Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[C:11]([NH:13][C:14]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(CCN(C)C)C.C([Li])(CC)C.CCCCCC.CN([CH:48]=[O:49])C>C1COCC1>[O:1]([C:8]1[CH:25]=[CH:24][CH:23]=[C:10]2[C:9]=1[CH:48]([OH:49])[N:13]([C:14]([CH3:15])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:22])[C:11]2=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(NC(=O)c1cccc(Oc2ccccc2)c1)c1ccccc1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(c1ccccc1)N1C(=O)c2cccc(Oc3ccccc3)c2C1O
Yield: 90.1 %

Procedure:
In a similar manner to Step 2 of Example 16, 3-phenoxy-N-(1-methyl-1-phenylethyl)benzamide (4.00 g, 12.1 mmol) was dissolved in THF (160 mL), and the solution was treated with TMEDA (5.80 mL, 38.7 mmol), sec-butyllithium-hexane solution (0.99 mol/L, 39.0 mL, 38.7 mmol) and DMF (2.10 mL, 26.6 mmol), followed by purification by slurry using diisopropylether to obtain 4-phenoxy-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (3.92 g, yield 90%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH2:9][CH2:10][O:11][CH2:12][CH:13]=2)=[N:6][CH:7]=1.ClC1C=C(C(OO)=[O:22])C=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]23[O:22][CH:9]2[CH2:10][O:11][CH2:12][CH2:13]3)=[N:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1cnc(C2=CCOCC2)nc1
Solvent: ClCCl
Product: Brc1cnc(C23CCOCC2O3)nc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 17.8 %

Procedure:
Compound i (105 mg; 0.436 mmol) was dissolved in DCM (15 mL) and cooled to 0° C., then solid 3-chlorobenzenecarboperoxoic acid (280 mg, 1.14 mmol) was added and the mixture stirred overnight. The mixture was quenched with 1M Na2S2O3 (aq) (5 mL), washed with sat. NaHCO3 (aq) (3×30 mL) followed by brine (1×30 mL). The organic fraction was dried (MgSO4). Purification by chromatography on silica eluting with 0-50% EtOAc-n-heptane gave ii (20 mg, 18%). MS: 256.9 & 258.8; 1:1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH:20]([SnH3])=[CH2:21].C(Cl)Cl>C1(C)C=CC=CC=1>[C:14]1([S:11]([N:6]2[C:7]3[C:3](=[C:2]([CH:20]=[CH2:21])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)cccc21
Reactant: C=C[SnH3]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Temperature: 110 °C
Yield: 61.4 %

Procedure:
4-Bromo-1-(phenylsulfonyl)-1H-indole (8.52 g, 25.3 mmol, Intermediate 44) was dissolved in dry toluene (20 mL) under an N2(g) atmosphere before vinylstannane (16.07 g, 50.7 mmol) and bis[triphenylphosphine)palladium(II) acetate (0.95 g, 1.3 mmol) was added. The reaction was heated to 110° C. for 16 h cooled the reaction mixture to RT and filtered the reaction mixture through a celite pad, and evaporated the solvent. Dissolved the obtained oil in acetonitrile and hexanes, separated the phases. Evaporated the acetonitrile phase and purified the obtained crude product by flash chromatography using 30% DCM in hexanes. Isolated 4.4 g of the desired product as a white solid, yield 62%. MS (ESI+) for C16H13NO2S m/z 284 (M+H)+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C.[Si]([O:30][CH:31]([C:63]([F:66])([F:65])[F:64])[CH:32]([NH:36][C:37](=[O:62])[CH2:38][N:39]1[C:44]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:43][CH:42]=[C:41]([NH:51][C:52]([O:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[O:53])[C:40]1=[O:61])[CH:33]([CH3:35])[CH3:34])(C(C)(C)C)(C)C>O1CCCC1>[O:61]=[C:40]1[C:41]([NH:51][C:52]([O:54][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)=[O:53])=[CH:42][CH:43]=[C:44]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:39]1[CH2:38][C:37]([NH:36][CH:32]([CH:33]([CH3:35])[CH3:34])[CH:31]([OH:30])[C:63]([F:65])([F:64])[F:66])=[O:62]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)Oc2ccccc2)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)Oc2ccccc2)c1=O)C(O)C(F)(F)F
Reaction time: 3 h

Procedure:
R=phenoxycarbonyl: Tetra-n-butylammonium fluoride (1.0M in tetrahydrofuran, 0.34 mL) and glacial acetic acid (0.02 mL) were added to dry tetrahydrofuran (1 mL). A solution of N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)-2-(2-oxo-3-phenoxycarbonylamino-6-phenyl-1,2,-dihydro-1-pyridyl)acetamide in dry tetrahydrofuran (2 mL) was added to the reaction vessel, and the addition syringe was washed out with an additional 2 mL tetrahydrofuran. The reaction mixture was stirred for 3 h; diluted with ethyl acetate (50 mL); washed with water and brine; dried and evaporated to an oil which was purified by flash chromatography, eluting with dichloromethane:ethyl acetate (90:10), to afford 2-(2-oxo-3-phenoxycarbonylamino-6-phenyl-1,2-dihydro-1-pyridyl)-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide as a white solid (0.110 g); TLC: Rf =0.30, ethyl acetate:dichloromethane (1:9); MS: m/z=518(M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])=[C:4]([CH:12]=[C:13]([CH2:16][NH:17][O:18][CH2:19][CH2:20][OH:21])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].CCN(CC)CC.C1C[O:41][CH2:40][CH2:39]1>>[C:40]([N:17]([CH2:16][C:13]1[C:14]([F:15])=[C:2]([F:1])[C:3]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])=[C:4]([CH:12]=1)[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6])[O:18][CH2:19][CH2:20][OH:21])(=[O:41])[CH3:39]
Reactant: O=C(NOCCO)c1cc(CNOCCO)c(F)c(F)c1Nc1ccc(I)cc1F
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N(Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F)OCCO
Reaction time: 12 h

Procedure:
CH3CO2H (300 mg), EDC.HCl (958 mg), and HODhbt (816 mg) were mixed in CH2Cl2 (5 mL) for 2 hours to give an active ester solution. A portion of this solution (0.2 mL) was added to a solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyamino)-methyl]-benzamide (80 mg) obtained in Example 6 and NEt3 (29 μL) in THF, and the mixture was stirred for 12 hours. The reaction mixture was washed with 0.3 N aqueous HCl and aqueous NaHCO3, and subjected to silica gel chromatography (CH2Cl2/MeOH as a developing solvent) to give the title compound (12.0 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]([C:11](Cl)=[O:12])=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][NH2:30])[CH2:25][CH2:24]1>>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][N:23]1[CH2:24][CH2:25][CH:26]([CH2:29][NH:30][C:11]([C:10]2[N:2]([CH3:1])[N:3]=[C:4]3[C:9]=2[CH:8]=[CH:7][CH:6]=[CH:5]3)=[O:12])[CH2:27][CH2:28]1
Reactant: Cn1nc2ccccc2c1C(=O)Cl
Reactant: NCC1CCN(CCc2ccccc2F)CC1
Product: Cn1nc2ccccc2c1C(=O)NCC1CCN(CCc2ccccc2F)CC1

Procedure:
The compound was obtained according to the procedure described in Example 7e) using as reactants 2-methyl-2H-indazole-3-carbonyl chloride (Example 1b) (880 mg; 4.5 mmol) and 1-[2-(2-fluorophenyl)ethyl]-4-piperidine methanamine (Example 12a) (1.06 g; 4.5 mmol).
Reaction SMILES: [CH2:1]([NH:10][C:11](=[O:15])[CH2:12][CH2:13]Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH2:1]([NH:10][C:11](=[O:15])[CH2:12][CH2:13][N:25]1[CH2:26][CH2:27][N:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23][CH2:24]1)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(CCBr)NCC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CCN1CCN(c2ccccc2)CC1)NCC(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A solution of N-phenacyl-3-bromopropanamide (10.2 g; 0.038 mole) and N-phenylpiperazine (12.0 g; 0.074 mole) in dry DMF (100 ml) was stirred with anhydrous, finely-powdered sodium carbonate (15.0 g) for 18 hours at room temperature. The temperature was then increased to 80° C. and held for 12 hours to complete the reaction. The DMF was evaporated off under vacuum and the residue diluted with water (100 ml). The mixture was extracted with chloroform (3 × 100 ml). The extracts were shaken with 2 × 100 ml 2N HCl and the organic layer discarded. The aqueous layer was basified with NaOH solution to pH 9 and extracted with 3 × 75 ml CHCl3. The extracts were washed with water and dried. After removal of the solvent the remaining viscous gum triturated with ether to give a buff-coloured solid. After recrystallisation from isopropanol the product weighed 6.0 g and melted at 126° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[N:22]([CH3:23])[CH:21]=[N:20][N:19]=3)[C:16](=O)[C:15]3[C:14]([C:25]([O:27]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.O.[NH2:31][NH2:32]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:9][C:10]3[C:15]4[C:16](=[N:31][NH:32][C:25](=[O:27])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[CH:17]2[C:18]2[N:22]([CH3:23])[CH:21]=[N:20][N:19]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nncn1C)C(c1ccc(F)cc1)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: Cn1cnnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18 %

Procedure:
A mixture of ethyl 2-(4-fluorophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (120 mg) in 85% hydrazine monohydrate (2 mL) and methanol (5 mL) was stirred at room temperature for 4 h. Then the solution was evaporated, the crude product was purified by prep-HPLC to obtain the title compound as a white solid (20 mg, yield 18%). LC-MS (ESI) m/z: 363 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.50 (s, 3H), 4.83-4.86 (d, J=11.6 Hz, 1H), 5.00-5.03 (d, J=11.6 Hz, 1H), 7.12-7.19 (m, 3H), 7.39-7.42 (m, 2H), 7.47-7.51 (m, 2H), 7.60-7.64 (t, J=8 Hz, 1H), 8.31 (s, 1H), 12.24 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11](COCC[Si](C)(C)C)[N:10]=2)=[N:6][C:7]=1F.[NH:32]1[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33]1>>[Br:1][C:2]1[C:7]([N:32]2[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33]2)=[N:6][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[NH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)c(F)n2)c2cc(-c3cccnc3)ncc21
Reactant: O[C@H]1CCNC1
Product: O[C@H]1CCN(c2nc(-c3n[nH]c4cnc(-c5cccnc5)cc34)ccc2Br)C1
Yield: 3 %

Procedure:
Following the procedures as described in Example 241 and starting with 3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and (S)-pyrrolidin-3-ol, 318 was obtained as an off-white solid (1.8 mg, 3.0%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.29-9.18 (m, 2H), 9.00 (s, 1H), 8.60 (d, J=4.6 Hz, 1H), 8.40 (d, J=8.0 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.54 (dd, J=8.0, 4.7 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 5.75 (s, 1H), 5.01 (d, J=3.5 Hz, 1H), 4.45 (s, 1H), 4.11-4.00 (m, 2H), 3.90-3.81 (m, 1H), 3.63 (d, J=10.7 Hz, 1H), 2.06 (dd, J=8.4, 4.2 Hz, 1H), 1.95 (s, 1H); ESI MS m/z=437.1 (M+1)
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[C:7]([C:9](=[CH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([O:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:23]=1)[C:10]([O:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])#[N:8]>>[C:7]([C:9](=[CH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:2]([O:4][CH2:5][CH3:6])=[O:3])=[C:24]([O:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:23]=1)[C:10]([O:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:11])#[N:8]
Reactant: CCOC(=O)Oc1cc(C=C(C#N)C(=O)OCCc2ccccc2)ccc1O
Reactant: CCOC(=O)Cl
Product: CCOC(=O)Oc1ccc(C=C(C#N)C(=O)OCCc2ccccc2)cc1OC(=O)OCC

Procedure:
Further, reduction of the amount of ethyl chloroformate to 1/2 in the above-described process selectively provided phenethyl 2-cyano-3-(3-ethoxycarbonyloxy-4-hydroxyphenyl)-2-propenoate (Compound 17).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:27]([O:34][C:35](=[O:43])[CH2:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)CC)C>C(Cl)Cl>[CH2:27]([O:34][C:35](=[O:43])[CH2:36][CH:37]1[CH2:38][CH2:39][N:40]([C:11](=[O:13])[C:10]([CH3:15])([CH3:14])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:41][CH2:42]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(CC1CCNCC1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(C)(C)C(=O)O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(C)(C)C(=O)N1CCC(CC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
Methyl 2,2-dimethyl-cyanoacetate (2.0 g) was stirred under a hydrogen atmosphere in a 1N ammonium-containing methanol/ethanol (1:1) mixed solution under the presence of rhodium-alumina catalyst at a room temperature for 6 hours. The catalyst was removed from the reaction solution by filtration and the solvents were distilled off. To the residue were added 4N caustic soda (3 ml) and dioxane (3 ml) and the mixture was stirred at a room temperature for 6 hours. To the resulting mixture were added a 2N aqueous solution of sodium carbonate (25 ml) and di-t-butyl carbonate (2.9 g) dissolved in dioxane (20 ml) and the mixture was stirred for 12 hours. After the solvents were distilled off from the reaction solution, the residue was dissolved in water, washed with ether and adjusted to pH 3 with citric acid under cooling with ice, followed by extraction three times with ethyl acetate. The organic layer was washed with saturated NaCl three times and dried over sodium sulfate. The solvents were distilled off to yield N-t-butoxycarbonyl-α,α-dimethyl-β-alanine (2.5 g). The obtained N-t-butoxycarbonyl-α,α-dimethyl-β-alanine (1.1 g), 4-piperidineacetic acid benzyl ester tosylate (1.52 g), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate (PyBrop, 2.20 g) and triethylamine (1.7 ml) were dissolved in methylene chloride (15 ml) and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off, the residue was applied to a silica gel column (φ 2.5×40 cm, Si-60, eluent: 30% ethyl acetate/hexane) for purification to yield N-(N-t-butoxycarbonyl-α,α-dimethyl-β-alanyl)-4-piperidineacetic acid benzyl ester (1.55 g, 96.0%).
Reaction SMILES: C([Li])CCC.Br[C:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[B:27](OCCCC)([O:33]CCCC)[O:28]CCCC.Cl>CCCCCC.C1COCC1.O>[C:21]1([C:7]([B:27]([OH:33])[OH:28])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: BrC(=C(c1ccccc1)c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: OB(O)C(=C(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
n-Butyllithium in hexane (2.5 M, 15 mL) was added slowly under nitrogen to a stirred solution of (2-bromoethene-1,1,2-triyl)tribenzene (5.00 g, 14.9 mmol) in THF (50 mL) at −78° C. and then the mixture was stirred further for 1 h. Tributyl borate (11.0 mL, 40.8 mmol) was added at −78° C. before the mixture was warmed slowly to room temperature and stirred for 8 hours. Water (100 mL) was added, followed by conc. HCl (100 mL) to acidify the mixture, which was then stirred for 2 hours. The reaction mixture was extracted with EtOAc and the combined organic phases were dried over MgSO4. Concentration under reduced pressure gave 1,2,2-triphenylvinylboronic acid, which, without further purification, was reacted with pinacol (1.73 g, 14.6 mmol) in toluene under reflux for 2 hours to effect condensation by the azeotropic removal of the water formed. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (hexanes/EtOAc=20/1) to afford D (2.41 g, 65%) as white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][NH:30][CH3:31])=[CH:27][CH:26]=1.C1CCN2C(=NCCC2)CC1>CN1C(=O)CCC1>[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][N:30]([CH3:31])[C:13]2[CH:12]=[C:11]3[C:16]([CH:17]=[C:8]([C:6]4[CH:7]=[C:2]([NH2:1])[C:3]([F:22])=[CH:4][C:5]=4[CH3:21])[C:9](=[O:20])[N:10]3[CH3:19])=[CH:15][N:14]=2)=[CH:27][CH:26]=1
Reactant: CNCc1ccc(OC)cc1
Reactant: Cc1cc(F)c(N)cc1-c1cc2cnc(Cl)cc2n(C)c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN1CCCC1=O
Product: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2cc(N)c(F)cc2C)c(=O)n3C)cc1
Temperature: 180 °C
Yield: 100.5 %

Procedure:
3-(5-amino-4-fluoro-2-methylphenyl)-7-chloro-1-methyl-1,6-naphthyridin-2(1H)-one (1.36 g, 4.28 mmol, 1.00 eq), 4-methoxy-N-methylbenzylamine (0.971 g, 6.42 mmol, 1.50 eq) and DBU (0.960 mL, 6.42 mmol, 1.50 eq) were combined in NMP (20 mL) and heated at 180° C. under Ar overnight. The mixture was cooled to RT and poured onto H2O (200 mL). The resulting solids were collected by filtration, rinsed very well with H2O, dried on the filter to dampness and then dissolved in EtOAc. The solution was dried (MgSO4), filtered and evaporated to afford 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-4-fluoro-2-methylphenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (1.86 g, 100% yield) as a brittle brown foam which was used as is in the next reaction. 1H NMR (400 MHz, DMSO-d6): δ 8.45 (s, 1H), 7.63 (s, 1H), 7.16 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 6.86-6.82 (m, 1H), 6.57 (d, J=9.6 Hz, 1H), 6.29 (s, 1H), 4.88 (br s, 2H), 4.85 (s, 2H), 3.69 (s, 3H), 3.52 (s, 3H), 3.07 (s, 3H), 1.94 (s, 3H); MS (ESI) m/z: 433.3 [M+H]+.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C:19]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][C:20]=1[CH2:26][OH:27])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].Cl>ClCCl>[CH2:11]([O:18][C:19]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][C:20]=1[CH:26]=[O:27])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCOc1cc(I)ccc1CO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCCCCCOc1cc(I)ccc1C=O
Temperature: 25 °C

Procedure:
A solution of dimethyl sulfoxide (3 ml, 41.4 mmol) in dichloromethane is added to a solution of oxalyl chloride (20.7 mmol, 1.8 ml) in dichloromethane (55 ml). A solution of (2-heptyloxy-4-iodophenyl)methanol (6.55 g, 18.8 mmol) in 25 ml of dichloromethane is added dropwise to the solution previously obtained, at −78° C. The mixture is stirred until the temperature returns to room temperature. The organic phase is acidified with a 2N hydrochloric acid solution. The desired product is extracted by addition of ethyl acetate. The organic phase is washed with water, dried with magnesium sulfate and concentrated using a rotary evaporator. 6.5 g (100%) of the expected compound are recovered in the form of a yellow solid.
Reaction SMILES: OC1C=C2C(CCC(=O)O2)=CC=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH3:25])=[O:23])=[C:16]([CH3:26])[CH:15]=1>[OH-].[Pd+2].[OH-]>[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:16]([CH3:26])[CH:15]=1
Reactant: COC(=O)/C=C/c1ccc(N)cc1C
Agent: [Pd+2]
Agent: O=C1CCc2ccc(O)cc2O1
Agent: [OH-]
Product: COC(=O)CCc1ccc(N)cc1C
Yield: 74.2 %

Procedure:
A reaction was performed according to the synthesis method of Intermediate 1 by using Intermediate 7 (2.0 g) and 10% palladium hydroxide/activated carbon (1.5 g). The reaction mixture was filtered through Celite, and the solvent of the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (Yamazen, n-hexane:ethyl acetate=3:1), and the solvent was evaporated under reduced pressure by using a rotary evaporator to obtain the title compound (1.5 g) (the reaction was performed in THF solvent (20 ml) for 20 hours).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]([C:7]2[CH:8]=[C:9]([N+:13]([O-])=O)[CH:10]=[CH:11][CH:12]=2)[NH:3]1.[H][H]>[Pt]=O.C(O)C>[CH3:1][N:2]1[CH:6]=[N:5][N:4]([C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[NH2:13])[NH:3]1
Reactant: CN1C=NN(c2cccc([N+](=O)[O-])c2)N1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CN1C=NN(c2cccc(N)c2)N1
Yield: 91.9 %

Procedure:
The nitro group is reduced as follows: To a 250 ml Parr bottle are added 800 mg (3.9 mmol) of 3-(1-methyltetrazol-3-yl)nitrobenzene, 200 mg platinum oxide, and 75 ml ethanol. The reaction is pressurized with 45 p.s.i. hydrogen for 1 hour, then catalyst removed by filtration, and the solvent evaporated to afford 635 mg (93.0%) of a white solid, mp 93°-95° C.
Reaction SMILES: C[CH:2]1[C:10]2[C:5](=CC=[CH:8][CH:9]=2)[NH:4][C:3]1=S.CC(C)([O-:15])C.[K+].C([O:20][CH2:21][CH3:22])C>>[NH:4]1[C:3]2[C:22](=[CH:8][CH:9]=[CH:10][CH:2]=2)[C:21](=[O:20])[C:5]1=[O:15]
Reactant: CCOCC
Reactant: CC1C(=S)Nc2ccccc21
Reactant: CC(C)(C)[O-]
Agent: [K+]
Product: O=C1Nc2ccccc2C1=O
Yield: 32 %

Procedure:
According to the general procedure, 0.48 g of 3-methylthiooxindole and an equimolar quantity (E.Q.) of sublimed potassium t-butoxide in 200 ml of dry diethyl ether was aerated for 4 h at 0° C. and 20 h at 25° C. Acidification with 0.22 ml of conc. hydrochloric acid in 25 ml of water followed by extraction with ether, drying of the extracts over anhydrous magnesium sulfate, filtration, and evaporation of the filtrate gave an orange solid. Recrystallization from chloroform gave 0.13 g (32% yield) of pure isatin, mp 199°-200° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:19])OC1C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[C:23]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:24]=[C:25]([Cl:27])[CH:26]=1>>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[NH:10][C:11]([N:31]1[CH2:30][CH2:29][N:28]([C:23]2[CH:22]=[C:21]([Cl:20])[CH:26]=[C:25]([Cl:27])[CH:24]=2)[CH2:33][CH2:32]1)=[O:19]
Reactant: Cc1cc(O)c(NC(=O)Oc2ccccc2)cc1C
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Product: Cc1cc(O)c(NC(=O)N2CCN(c3cc(Cl)cc(Cl)c3)CC2)cc1C
Yield: 77 %

Procedure:
Phenyl N-(2-hydroxy-4,5-dimethylphenyl)carbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 228 to obtain the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8][C:7]=2[CH:14]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N+:28]([O-])([O-:30])=[O:29].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[C:4]([N+:28]([O-:30])=[O:29])=[CH:5][C:6]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8][C:7]=2[CH:14]=1
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccc2c(c1)CCC(=O)CC2
Agent: [K+]
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cc2c(cc1[N+](=O)[O-])CCC(=O)CC2
Temperature: 25 °C

Procedure:
2-Methoxy-5,6,8,9-tetrahydro-benzocyclohepten-7-one (6.00 g, 0.0315 mol) was dissolved in Acetonitrile (280 mL, 5.4 mol) and was added to a mixture of Trifluoroacetic anhydride (13.4 mL, 0.0946 mol) in Acetonitrile at 0° C. Potassium nitrate (3.19 g, 0.0315 mol) was then added and the reaction was allowed to warm to room temperature. When HPLC showed consumption of starting material, the mixture was poured over saturated sodium bicarbonate, and organics were extracted with ethyl acetate/dichloromethane. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo. The crude mixture was purified by Isco flash column chromatography (Hexane/Ethyl Acetate). The gradient run was 0% EA-50% EA. Combined fractions were reduced en vacuo to afford 3.62 (49%) of 2-Methoxy-3-nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one and 1.80 grams (25%).