Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]2[C:7]=1[C:8](=[O:33])[N:9]([C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:10]2)=[O:4].[CH3:34][NH:35][CH3:36].Cl>CC#N.CCOCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:35]([CH3:36])[CH3:34])=[C:7]2[C:11]=1[CH2:10][N:9]([C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:17][S:18]([CH3:21])(=[O:19])=[O:20])[C:8]2=[O:33]
Reactant: CNC
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(Cl)ccc(NC(=O)CCl)c3C2=O)ccc1OC
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(Cl)ccc(NC(=O)CN(C)C)c3C2=O)ccc1OC
Temperature: 70 °C

Procedure:
To a solution of (1S)-2-chloro-N-{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide (400 mg, 0.78 mmol) in CH3CN (10 ml) was added dimethylamine (2N in MeOH, 1.6 ml, 3.2 mmol). The mixture was heated at 70° C. for 2 hrs. The reaction mixture was concentrated on rota-vap and extracted with water (50 ml) and EtOAc (50 ml). The organic layer was washed with water (50 ml), brine (25 ml), dried over Na2SO4 and concentrated. The resulted oil was purified by chromatography to give an oil which was stirred with HCl in ether (3 ml) to give (1S)-N-{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-2-dimethylamino-acetamide; hydrochloride as a white solid (300 mg, 68% yield): mp, 198-200° C.; 1H NMR (DMSO-d6) δ 1.32 (t, J=7.5 Hz, 3H, OCH2CH3), 2.87 (s, 6H, N(CH3)2), 3.04 (s, 3H, CH3), 3.74 (s, 3H, CH3), 3.94-4.16 (m, 4H, OCH2CH3+NCHH+CHHSO2), 4.36-4.50 (m, 3H, CHHSO2+CH2NCO), 4.73 (d, J=18 Hz, 1H, CHHN), 5.85-5.91 (m, 1H, NCH), 6.98 (s, 2H, Ar), 7.05 (s, 1H, Ar), 7.69 (d, J=8 Hz, 1H, Ar), 8.18 (d, J=8 Hz, 1H, Ar), 10.21 (bs, 1H, HCl); 10.45 (s, 1H, NHCO); 13C NMR (DMSO-d6) δ 15.17, 23.25, 41.51, 43.86, 46.03, 49.41, 53.88, 56.00, 58.52, 64.41, 112.50, 112.80, 120.23, 121.25, 123.33, 130.22, 133.21, 134.72, 140.60, 148.55, 149.46, 154.53, 167.02, 180.13, Anal Calcd for C24H31Cl2N3O6S+0.41 H2O: C, 50.78; H, 5.65; N, 7.40. Found: C, 50.81; H, 5.55; N, 7.18, H2O, 1.30.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[CH3:10][C:11](=O)[CH2:12][CH2:13][C:14](=O)[CH3:15]>C(O)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]2[CH3:10])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)ccc1Br
Reactant: CC(=O)CCC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(-n2c(C)ccc2C)ccc1Br
Yield: 82.5 %

Procedure:
Acetic acid (30 mL) solution of 9.30 g of 4-bromo-3-methylaniline and 6.85 g of 2,5-hexanedione was stirred at 80° C. for 5 hours. The reaction liquid was concentrated, aqueous saturated sodium hydrogencarbonate solution was added thereto, extracted with ethyl acetate, washed with saturated saline water, and dried with anhydrous magnesium sulfate. This was filtered through silica gel column chromatography (ethyl acetate), the solvent was concentrated, hexane was added to it, and the formed solid was collected to obtain 10.90 g of the entitled compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:21][N:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=3.[C:30](Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[N:21]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21
Reactant: CC(C)(C)C(=O)Cl
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn(C(=O)C(C)(C)C)n4)ccc3n(C)c21

Procedure:
The process is carried out as indicated in Example 99 above, with the compound from Ex 39, 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(2H-pyrazol-3-yl)-1,9-dihydro-pyrido[2,3-b]indol-2-one and pivaloyl chloride.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][N:5]2[C:11]=1I.C([Li])CCC.C1(C)C=CC(S([C:27]#[N:28])(=O)=O)=CC=1>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][N:5]2[C:11]=1[C:27]#[N:28]
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: Fc1ccc2nc(Cl)c(I)n2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1c(Cl)nc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a cooled −78° C. solution of the title compound from Example 3 Step A (0.30 g, 1.01 mmol) in tetrahydrofuran (5.06 ml) was added a solution of n-butyllithium in hexanes (1.6 M, 0.696 ml, 1.11 mmol). After 5 minutes, p-toluenesulfonyl cyanide (0.238 g, 1.32 mmol) was added, and the resulting mixture was allowed to slowly warm to room temperature overnight. The resulting mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel (10-50% ethyl acetate in hexanes) to afford the title compound: LCMS m/z 195.88 [M+H]+, 197.86 [M+2+H]+; 1H NMR (500 MHz, CDCl3) δ 8.25 (d, J=2.4 Hz, 1H), 7.69 (dd, J=9.6, 4.8 Hz, 1H), 7.46-7.42 (m, 1H).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[K+].C(O)(=O)C.[CH3:17][C:18]([CH3:20])=O>>[C:18](=[C:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:10])([CH3:20])[CH3:17]
Reactant: O=C1CCc2ccccc21
Reactant: CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)=C1Cc2ccccc2C1=O
Yield: 18.5 %

Procedure:
To a solution of 1-indanone (120 g, 0.908 mole) in acetone (180 g) inside of 500 mL round-bottom flask was added 9 mL of ethanolic potassium hydroxide (3 g, 0.054 mole) solution. The solution was heated under reflux for 7.5 hours and then acidified with acetic acid. Volatile components were removed by a rotary evaporator. To the residue diethyl ether (200 mL) and water (100 mL) were added. The aqueous layer was extracted with diethyl ether (4*200 mL). All etheral layers were combined, washed with water (50 mL), dried over anhydrous magnesium sulfate and concentrated to yield 152 g of crude product. Fractional distillation (80 to 120° C./0.3 mmHg) and recrystallization from methanol yielded 29 g of 2-isopropylidene-1-indanone. H-NMR (CDCl3) δ 1.99 (s, 3 H), 2.43 (s, 3 H), 3.62 (s, 2 H), 7.36 (br t, J=7.6 Hz, 1 H), 7.45 (br d, J=7.6 Hz, 1 H), 7.53 (td, J=7.6, 1.2 Hz, 1H), 7.80 (br d, J=7.6 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[N:23]([CH2:33][C:34](Cl)=[O:35])[N:22]=2)=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:34](=[O:35])[CH2:33][N:23]2[C:24]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[N:25][C:21]([C:18]3[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=3)=[N:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Cn2nc(-c3ccc(F)cc3)nc2-c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.9 %

Procedure:
1.8 g piperazine-1-carboxylic acid tert-butyl ester was added to 3.2 g (3,5-Bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetyl chloride and 1 g triethylamine in 50 mL dichlormethane. The reaction was stirred 1 day at RT, evaporated and purified by chromatography on silica gel (petrolether/diethylether:1/1) to yield 3.1 g of the desired compound.
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].CC(C)([O-])C.[K+].[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl.C1OCCOCCOCCOCCOCCOC1>C(O)(C)(C)C.O>[O:20]1[CH2:19][CH:18]1[CH2:16][O:3][C:2]1[CH:4]=[CH:5][CH:6]=[CH:7][C:1]=1[O:8][CH3:9]
Reactant: ClCC1CO1
Reactant: COc1ccccc1O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccccc1OCC1CO1
Temperature: 50 °C

Procedure:
Guaiacol (8.6 g, 69 mmol), potassium t-butoxide (7.8 g, 69 mmol), epichlorohydrin (19.3 g, 209 mmol), and 18-crown-6 (0.8 g) were mixed in t-butanol (100 ml) and heated to 50° C. for 2 h. Water was added and the product was extracted with two portions of dichlorometane. Washing with water, twice, was followed by drying and evaporation. Quantitative yield.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][C:16]3[CH:15]=[CH:14][NH:13][C:12](=[O:25])[C:11]=3[N:10]=2)=[CH:5][CH:4]=1>C(Cl)(Cl)Cl.C(#N)C.[O-2].[O-2].[Mn+4]>[O:25]=[C:12]1[C:11]2[N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=3)[C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:17][C:16]=2[CH:15]=[CH:14][NH:13]1
Reactant: O=c1[nH]ccc2cc(-c3ccccc3)c(-c3ccc(CO)cc3)nc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: O=Cc1ccc(-c2nc3c(=O)[nH]ccc3cc2-c2ccccc2)cc1
Temperature: 60 °C

Procedure:
To a solution of 2-[4-(hydroxymethyl)phenyl]-3-phenyl-1,7-naphthyridin-8(7H)-one (46 mg, 0.14 mmol) in chloroform (4 mL) and acetonitrile (4 mL) was added activated manganese dioxide (200 mg, 2.2 mmol). This suspension was warmed at 60° C. for three hours. The warm suspension was filtered, rinsed with chloroform and the solvents removed in vacuo to give the title compound. 1H-NMR (500 MHz, CDCl3): δ 12.68 (1H, s), 10.00 (1H, br s), 7.99 (1H, s), 7.82 (2H, d, J=8.3 Hz), 7.77 (2H, d, J=8.3 Hz), 7.40 (1H, d, J=6.9 Hz), 7.31-7.37 (3H, m), 7.20-7.24 (2H, m), 6.61 (1H, d, J=7.1 Hz). m/e (m+1): 327.2.
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[C:9](B(O)O)=[CH:8][CH:7]=[C:6]([Cl:13])[N:5]=1>C(Cl)Cl>[Cl:3][C:4]1[C:9]([OH:1])=[CH:8][CH:7]=[C:6]([Cl:13])[N:5]=1
Reactant: OO
Reactant: OB(O)c1ccc(Cl)nc1Cl
Solvent: ClCCl
Product: Oc1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.8 %

Procedure:
H2O2 (1.60 g, 47.12 mmol) was added slowly to the solution of compound 2,6-dichloropyridin-3-ylboronic acid (3 g, 15.71 mmol) in CH2Cl2 (30 mL) at 0° C. After stirred at room temperature for about 15 hours, the mixture was quenched with sat. Na2S2O3 aqueous (50 mL) and adjusted to pH<7 with 1N HCl. The mixture was extracted with EtOAc (40 mL×3). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and the solvent was concentrated in vacuo to provide 2,6-dichloropyridin-3-ol (2.34 g, yield: 91.4%). 1H-NMR (CDCl3, 400 MHz) δ 7.30 (d, J=8.4 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 5.70 (br, 1H). MS (M+H)+: 164/166/168.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([S:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[SH:18][C:19]1[O:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[O:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[S:18][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([S:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8]
Reactant: Sc1nc2ccccc2o1
Reactant: CSc1ncccc1NC(=O)CCCCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncccc1NC(=O)CCCCCSc1nc2ccccc2o1
Temperature: 80 °C
Reaction time: 3 h
Yield: 80512.2 %

Procedure:
To a DMF (2 ml) solution of this amide (159 mg, 0.5 mmol) and 2-mercaptobenzoxazole (83 mg, 0.55 mmol) were added 18-crown-6 (13 mg, 0.05 mmol) and potassium carbonate (83 mg, 0.6 mmol), and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 20 g, eluent—hexane:ethyl acetate=5:2→2:1) to obtain 156 g (yield 81%) of a desired compound as a colorless needle crystal.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:26])[CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2].Br[C:28]1[CH:42]=[CH:41][C:31]([CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].CN(C=O)C>O.[Pd](Cl)Cl>[C:1]([CH2:3][NH:4][C:5]([CH:6]([C:11]1[CH:12]=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:41][CH:42]=2)[CH:14]=[CH:15][CH:16]=1)[CH2:7][CH:8]([CH3:9])[CH3:10])=[O:26])#[N:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
Reactant: CC(C)CC(C(=O)NCC#N)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CC(C(=O)NCC#N)c1cccc(-c2ccc(CNC(=O)OC(C)(C)C)cc2)c1
Temperature: 82.5 °C
Yield: 82.1 %

Procedure:
A mixture comprised of N-cyanomethyl-4-methyl-2-[3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]pentanamide (250 mg, 0.702 mmol), tert-butyl 4-bromobenzylcarbamate (303 mg, 1.053 mmol), sodium bicarbonate (1.1 mL, 2.11 mmol), palladium(II) chloride (18 mg, 0.0211 mmol) and DMF (15.8 mL) was stirred under nitrogen at between 80-85° C. until the reaction was complete. The mixture was diluted with water and the product was extracted with diethyl ether (3×). The combined extracts were washed with brine, dried (MgSO4) and then concentrated in vacuo. The product was purified from the residue by flash chromatography over silica gel (ethyl acetate/hexanes) to provide tert-butyl 3′-(1-cyanomethylcarbamoyl-3-methylbutyl)biphenyl-4-ylmethylcarbamate (252 mg, 0.576 mmol). 1H NMR (400 MHz, d6-DMSO): δ 8.79 (br s, 1H), 7.58-7.26 (m, 9H), 4.16 (d, J=5.2 Hz, 2H), 4.11 (br s, 2H), 3.67 (dd, J=7.2, 7.2 Hz, 1H), 1.95-1.91 (m, 1H), 1.57-1.53 (m, 1H), 1.40-1.33 (m, 10H), 0.88 (dd, J=6.7, 6.7 Hz, 6H); MS (−ESI) m/z 434.6 (M−H)−.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[F:7][C:8]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:9]=1[NH2:10].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[F:7][C:8]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:9]=1[NH:10][C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:5]
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cc([N+](=O)[O-])ccc1F)C1CC1
Reaction time: 8 h
Yield: 98.1 %

Procedure:
Cyclopropanecarbonyl chloride (5.4 mL, 60 mmol) was added dropwise over 5 min to a stirred solution of 2-fluoro-5-nitroaniline (1.56 g, 10.0 mmol) and solid NaHCO3 (7.65 g, 90 mmol) in DCM (50 mL) at room temperature under nitrogen. The mixture was stirred overnight then diluted with DCM (50 mL) and H2O (100 mL) and stirred for 30 min. The aqueous and organic layers were partitioned and the aqueous layer extracted with DCM (2×50 mL). The combined organic layers were dried (Na2SO4), filtered and the solvent removed under vacuum to leave a crude residue. The residue was dry-loaded onto silica gel and purified by column chromatography on silica gel using EtOAc/heptane (1:9 to 4:6) as eluent to give the product (2.2 g, 98% yield) as a solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[CH2:18][CH3:19])[C:5]1=[O:23])(=O)C.[NH2:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1>>[CH2:32]([O:31][C:29]([C:28]1[CH:34]=[CH:35][C:25]([NH:24]/[C:17](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[CH2:18][CH3:19])=[CH:26][CH:27]=1)=[O:30])[CH3:33]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCOC(CC)=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21
Product: CCOC(=O)c1ccc(N/C(CC)=C2\C(=O)Nc3cc(OC)c(OC)cc32)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone and ethyl 4-aminobenzoate
Reaction SMILES: C([O:4][C:5]([CH3:7])=[CH2:6])(=O)C.[Cl:8][C:9]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[C:10]=1N.C(=O)([O-])[O-].[K+].[K+].N(OC(C)(C)C)=O>CC(C)=O>[Cl:8][C:9]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[C:10]=1[CH2:4][C:5](=[O:6])[CH3:7]
Reactant: C=C(C)OC(C)=O
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Agent: CC(C)(C)ON=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Cc1c(Cl)cc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 58 %

Procedure:
A mixture of isopropenyl acetate (12.2 g, 122 mmol), 2,4,6-trichloroaniline (16.0 g, 81.4 mmol), potassium carbonate (100 mg, 0.7 mmol), and acetone (100 g) was cooled to 10° C. tert-Butyl nitrite (90%, 10 g, 87.3 mmol) was dosed over 30 minutes. The reaction was stirred for further 90 minutes, and it was concentrated to a black oil. The residue was triturated with water, and the pH was adjusted to 10.5 with sodium hydroxide solution. The precipitate was filtered and recrystallized from methanol-water 1:1. The solid was filtered, washed with methanol-water 1:1, and dried. The product was obtained as dark-brown crystalline material (15.9 g, 70.7% purity, 47.3 mmol, 58% yield). Further purification was achieved by recrystallization from hexanes. 1H NMR (400 MHz, CDCl3): δ 2.23 (s, 3H, CH3), 4.02 (s, 2H, CH2), 7.31 (s, 2H, CH).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[S:6][C:7]([C:15]([O:17]C)=[O:16])=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4]=2[CH:3]=1.[OH-].[Na+].Cl>CO>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[S:6][C:7]([C:15]([OH:17])=[O:16])=[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:4]=2[CH:3]=1
Reactant: COC(=O)c1sc2ccc(Br)cc2c1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1sc2ccc(Br)cc2c1-c1ccccc1

Procedure:
Heat 3 g. of methyl 5-bromo-3-phenyl-benzo[b]-thiophene-2-carboxylate in a mixture of 50 ml. of methanol and 30 ml of 10% sodium hydroxide under reflux for one hour. Add concentrated hydrochloric acid to yield the title compound as a precipitate. Recrystallize it from benzene; m.p. 265°-266°.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]2)[CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:19][CH2:20][N:21]([CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][N:27]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH2:26]2)[CH2:22][CH2:23]1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccccc1N1CCN(CC2CCCNC2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(CC2CCCN(C(=O)c3ccccc3)C2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 78.4 %

Procedure:
Benzoyl chloride (0.49 g, 3.5 mmol) was added to a solution of 1-(2-methoxyphenyl)-4-piperidin-3-ylmethyl-piperazine (1.0 g, 3.5 mmol) from example 6 and triethylamine (2 equivalents, 1 mL) in CH2Cl2 (30 mL) and the solution stirred under N2 at 0° C. for 16 hours. The mixture was concentrated under vacuum, water (50(mL) added and the product extracted into ethyl acetate (3×25 mL). The combined organics were washed with water (25 mL), saturated sodium bicarbonate (20 mL) and brine (25 mL). After drying over sodium sulfate, filtration and concentration under vacuum afforded the titled product (1.08 g, 79% yield). An ethanolic solution of the product was treated
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:21])[CH:15]=1.Cl[C:23]1[C:24]([C:33]([OH:35])=[O:34])=[N:25][C:26]2[N:27]([N:30]=[CH:31][CH:32]=2)[C:28]=1[F:29]>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:23]2[C:24]([C:33]([OH:35])=[O:34])=[N:25][C:26]3[N:27]([N:30]=[CH:31][CH:32]=3)[C:28]=2[F:29])=[C:16]([F:21])[CH:15]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: O=C(O)c1nc2ccnn2c(F)c1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1nc2ccnn2c(F)c1Nc1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of i-Pr2NH (3.50 equivalents) in THF at 0° C. is added n-BuLi (3.50 equivalents, 2.5 M solution in hexanes). After stirring 15 minutes, the mixture is cooled to −78° C. 4-Bromo-2-fluorophenylamine (2.50 equivalents) is added. After vigorous stirring for 10 minutes, a mixture of the 6-chloro-7-fluoropyrazolo[1,5-a]pyrimidine-5-carboxylic acid (1.00 equivalent) in THF is added. The dry-ice bath is removed after 30 minutes, and the reaction mixture is stirred for 17 hours at room temperature. The reaction mixture is treated with a 10% aqueous HCl solution, extracted with EtOAc, dried (MgSO4), and concentrated. Trituration with methylene chloride give desired product.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]2[C:11]([O:13][C:14](=[O:15])[C:2]=12)=[O:12].[NH2:16][C:17]([CH3:24])([CH:21]([CH3:23])[CH3:22])[C:18]([NH2:20])=[O:19]>O1CCCC1>[C:18]([C:17]([NH:16][C:14]([C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:15])([CH3:24])[CH:21]([CH3:23])[CH3:22])(=[O:19])[NH2:20]
Reactant: O=C1OC(=O)c2nc3ccccc3cc21
Reactant: CC(C)C(C)(N)C(N)=O
Solvent: C1CCOC1
Product: CC(C)C(C)(NC(=O)c1nc2ccccc2cc1C(=O)O)C(N)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2,3-quinolinedicarboxylic anhydride (0.037 mol) in tetrahydrofuran (THF, 250 ml) is stirred at 5° C. under a drying tube, and a solution of 2-amino-2,3-dimethylbutyramide (0.037 mol) in THF (50 ml) added thereto, in small increments, over a 15 minute period. The reaction mixture is allowed to warm slowly to room temperature for an extended period of time, i.e. about 17 hours. The solvent is evaporated in vacuo to afford a gummy residue, which is triturated with hot ethyl acetate (400 ml) and then filtered to afford the desired 2-[(1-carbamoyl-1,2-dimethylpropyl)carbamoyl]-3-quinolinecarboxylic acid, mp 172.5°-173.5° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:34])[CH2:15][CH:16]([C:22]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([O:30][CH3:31])=[CH:24][C:23]=1[O:32][CH3:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:4])([CH3:3])[CH3:2].[C:35](OC(=O)C)(=[O:37])[CH3:36]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:35](=[O:37])[CH3:36])=[CH:7][C:6]=1[NH:13][C:14](=[O:34])[CH2:15][CH:16]([C:22]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([O:30][CH3:31])=[CH:24][C:23]=1[O:32][CH3:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(CN)ccc1C(C)(C)C)c1c(OC)cc(OC)cc1OC
Reactant: CC(=O)OC(C)=O
Product: CCCCCC(CC(=O)Nc1cc(CNC(C)=O)ccc1C(C)(C)C)c1c(OC)cc(OC)cc1OC

Procedure:
Following a similar procedure to that described in Example 144, but using N-(2-t-butyl-5-aminomethylphenyl)-3-(2,4,6-trimethoxyphenyl)octanamide (prepared as described in Preparation 72C) and acetic anhydride, the title compound was obtained as a colorless foam-like substance.