NH:64][C:54]1[CH:55]=[C:56]3[C:51](=[CH:52][CH:53]=1)[C:50]([O:49][CH2:48][C:46]([O-:47])=[O:45])=[CH:59][C:58]([S:60]([OH:63])(=[O:62])=[O:61])=[CH:57]3)=[O:66])=[CH:77]2
Reactant: CCOC(=O)COc1cc(S(=O)(=O)O)cc2cc(NC(=O)Nc3ccc4c(O)cc(S(=O)(=O)[O-])cc4c3)ccc12
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Product: O=C([O-])COc1cc(S(=O)(=O)O)cc2cc(NC(=O)Nc3ccc4c(O)cc(S(=O)(=O)O)cc4c3)ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 25 mg (0.04 mmol) of compound 94 was added 1 mL of 5 N NaOH. The solution was allowed to stir for 18 hours at ambient temperature. The pH was lowered to 1 with aqueous HCl and the resulting solid was collected by vacuum filtration to afford 16 mg of compound 96.
Reaction SMILES: S(Cl)(Cl)(=O)=O.CS[S:8][CH3:9].[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:16]=[C:15]2[CH2:28][C:29]([NH2:31])=[O:30].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]([S:8][CH3:9])=[C:15]2[CH2:28][C:29]([NH2:31])=[O:30]
Reactant: CSSC
Reactant: COc1ccc2c(c1)c(CC(N)=O)cn2Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)c(CC(N)=O)c(SC)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 31 %

Procedure:
Sulfuryl chloride (0.8 mL, 10 mmol) was added to an ice-bath cooled solution of 1.0 mL of dimethyldisulfide in 25 mL of methylene chloride, the cooling bath removed, and the mixture allowed to warm to room temperature. Three mL of this solution (containing methanesulfenyl chloride) was added to 320 mg (1.1 mmol) of 5-methoxy-1-(phenylmethyl)-1H-indole-3-acetamide (Example 3) in 100 mL of methylene chloride, stirred 0.33 hours, saturated NaHCO3 solution added, stirred well, and the methylene chloride solution separated, washed with saturated NaCl, dried (Na2SO4), and concentrated at reduced pressure. The residue chromatographed on silica was eluted with 40% EtOAc/hexane→100% EtOAc to give 115 mg (31% yield) of 5-methoxy-2-(methylthio)-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 195°-197° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.C[N:15](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.N.O1CCOCC1>C1COCC1>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: Cc1cc(F)cc(C(=O)O)c1N
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1cc(F)cc(C(N)=O)c1N
Reaction time: 3 h

Procedure:
To a solution of 2-amino-5-fluoro-3-methyl-benzoic acid (4.80 g, 28.4 mmol) in THF (60 ml) is added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (10.9 g, 56.8 mmol), 1-hydroxybenzotriazole hydrate (4.34 g, 28.4 mmol) and ammonia as 5 M solution in dioxane (283 ml, 142 mmol). The resulting slurry is stirred for 3 hours. The reaction mixture is filtered through Celite and washed with THF. The filtrate is evaporated and partitioned between water and ethyl acetate. The organic phase is dried over sodium sulfate and evaporated. The residue is crystallized from 2-propanol to afford 2-amino-5-fluoro-3-methyl-benzamide as beige crystals; HPLC/MS 1.68 min (B), [M+H] 169.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][NH2:30])=[CH:28][C:23]=2[CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>>[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][NH:30][C:3]3[S:4]/[C:5](=[CH:9]\[C:10]4[CH:11]=[C:12]5[C:17](=[CH:18][CH:19]=4)[N:16]=[CH:15][CH:14]=[CH:13]5)/[C:6](=[O:8])[N:7]=3)=[CH:28][C:23]=2[CH2:22][CH2:21]1
Reactant: NCc1ccc2c(c1)CCO2
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCc2ccc3c(c2)CCO3)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (2,3-Dihydro-benzofuran-5-ylmethyl) amine and DIEA to give 2-[(2,3-dihydro-benzofuran-5-ylmethyl)-amino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 388 (MH+).
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([O:15][CH2:16][CH:17](O)[CH2:18][O:19][CH2:20][CH3:21])[CH3:14]>>[C:1]([O:12][CH:17]([CH2:18][O:19][CH2:20][CH3:21])[CH2:16][O:15][CH2:13][CH3:14])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCOCC(O)COCC
Product: CCCCCCC/C=C/C(=O)OC(COCC)COCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 1,3-diethoxy-2-propanol as starting materials to give the aimed compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[CH:16]=[C:15]([CH3:17])[S:14][C:5]=2[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.CS(C)=O.C1(C)C=CC=CC=1.[NH:29]1[CH2:34][CH2:33]N[CH2:31][CH2:30]1>O>[CH3:17][C:15]1[S:14][C:5]2[NH:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[N:9]=[C:3]([N:2]3[CH2:33][CH2:34][NH:29][CH2:30][CH2:31]3)[C:4]=2[CH:16]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Reactant: C1CNCCN1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCNCC1
Temperature: 125 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
Starting material C (prepared according to the above, 140 mg, 0.53 mmol) was added to a mixture of dry dimethyl sulfoxide (1 ml), dry toluene (1 ml), and piperazine (140 mg, 1.6 mmol). The stirred solution was then heated at 125° C. under nitrogen for 5 h and cooled to room temperature. Then distilled water (2 ml) was added, while the temperature is kept below 25° C. After stirring at 5° C. for 30 minute, the suspension was cooled overnight and the solid D was filtered, washed with chilled water, and dried at 70° C. under reduced pressure; yield 69%.