Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]4[CH:28]=[CH:29][C:30]5[N:31]([CH2:40][CH3:41])[C:32]6[C:37]([C:38]=5[CH:39]=4)=[CH:36][CH:35]=[CH:34][CH:33]=6)[N:21]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:40]([N:31]1[C:30]2[CH:29]=[CH:28][C:27]([NH:26][C:22]3[N:21]=[C:20]([C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[N:15][CH:16]=4)[CH:25]=[CH:24][N:23]=3)=[CH:39][C:38]=2[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH3:41]
Reactant: CCn1c2ccccc2c2cc(Nc3nccc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)n3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1c2ccccc2c2cc(Nc3nccc(-c4ccc(N5CCNCC5)nc4)n3)ccc21
Yield: 51.9 %

Procedure:
A solution of 4-(2-(4-tert-butoxycarbonylpiperazin-1-yl)pyrid-5-yl)-N-(9-ethylcarbazol-3-yl)-2-pyrimidineamine (65 mg, 0.12 mmol) in dichloromethane (2 ml) was treated with trifluoroacetic acid (2 ml). After 2h the mixture was evaporated and the residue reconcentrated five times from dichloromethane then three times from diethyl ether. The residue was subjected to column chromatography (silica, 0.88 ammonia solution-methanol-dichloromethane 1:5:94) to afford the title compound (28 mg) as a pale yellow solid m.p. 131-137°. δH (d6DMSO) 1.31 (3H, t, J 7.1 Hz), 2.80 (4H, m), 3.56 (4H, m), 4.42 (2H, q, J 7.1 Hz), 6.93 (1H, d, J 9.1 Hz), 7.17 (1H, m), 7.25 (1H, d, J 5.3 Hz), 7.43 (1H, m), 7.55 (2H, m), 7.76 (1H, dd, J 2.9, 8.8 Hz), 8.03 (1H, d, J 7.4 Hz), 8.27 (1H, dd, J 2.1, 9.1 Hz), 8.41 (1H, d, J 5.3 Hz), 8.57 (1H, d, J 1.8 Hz), 8.95 (1H, d, J 2.1 Hz) and 9.45 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:17])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.C(O[B:30]1[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]1)(C)C>O1CCCC1.C1COCC1.CCCCCC>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:17])=[C:9]1[B:30]1[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)n(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 462 mg 3-Methyl-indole-1-carboxylic acid tert-butyl ester in 2.5 ml anhydrous tetrahydrofuran at −78° C. under argon is added 1.2 ml of a 2M LDA solution in THF/hexane and stirred at 0° C. for 30 min to complete the deprotonation. The reaction mixture is cooled to −78° C., 0.6 ml 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane are added, and stirred at 0° C. for 60 min. The reaction is quenched by the addition of 2 ml MeOH/water (1:1), diluted into water and extracted with ethylacetate. After evaporation of the solvent and purification on silica gel, 385 mg of 3-Methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indole-1-carboxylic acid tert-butyl ester are obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][N:11]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:19]=2)[C:14]([OH:29])=[C:13]([C:30](OCC)=[O:31])[C:12]1=[O:35].[CH3:36][O:37][CH2:38][CH2:39][NH2:40]>>[O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][N:11]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH:19]=2)[C:14]([OH:29])=[C:13]([C:30]([NH:40][CH2:39][CH2:38][O:37][CH3:36])=[O:31])[C:12]1=[O:35]
Reactant: COCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2C(=O)CCC2=O)c1=O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2C(=O)CCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 1-[3-(2,5-dioxo-1-pyrrolidinyl)propyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine employing methods similar to those described in Example 202 and was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.27 (s, 1 H), 8.56 (s, 1 H), 7.34 (s, 1 H), 7.19 (dd, J=8.4, 5.4 Hz, 2 H), 7.04 (t, J=8.6 Hz, 2 H), 4.18-4.12 (m, 4 H), 3.64 (m, 2 H), 3.61-3.57 (m, 4 H), 3.42 (s, 3 H), 2.73 (s, 4 H), 1.91 (m, 2 H); HRMS C26H27FN4O6 (M+H)+ calcd 511.1915, found 511.1988.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[C:18]([CH3:30])=[N:19][C:20]2[C:25]([C:26]=1C(O)=O)=[CH:24][CH:23]=[CH:22][CH:21]=2.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[C:18]([CH3:30])=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2
Reactant: Cc1nc2ccccc2c(C(=O)O)c1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OC
Temperature: 160 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (240 mg), 3-hydroxy-2-methyl-quinoline-4-carboxylic acid (232 mg), and 4-dimethylaminopyridine (372 mg) were dissolved in o-dichlorobenzene (10 ml) to prepare a solution which was stirred at 160° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (37 mg, yield 11%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]1[C:15]2=[C:16]3[C:11](=[CH:12][CH:13]=[CH:14]2)[CH2:10][CH2:9][C:8](=[O:17])[N:7]3[CH2:6]1.[Cl:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24]>ClCCCl>[Cl:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([C:13]1[CH:12]=[C:11]2[C:16]3=[C:15]([CH2:5][CH2:6][N:7]3[C:8](=[O:17])[CH2:9][CH2:10]2)[CH:14]=1)=[O:24]
Reactant: O=C(Cl)CCCCCl
Reactant: O=C1CCc2cccc3c2N1CC3
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(CCCCCl)c1cc2c3c(c1)CCN3C(=O)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Aluminum chloride (55 g, 410 mmol) was added by portions to a solution of 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (30.0 g) and 5-chlorovaleryl chloride (26.8 ml) in 1,2-dichloroethane (70 ml) under ice-cooling. After stirring at room temperature for 30 minutes, the reaction mixture was poured into ice (500 g), extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol-diethyl ether to give a pale yellow solid (36.5 g). Further recrystallization from ethanol-diethyl ether afforded the title compound as colorless crystals (32.4 g) having a melting point of 110-111° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([NH:13][C:14]1[S:15][C:16]([NH:24][C:25]([C:27]3[CH:31]=[CH:30][S:29][CH:28]=3)=[O:26])=[C:17]([C:19]([O:21]CC)=O)[N:18]=1)=[CH:8]2.[NH3:32].CO>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([NH:13][C:14]1[S:15][C:16]([NH:24][C:25]([C:27]3[CH:31]=[CH:30][S:29][CH:28]=3)=[O:26])=[C:17]([C:19]([NH2:32])=[O:21])[N:18]=1)=[CH:8]2
Reactant: CCOC(=O)c1nc(Nc2ccc3c(OC)cccc3c2)sc1NC(=O)c1ccsc1
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc2cc(Nc3nc(C(N)=O)c(NC(=O)c4ccsc4)s3)ccc12
Temperature: 80 °C
Yield: 92 %

Procedure:
To a solution of ethyl 2-[(5-methoxynaphthalen-2-yl)amino]-5-(thiophene-3-carboxamido)-thiazole-4-carboxylate (0.105 g, 0.23 mmol) in THF (5 mL) was added 7N NH3—MeOH (5 mL), and the mixture was heated at 80° C. for 16 hrs in a sealed tube. The solvent was evaporated in vacuo, and the resulting solids were collected by filtration and washed with MeOH to give 90 mg (92% yield) of the titled compound.
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=O)=[N+:2]=[N-:3].[NH2:13][C:14]1[C:21]([Cl:22])=[CH:20][C:19]([F:23])=[CH:18][C:15]=1[C:16]#[N:17].C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:13]/[C:14]1[C:21]([Cl:22])=[CH:20][C:19]([F:23])=[CH:18][C:15]=1[C:16]#[N:17])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1c(F)cncc1C=O
Reactant: N#Cc1cc(F)cc(Cl)c1N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cc(F)cc(Cl)c1/N=C/c1cncc(F)c1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
A solution of 4-azido-5-fluoro-3-pyridinecarboxaldehyde (1.0 g, 6.02 mmol) and 2-amino-3-chloro-5-fluorobenzonitrile (1.03 g, 6.02 mmol) in anhydrous DCM (20 mL) was cooled in an icebath and triethylamine (2.52 mL, 18.07 mmol) was added, followed by titanium (IV) chloride (1 N in DCM, 3.6 mL, 3.6 mmol). The reaction mixture was stirred at 0° C. for 3 hours and then at room temperature overnight. The resultant mixture was concentrated under reduced pressure and the residue was suspended in ethyl acetate and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford the title compound as a pale brown solid (1.67 g, 89% yield), which was used directly in the next step without purification. LCMS (Method C): RT=3.74 min, m/z: 291 [M+H+−N2].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12].[Cl:13][S:14](O)(=[O:16])=[O:15].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([O:11][CH3:12])=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][C:8]=1[S:14]([Cl:13])(=[O:16])=[O:15]
Reactant: COc1cccc(OC)c1OC
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(S(=O)(=O)Cl)c(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 2.8 %

Procedure:
To a solution of 10.0 g of 1,2,3-trimethoxy benzene in CHCl3 (100 ml) was added dropwise 6.90 g of chlorosulfonic acid over 10 minutes under ice cooling. After stirring at room temperature for two hours, the solution was poured into ice water and the resulting mixture was extracted with CHCl3. The aqueous layer was filtered with celite, the filtrate was neutralized with an aqueous solution of 2 mol/L KOH (pH=9), and the solvent was evaporated under reduced pressure to obtain 1.40 g. Phosphorus oxychloride (7 ml) was added to the obtained residue and the mixture was stirred at external temperature of 100° C. for one hour. The solution was poured into ice water, the resulting mixture was extracted with Et2O, the organic layer was washed with water and with saturated brine and then dried over MgSO4; the drying agent was separated by filtration, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60N; mobile phase: EtOAc/n-hexane=1/10 to 1/4; v/v) to obtain 450 mg of the title compound.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][S:14]([C:17]1[CH:18]=[C:19]([C:29](O)=[O:30])[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:21][CH:22]=1)(=[O:16])=[O:15]>>[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:19]([C:29]([N:10]2[CH2:11][CH2:12][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)=[O:30])[CH:18]=1)(=[O:15])=[O:16]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)N2CCN(c3ccccc3)CC2)c1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from phenyl piperazine [189457-54-3] and 4-Methanesulfonyl-biphenyl-2-carboxylic acid (Example V). MS (ISP): 421.3 MH+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]([CH3:17])[C:13](SC)=[N:12]3)[CH2:10][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[O:8][C:5]2=[CH:6][CH:7]=1.[NH4+:27].[I-].N.CCO>>[NH2:27][C:13]1[N:14]([CH3:17])[C:15](=[O:16])[C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[CH2:10]2)[N:12]=1
Reactant: [NH4+]
Reactant: CSC1=NC2(CC(c3ccccc3F)Oc3ccc(Br)cc32)C(=O)N1C
Agent: N
Agent: [I-]
Solvent: CCO
Product: CN1C(=O)C2(CC(c3ccccc3F)Oc3ccc(Br)cc32)N=C1N
Yield: 70.3 %

Procedure:
A solution of 6-bromo-2-(2-fluorophenyl)-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (80 mg, 0.183 mmol) and NH4I (53.21 mg, 0.367 mmol) in a solution of NH3/EtOH (2 mL, 1.5 N) was heated at 110° C. in a tube under microwave reactor for 3 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-2-(2-fluorophenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (52 mg, 70%). 1H-NMR (MeOD): 2.15 (d, 1H), 2.25 (d, 1H), 3.20 (s, 3H), 6.15 (d, 1H), 6.78 (d, 1H), 6.99 (t, 1H), 7.05 (s, 1H), 7.15 (t, 1H), 7.25 (d, 2H), 7.50 (t, 1H).
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].Br[C:8]1[CH:9]=[C:10]([C:14]([CH3:18])([CH3:17])[C:15]#[N:16])[CH:11]=[CH:12][CH:13]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(#N)C>[CH3:18][C:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:2]#[C:1][Si:3]([CH3:6])([CH3:5])[CH3:4])[CH:9]=1)([CH3:17])[C:15]#[N:16]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C#N)c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Product: CC(C)(C#N)c1cccc(C#C[Si](C)(C)C)c1
Temperature: 25 °C

Procedure:
Ethynyltrimethylsilane (4.0 mL, 28.9 mmol) was added to a mixture of ACN (100 mL), TEA (25 mL), 2-(3-bromophenyl)-2-methylpropionitrile (5.0 g, 22.3 mmol), (Ph3P)2PdCl2 (780 mg, 1.11 mmol) and copper(I) iodide (130 mg, 0.68 mmol) under nitrogen atmosphere. The reaction mixture was refluxed for 3 hours, cooled to ambient temperature, concentrated to a black residue and filtered through silica gel with 20% ethyl acetate in hexane. The filtrate was concentrated to a red oil and chromatographed on silica gel with 2% ethyl acetate in hexane. Obtained 2-methyl-2-(3-trimethylsilanylethynylphenyl)-propionitrile (4.00 g, 74%) as an orange oil. 1H NMR (DMSO-d6) δ: 0.24 (s, 9H), 1.69 (s, 6H), 7.43 (m, 2H), 7.56 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Yield: 93.7 %

Procedure:
A mixture of 4-(6-nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (3.40 g, 11.0 mmol) and 10% Pd—C (400 mg, 0.376 mmol) in ethanol (100 ml) and ethyl acetate (100 ml) is agitated under 1 atmosphere pressure of hydrogen overnight. The mixture is filtered and concentrated to give of 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (2.87 g, 94% yield). MS(ESI) m/z 278 (M+H)+
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]1[O:26][C:25]2[CH:24]=[CH:23][C:22]([N:27]=[C:28]=[O:29])=[CH:21][C:20]=2[O:19]1>>[O:26]1[C:25]2[CH:24]=[CH:23][C:22]([NH:27][C:28](=[O:29])[O:17][C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]4)=[CH:21][C:20]=2[O:19][CH2:18]1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Product: O=C(Nc1ccc2c(c1)OCO2)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (35.0 mg, 0.155 mmol) using the same procedure employed for Example 2 (2), but with 3,4-(methylenedioxy)phenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (21.6 mg, 34%) having the following characteristics.
Reaction SMILES: [C:1]([C:3]1[C:8]2[CH2:9][C:10](=O)[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].O.[NH2:20][NH2:21]>C(O)C>[C:1]([C:3]1[C:8]2[CH2:9][C:10](=[N:20][NH2:21])[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: NN
Reactant: N#Cc1cccc2c1CC(=O)c1ccccc1S2
Solvent: O
Solvent: CCO
Product: N#Cc1cccc2c1CC(=NN)c1ccccc1S2
Yield: 63.1 %

Procedure:
0.9 g of 9-cyano-10,11-dihydro-11-oxo-dibenzo[b,f]thiepin and 1 g of 100% hydrazine hydrate were dissolved in 10 ml of ethanol and the resulting mixture was heated under reflux for 3.5 hours. The reaction mixture was concentrated to 5 ml to separate crystals on cooling, which were collected by filtration. Recrystallization from ethanol afforded 0.6 g of 9-cyano-10,11-dihydro-11-oxo-dibenzo[b,f]thiepin hydrazone as palo brown prismatic crystals having a melting point of 175°-177° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][NH:15][CH:16]([CH3:18])[CH3:17])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[Cl:19][CH:20]([Cl:24])[C:21](Cl)=[O:22]>C1(C)C=CC=CC=1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][N:15]([CH:16]([CH3:18])[CH3:17])[C:21](=[O:22])[CH:20]([Cl:24])[Cl:19])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: COc1ccc(CCNC(C)C)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc(CCN(C(=O)C(Cl)Cl)C(C)C)cc1OC
Reaction time: 2 h

Procedure:
In a sulfuration-flask, there is added while stirring 20 ml of 20% aqueous sodium hydroxide to 22,3 g of N-(3,4-dimethoxyphenylethyl)-N-isopropyl amine. The reaction-mixture is then cooled in CO2 alcohol-cooling-bath to a temperature of -10° to -15°, to which is then added dropwise, while stirring a solution of 14.7 g of dichloroacetylchloride in 10 ml toluene. After everything has been added, the cooling-bath is removed and the reaction mixture is stirred for another 2 hours until it reaches room-temperature. It is then poured into an ice/water mixture and the organic material is extracted with toluene. The toluene extracts are washed once with diluted sodium hydroxide and with diluted hydrochloric acid and twice with water dried over sodium sulfate and concentrated in a rotatory evaporator. The title product is thus obtained as viscous oil in a yield of 28.4 g.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][C:42]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:39][O:40][C:41]1[CH:42]=[CH:43][C:44]([C:47]([F:48])([F:49])[F:50])=[CH:45][C:46]=1[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: COc1ccc(C(F)(F)F)cc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(C(F)(F)F)cc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Yield: 84.4 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.17 mmol) was treated with (2-methoxy-5-(trifluoromethyl)phenyl)boronic acid (89 mg, 0.40 mmol), sodium carbonate (43 mg, 0.40 mmols) and bis(triphenylphosphine)palladium(II) dichloride (12 mg, 0.02 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100%, dichloromethane-ethyl acetate) to give 99 mg (85% yield) of the title compound. Purity 100%.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:4]=2[N:3]=1>N.CO>[Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:4]=2[N:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)ccc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CO
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)ccc32)[C@H](O)[C@@H]1O

Procedure:
A solution of 0.226 g (0.508 mmole) of 72 in 10 mL of NH3 /MeOH was stirred in a pressure bottle at room temperature for 5 hr. The reaction mixture was evaporated and coevaporated with MeOH (3×) to give a solid. This solid was recrystallized from MeOH to give 0.136 g (76%, based on C12H12Cl2N2O4MeOH) of 73 as white crystals. MP 102°-150° C. (melted over a large range of temperature). MS (CI) m/e 319.0242 (37%, MH+ =319.0252). 1H NMR (DMSO-d6): d 8.06 (d, 1, 7-H, J7-6 =9.0 Hz), 7.73 (d, 1, 4-H, J4-6 =2.0 Hz), 7.30 (dd, 1, 6-H), 5.89 (d, 1, 1'-H, J1-2 =8.0 Hz), 5.51 (d, 1, 2'-OH, J2'-2'OH =65 Hz), 5.29 (d, 1, 3'-OH J3'-3'OH =4.5 Hz),5.26 (t, 1, 5'-OH, J5'-5'OH =5-0 Hz), 4.45 (m, 1, 2'-H, J2'-3' =5.5 Hz), 4.12 (m, 1, 3'-H, J3'-4' =2.0 Hz), 3.99 (m, 1, 4'-H, J4'-5' =J4'-5" =3.5 Hz), 3.69 (m, 2, 5'-H and 5"-H, J5'-5" =12.0 Hz). 13C NMR (DMSO-d6) d 142.36 (C3a), 141.40 (C2), 131.88 (C7a), 127.49 (C5), 123.32 (C6), 118.40 (C4), 114.51 (C7), 89.07 (C1'), 86.23 (C4'), 71.49 (C2'), 69.75 (C3'), 61.23 (C5').
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:21])[N:12]([C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)[N:13]=1.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:21])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([O:24][C:23]([F:22])([F:34])[F:35])[CH:26]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(-c2cccc(OC(F)(F)F)c2)cc1
Yield: 23 %

Procedure:
The title compound was prepared according to the procedure described in Example-2 using 5-(2-chloro-6-fluorophenyl)-2-(4-iodophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (step-4 of Intermediate-2, 0.100 g, 0.242 mmol), [3-(trifluoromethoxy)phenyl]boronic acid (0.075 g, 0.363 mmol), K2CO3 (0.100 g, 0.726 mmol), tetrakistriphenyl phosphine palladium (0) (0.055 g, 0.048 mmol) and DMSO (3.0 mL) to afford 0.025 g of desired product. 1H NMR (300 MHz, CDCl3): δ 7.19 (d, J=8.4 Hz, 1H), 7.35 (s, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.46 (d, J=6.6 Hz, 1H), 7.53 (t, J=7.8 Hz, 2H), 7.65 (d, J=8.4 Hz, 2H), 8.12 (d, J=8.4 Hz, 2H), 10.01 (br s, 1H).