Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.[CH2:11](Br)[C:12]#[CH:13].C(N(CC)CC)C.Cl.[CH3:23][N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1>C(O)C>[CH3:23][N:24]1[CH2:29][CH2:28][C:27]2[N:8]([CH2:13][C:12]#[CH:11])[C:5]3[CH:4]=[CH:3][C:2]([CH3:10])=[CH:7][C:6]=3[C:26]=2[CH2:25]1
Reactant: C#CCBr
Reactant: Cc1ccc(NN)cc1
Reactant: CN1CCC(=O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: C#CCn1c2c(c3cc(C)ccc31)CN(C)CC2
Yield: 16 %

Procedure:
p-Tolylhydrazine hydrochloride (600 mg, 3.7 mmol), propargyl bromide (80 wt % solution in toluene, 0.34 ml, 3.7 mmol), triethylamine (1.5 ml, 11.3 mmol) and N-methyl-4-piperidone hydrochloride (316 mg, 2.1 mmol) were taken in ethanol (15 ml) to obtain 80 mg of 2, 3,4,5-tetrahydro-2,8-dimethyl-5-(prop-2-ynyl)-1H-pyrido[4,3-b]indole after purification on silica gel (230-400 mesh) chromatography, eluting with methanol-dichloromethane gradient. 1H NMR (CDCl3) 7.30-7.25 (d, 1H), 7.20 (s, 1H), 7.00-6.90 (d, 1H), 4.80 (s, 2H), 3.70 (s, 2H), 2.95 (m, 4H), 2.60 (s, 3H), 2.40 (s, 3H), 2.10-2.00 (t, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([Cl:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ClN1C(=O)CCC1=O.[CH3:21][S:22][CH3:23].C(N(CC)CC)C>ClCCl>[C:1]([C:5]1[CH:11]=[C:10]([CH2:21][S:22][CH3:23])[C:8]([NH2:9])=[C:7]([Cl:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CSC
Reactant: CC(C)(C)c1ccc(N)c(Cl)c1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSCc1cc(C(C)(C)C)cc(Cl)c1N
Temperature: -5 °C
Reaction time: 1 h

Procedure:
4-t-Butyl-2-chloroaniline (30 g) was dissolved in dichloromethane (1.21) and the solution was cooled to -5° C. N-chlorosuccinimide (21.7 g) was added portionwise to the vigorously stirred solution and stirring was continued for 1 h. Dimethyl sulfide (35 ml) was added to the solution (-5° C.) and stirring was continued for a further 1 h. The solution was then cooled to -65° C. and triethylamine (27 ml) was added. This solution was allowed to warm to room temperature overnight. The solution was evaporated to half volume, washed with sodium hydroxide (1N), water and brine successively. The organic solution was dried and evaporated and the residue was purified on silica using hexane to 3% ether in hexane as eluant. This afforded the product (31.2 g) as a red oil. 1H NMR (CDCl3, 250 MHz) δ 1.27 (9H, s, (CH3)3), 1.99 (3H, s, SCH3 ), 3.69 (2H, s, CH2SCH3), 4.38 (2H, br s, NH2), 6.92 (1H, d, J=2.0 Hz, ArH), 7.21 (1H, d, J=2.0 Hz, ArH). MS (CI+) m/z 244 (M+ +1, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]2[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([F:16])[CH:22]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CCOC(=O)c1cc2ccc(Cl)cc2[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc2ccc(Cl)cc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.3 %

Procedure:
Activated molecular sieves (8.9 g) 4 Å were placed in an oven dried round bottom flask and cooled to room temperature under nitrogen. Ethyl 6-chloro-1H-indole-2-carboxylate (from AsymChem, 0.500 g, 2.24 mmol), (3-fluorophenyl)boronic acid (0.938 g, 6.71 mmol), copper acetate (0.40 g, 3.3 mmol), methylene chloride (80 mL) was added to the flask, followed by pyridine (0.723 mL, 8.94 mmol). The reaction mixture was stirred at room temperature for 2 days, and then filtered through Celite. The filtrate was concentrated under reduced pressure. The resultant residue was purified by chromatography on silica gel (eluting with 0 to 50% EtOAc in hexane) to give the desired product (0.60 g). LCMS calculated for C17H14ClFNO2(M+H)+: m/z=318.1. Found: 318.1.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[CH3:16][C:17]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][N:18]=1.C[O:25][C:26](=[O:35])[CH:27](Br)[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1([CH2:28][CH:27]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:23][C:22]3[C:17]([CH3:16])=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:6]=[N:5]2)[C:26]([OH:25])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: Cc1ncccc1O
Reactant: COC(=O)C(Br)CC1CCCC1
Product: Cc1ncccc1Oc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Yield: 67 %

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2-methyl-pyridin-3-ol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[4-(2-methyl-pyridin-3-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (10.4 g, 67%) as a white solid; LC-MS 344 [M+H+]; HPLC (0.17% trifluoroacetic acid in acetonitrile/water, 50%-100% acetonitrile, gradient, 1 mL/min, Venusil MP-C18, C18-15 cm×4.6 mm-5 μm), purity>95% (214 nm). 1H-NMR (300 MHz, DMSO-d6) δ 13.01 (bs, 1H), 8.21 (s, 1H), 8.14 (s, 1H), 7.73 (m, 1H), 7.36 (m, 1H), 5.79 (s, 1H), 5.30 (m, 1H), 1.01-2.19 (m, 11H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1([CH3:9])[O:8][CH2:7][CH2:6][O:5]1.BrC(Br)C.[Mg].[C:15]1([C:21]#[CH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([Li])CCC.[C:28]1(=[O:35])[CH:33]=[CH:32][C:31](=[O:34])[CH:30]=[CH:29]1.CN1C(=O)N(C)CCC1>C1COCC1>[OH:34][C:31]1([C:22]#[C:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:32]([CH2:2][CH2:3][C:4]2([CH3:9])[O:8][CH2:7][CH2:6][O:5]2)[CH2:33][C:28](=[O:35])[CH:29]=[CH:30]1
Reactant: O=C1C=CC(=O)C=C1
Reactant: C#Cc1ccccc1
Reactant: CC1(CCBr)OCCO1
Agent: CC(Br)Br
Agent: [Li]CCCC
Agent: [Mg]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CC1(CCC2CC(=O)C=CC2(O)C#Cc2ccccc2)OCCO1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 19.4 %

Procedure:
A solution of the product of Example 7a (9.75 g, 0.05 mole, 1.3 eq), dibromoethane (6.4 g, 0.03 mole, 0.8 eq), and 30 mL of dry THF was added over a 2.5 hr period to a slurry of 99.9% magnesium turnings (3.6 g, 0.15 mole, 3 eq) and 75 mL THF with vigorous stirring. The temperature was maintained at 24°-27° C. by external cooling. The resulting Grignard solution was then cooled to -78° C. until further use. In a separate flask, phenylacetylene (3.9 g, 0.038 mole, 1 eq) in 20 mL THF was cooled to -78° C., n-butyllithium (1.38 molar, 28 mL, 0.038 mole, 1 eq) was added via syringe, the solution stirred 30 min at -78° C., warmed to 0° C. for 30 min and cooled again to -78° C. In a separate flask, benzoquinone (4.2 g, 0.038 mole, 1 eq) in 20 mL of THF was cooled to -78° C., the phenylacetylide solution was added dropwise, resulting in a blue solution which was stirred 25 min at -78° C. DMPU (30 g, 0.23 mole, 6 eq) was added, the reaction warmed to -5° C., and the Grignard reagent solution added over about a 15 min period. The cooling bath was allowed to warm to RT and the reaction stirred overnight. The reaction mixture was quenched with 100 mL of saturated ammonium chloride solution, 100 mL of water added, the layers separated and the aqueous layer extracted with three 150 mL portions of ether. The combined organic layers were washed with water, brine and dried over anhydrous sodium sulfate. The dried solution was evaporated in vacuo to give a brown oil, 9.21 g portion of which was purified by trituration with ether followed by flash chromatography on silica gel eluting with 3:1 hexane/EtOAc to 1:1 hexane/EtOAc to yield 2.4 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:23])=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:18]=2)[C:5]([O:11][CH3:12])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:30].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[C:3]([CH3:23])=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:18]=2)[C:5]([O:11][CH3:12])=[C:6]([CH:8]([NH2:30])[CH3:9])[CH:7]=1
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1-c1cncc(S(C)(=O)=O)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(C(C)N)cc(Cl)c(C)c1-c1cncc(S(C)(=O)=O)c1
Temperature: 25 °C

Procedure:
A mixture of 1-{5-chloro-2-methoxy-4-methyl-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethanone (0.035 g, 0.099 mmol), ammonium acetate (0.08 g, 1 mmol) and 1.0 M sodium cyanoborohydride in tetrahydrofuran (THF) (0.25 mL, 0.25 mmol) in methanol (0.2 mL) and acetonitrile (0.2 mL) was heated at 65° C. overnight. The mixture was cooled to room temperature (rt), quenched with sat. NaHCO3 solution, and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product, which was used in the next step directly (0.024 g, 69%). LCMS calculated for C16H17ClNO3S (M−NH2)+: m/z=338.1. found: 338.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[N:9]/[CH3:10])=[C:4]([F:11])[CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](/[C:19](=[CH:22]/[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])/[C:20]#[N:21])=[C:15]([F:28])[CH:14]=1.[OH-].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:19]([C:16]3[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][C:15]=3[F:28])([C:20]#[N:21])[CH:22]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)=[C:4]([F:11])[CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:20]#[N:21])[CH:22]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[F:11])[NH:9][CH2:10]2)=[C:15]([F:28])[CH:14]=1
Reactant: C/N=C/c1ccc(Cl)cc1F
Reactant: CC(C)(C)C/C=C(\C#N)c1ccc(Cl)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1C(c2ccc(Cl)cc2F)NCC1(C#N)c1ccc(Cl)cc1F
Product: CC(C)(C)CC1CNC(c2ccc(Cl)cc2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 13.3 %
Yield: 19.7 %

Procedure:
In a manner similar to the method described in Example 3a, [1-(4-chloro-2-fluoro-phenyl)-meth-(E)-ylidene]-methyl-amine (3.43 g, 20.00 mmol) reacted with (Z)-2-(4-chloro-2-fluoro-phenyl)-5,5-dimethyl-hex-2-enenitrile (5.03 g, 20.00 mmol) in DMSO (30 mL) in the presence of KOH powder (5.72 g, 56.11 mmol) to give rac-(2S,3S,4S)-2,3-bis-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (1.12 g 13.3%) and rac-(3S,4S,5S)-3,5-bis-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (1.66 g 19.7%). HRMS (ES+) m/z Calcd for C22H22Cl2F2N2+H [(M+H)+]: 423.1201, found: 423.1200.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14]1[C:15](=[O:27])[N:16]([CH3:26])[C:17](=[O:25])[N:18]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:19]=1[NH2:20].[Cl:28][C:29]1[C:38]2[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=2)[C:32]([CH2:43][C:44](O)=O)=[CH:31][N:30]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[ClH:28].[Cl:28][C:29]1[C:38]2[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=2)[C:32]([CH2:43][C:44]2[NH:13][C:14]3[C:15](=[O:27])[N:16]([CH3:26])[C:17](=[O:25])[N:18]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:19]=3[N:20]=2)=[CH:31][N:30]=1
Reactant: COc1cc2c(CC(=O)O)cnc(Cl)c2cc1OC
Reactant: CC(C)Cn1c(N)c(N)c(=O)n(C)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)C)cnc(Cl)c2cc1OC
Reaction time: 18 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.6M aqueous solution, 0.33 ml, 1.85 mmol) is added to a suspension of 5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4-dione (0.327 g, 1.54 mmol), (1-chloro-6,7-dimethoxy-isoquinolin-4-yl)-acetic acid (0.414 g, 1.54 mmol) and 1-hydroxybenzotriazole (0.251 g, 1.85 mmol) in CH2Cl2 (2 ml). Water (2 ml) is added, the biphasic mixture is shaken for 18 hours and the the resultant solid is collected by filtration. This intermediate is suspended in methanol (10 ml), 4M aqueous NaOH (5 ml) is added and the mixture heated to reflux for 4 hours. After evaporation of the methanol, the residue is acidified to pH2 with concentrated hydrochloric acid and the resultant solid collected by filtration and purified by preparative HPLC to afford 8(1-chloro-6,7-dimethoxy-isoquinolin-4-ylmethyl)-3-isobutyl-1-methyl-3,7-dihydro-purine-2,6-dione hydrochloride, [M]+ 458.
Reaction SMILES: C([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13](OC(C)(C)C)=[O:14])[C:8]([C:20]1C(Cl)=[N:22][C:23]3[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:7]2)(=O)C.[C:31](O)(=[O:33])[CH3:32]>O>[C:31]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:20]([C:8]1[C:13](=[O:14])[NH:9][C:10]3[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:12][CH:11]=3)=[CH:29]2)(=[O:33])[CH3:32]
Reactant: CC(=O)O
Reactant: CC(=O)c1ccc2c(c1)cc(-c1cc3ccccc3nc1Cl)n2C(=O)OC(C)(C)C
Solvent: O
Product: CC(=O)c1ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)cc2c1

Procedure:
A solution of tert-butyl 5-acetyl-2-(2-chloro-3-quinolinyl)-1H-indole-1-carboxylate (8-3, 400 mg, 0.95 mmol) was heated in a 3:1 mixture of acetic acid and water at reflux for 20 h The reaction mixture was cooled, then concentrated to dryness. The residue was suspended in ethyl ether (50 mL) with the aid of sonication, then filtered and air dried to give 3-(5-acetyl-1H-indol-2-yl)-2(1H)-quinolinone (8-4) as a yellow solid. 1H NMR (400 MHz, DMSO) δ 12.22 (s, 1H), 11.94 (s, 1H), 8.59 (s, 1H), 8.31 (s, 1H), 7.76 (d, 2H, J=7.9 Hz), 7.60 (d, 1H, J=8.6 Hz), 7.55 (t, 1H, J=7.5 Hz), 7.49 (s, 1H), 7.39 (d, 1H, J=7.9 Hz), 7.26 (t, 1H, J=7.5 Hz), 2.62 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:14]=[CH:13][C:5]=1[C:6](N1C=NC=N1)=[O:7])([O-:3])=[O:2].[C:21]1(=[O:28])[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:1]([C:4]1[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:14]=[CH:13][C:5]=1[C:6]([CH:22]1[C:23](=[O:27])[CH2:24][CH2:25][CH2:26][C:21]1=[O:28])=[O:7])([O-:3])=[O:2]
Reactant: O=C1CCCC(=O)C1
Reactant: CS(=O)(=O)c1ccc(C(=O)n2cncn2)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(C(=O)C2C(=O)CCCC2=O)c([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 103.4 %

Procedure:
1-(2-Nitro-4-methanesulphonylbenzoyl)-1,2,4-triazole (666 mg), cyclohexan-1,3-dione (254 mg) and potassium carbonate (419 mg, 1.8 mmol, 1.4 equiv) were suspended in acetonitrile (30 ml) and stirred overnight. The acetonitrile was removed under reduced pressure, the residue dissolved in water (100 ml) and acidified with 1 M hydrogen chloride solution to pH 1.5. The solution was extracted with dichloromethane, dried (magnesium sulfate), filtered and the solvent removed under reduced pressure to afford the title compound as a pale yellow solid (0.789g, quant).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]([CH3:15])[CH:8]([OH:14])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])(=[O:3])[CH3:2].[CH2:16]([O:18][CH:19]=[CH2:20])[CH3:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[C:1]([O:4][CH2:5][CH2:6][CH:7]([CH3:15])[CH:8]([O:14][CH:16]([O:18][CH2:19][CH3:20])[CH3:17])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC(C)C(O)CC=C(C)C
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Product: CCOC(C)OC(CC=C(C)C)C(C)CCOC(C)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 8-acetoxy-2,6-dimethyl-5-hydroxy-2-octene (2.27 g, 10.6 mmole), ethyl vinylether (0.82 g. 11.4 mmole), p-toluenesulfonic acid monohydrate (catalytic amount) and ether (50 ml) is stirred at room temperature for 16 hours. The resulting mixture is treated with ether (150 ml) and washed with 5% sodium bicarbonate solution (2×100 ml). The organic phase is dried (Na2SO4), and evaporated in vacuo to give the crude product. The crude material is further purified by column chromatography on silica gel (25 g, 5% ethyl acetate in hexane) to give 8-acetoxy-2,6-dimethyl-5-[(1-ethoxyethoxy)]-2-octene as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[NH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.[Mn]([O-])(=O)(=O)=[O:24].[K+].[OH-:29].[Na+]>>[F:22][C:2]([F:21])([F:1])[C:3]1[CH:4]=[C:5]([C:9]2[NH:10][N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([OH:24])=[O:29])[N:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ccccc1-c1nc(-c2cccc(C(F)(F)F)c2)n[nH]1
Agent: [K+]
Agent: [Na+]
Product: O=C(O)c1ccccc1-c1n[nH]c(-c2cccc(C(F)(F)F)c2)n1
Yield: 32 %

Procedure:
A solution of 3-(3-trifluoromethylphenyl)-5-(2-methylphenyl)-1,2,4-triazol (6.3 g, 0.021 mol), potassium permanganate (15 g, 0.095 mol) and 10% sodium hydroxide solution (100 ml) was held at reflux for one hour, cooled and filtered through celite. The filtrate was acidified with concentrated HCl and the solid precipitate was collected. The solid was washed with ether to give 2.2 g of 2-[5-(3-trifluoromethylphenyl)-1,2,4-triazol-3-yl]benzoic acid in 32% yield, mp ~200°.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][NH:9]1.[Cl:17][C:18]([Cl:23])([Cl:22])[C:19](Cl)=[O:20]>C(Cl)(Cl)Cl>[Cl:17][C:18]([Cl:23])([Cl:22])[C:19]([N:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8]1)=[O:20]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: c1ccc2c(c1)CNC2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(N1Cc2ccccc2C1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
Triethylamine (3.48 mL, 25.0 mmol) was added to a solution of isoindoline (4.98 g, 25.0 mmol) in chloroform (100 mL) at room temperature and the mixture was cooled in ice. Trichloroacetic acid chloride (2.79 mL, 25.0 mmol) was added dropwise thereto and the reaction mixture was warmed to room temperature and stirred for 1 hr. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to afford 2,2,2-trichloro-1-(1,3-dihydro-2 H-isoindol-2-yl)ethanone as a purple powder (6.59 g).
Reaction SMILES: CO[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=O.[NH2:12][NH2:13]>>[OH:11][N:9]1[C:8]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:13]=[N:12]1
Reactant: COc1cnccc1[N+](=O)[O-]
Reactant: NN
Product: On1nnc2cnccc21

Procedure:
By reacting either 3-methoxy-4-nitro pyridine or 3-halo-4-nitro pyridine (wherein halo is chloro, bromo or fluoro) with hydrazine in accordance with the procedure of Example 1, the title compound is prepared.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[CH:17]=[N:16][CH:15]=[C:14]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[C:10]=1[C:11]([OH:13])=[O:12]>C1COCC1.CO>[CH3:1][O:12][C:11](=[O:13])[C:10]1[C:14]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[CH:15][N:16]=[CH:17][C:9]=1[Br:8].[Br:8][C:9]1[CH:17]=[N:16][CH:15]=[C:14]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[C:10]=1[C:11]([OH:13])=[O:12]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: O=C(O)c1c(Br)cncc1Nc1ccccc1F
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(Br)cncc1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
(Trimethylsilyl)diazomethane (8.1 mL, 2M in THF, 16.2 mmol) was added to a solution of 3-bromo-5-(2-fluoro-phenylamino)-isonicotinic acid (4.2 g, 13.5 mmol) in THF/MeOH (72 mL, 9/1, v/v) and stirred for 2 h at room temperature. The reaction solution was quenched with acetic acid, and then concentrated. The crude product was purified via Biotage eluting with a gradient of 0 to 50% EtOAc in hexanes to afford the desired product (4.1 g, 94%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].O=S(Cl)[Cl:18]>CN(C=O)C>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cc2c(O)ncnc2cc1F
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1F
Yield: 94.4 %

Procedure:
7-fluoro-6-nitroquinazolin-4-ol (15 g, 0.072 mol) was added into 150 mL SOCl2 and 10 drops of DMF was added. The solution was heated to reflux for 4 hours, then SOCl2 was removed under reduce pressure to give 4-chloro-7-fluoro-6-nitro quinazoline as a yellow powder 15.4 g (94.4% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([NH2:23])=O)[NH:6]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>O1CCCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21](=[S:33])[NH2:23])[NH:6]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(N)=O)cc12
Solvent: C1CCOC1
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(N)=S)cc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A mixture of 4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (1.78 g), Lawesson's reagent (2.26 g) and tetrahydrofuran (120 ml) was stirred at 60° C. for 2 hr. The reaction solution was concentrated under reduced pressure, and the obtained oil was crystallized from dichloromethane-toluene to give the title compound (1.56 g, yield 84%) as pale-yellow crystals. MS: 366 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:20][CH:19]=3)[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:7]([CH3:35])[C:6]=2[CH:36]=1.[CH3:37][O:38][C:39]1[N:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH:11]1([CH:10]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:22][CH:23]=2)[C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([C:42]4[CH:43]=[N:44][C:39]([O:38][CH3:37])=[CH:40][CH:41]=4)=[CH:36][C:6]=3[C:7]=2[CH3:35])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(Br)cc3c2C)C2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(-c4ccc(OC)nc4)cc3c2C)C2CCCCC2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
To a solution (5 mL) of ethyl 3-{[(4-{[(5-bromo-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl]methyl)amino}propanoate (0.25 g) synthesized in the above-mentioned (3) in N,N-dimethylacetamide were added (6-methoxypyridin-3-yl)boronic acid (0.14 g), potassium carbonate (0.13 g) and tetrakistriphenylphosphine palladium (0.05 g), and the mixture was stirred at 90° C. for 12 hr under nitrogen atmosphere. The reaction mixture was cooled to room temperature, and filtered-through celite and the residue was washed with diethyl ether. Water was added to the filtrate, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give ethyl 3-[{[4-({cyclohexyl[5-(6-methoxypyridin-3-yl)-3-methyl-1-benzofuran-2-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (0.15 g, 58%) as a pale-yellow oil. The obtained oil was dissolved in ethanol (1 mL), 1N aqueous sodium hydroxide solution (1.0 mL) was added at room temperature, and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (1.0 mL) was added to the residue. The precipitate was washed with water to give the title object compound (0.12 g, 85%) as a pale-yellow solid.