Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH2:9])=[O:8].[C:10]([O:14][C:15]([NH:17][CH2:18][C:19](O)=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].C(Cl)CCl>C1COCC1>[C:7]([C:3]1[N:2]([NH:1][C:19](=[O:20])[CH2:18][NH:17][C:15](=[O:16])[O:14][C:10]([CH3:11])([CH3:12])[CH3:13])[CH:6]=[CH:5][CH:4]=1)(=[O:8])[NH2:9]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NC(=O)c1cccn1N
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCC(=O)Nn1cccc1C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.3 %

Procedure:
1-Amino-1H-pyrrole-2-carboxamide (5.00 g, 40.0 mmol) and 2-(tert-butoxycarbonylamino)acetic acid (7.70 g, 44.0 mmol) were combined and dissolved in THF (250 mL). To this solution was added EDC (8.43 g, 44.0 mmol). The reaction was stirred at room temperature for 16 h, after which the reaction was concentrated in vacuo. The residue was partitioned between EtOAc (250 mL) and water (200 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (150 mL). The combined organics were dried (MgSO4) and filtered. The filtrate was treated with activated charcoal and filtered over Celite. The filtrate was concentrated in vacuo to remove most of the solvent, then diluted with hexanes to ˜1 L. A solid was filtered off and dried to give 21A (8.73 g). The aqueous layer was extracted again with EtOAc (2×100 mL). A second crop was obtained similarly to above to give 465 mg, for a total yield of 9.20 g (82%). 21A had an analytical HPLC retention time=1.75 min (Phenomonex-Luna (4.6×50 mm S10); 10-90% MeOH/H2O (0.1% TFA) over 4 min; flow=4 mL/min) and a LC/MS M+-Boc+1=183.
Reaction SMILES: N1C2C(=C(C[NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:23]=[C:22]([CH:24]5[CH2:28][CH2:27]CO5)[NH:21][N:20]=4)[CH:15]=[CH:14][N:13]=3)C=CC=2)C=C1.ClC1N=C(NC2C=C([C@@H]3C[C@H]3C3C=CC=CC=3[F:51])NN=2)C=CN=1>>[CH:24]1([C:22]2[NH:21][N:20]=[C:19]([NH:18][C:16]3[C:15]([F:51])=[CH:14][N:13]=[C:12]([NH2:11])[N:17]=3)[CH:23]=2)[CH2:28][CH2:27]1
Reactant: c1cc(CNc2nccc(Nc3cc(C4CCCO4)[nH]n3)n2)c2cc[nH]c2c1
Reactant: Fc1ccccc1[C@@H]1C[C@H]1c1cc(Nc2ccnc(Cl)n2)n[nH]1
Product: Nc1ncc(F)c(Nc2cc(C3CC3)[nH]n2)n1

Procedure:
N2-((1H-indol-4-yl)methyl)-N4-(5-(tetrahydrofuran-2-yl)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (I-119) and N2-(1H-indol-4-yl)methyl)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoropyrimidine-2,4-diamine (I-120) were prepared analogously except 2-chloro-N-(5-(trans-2-(2-fluorophenyl)cyclopropyl)-1H-pyrazol-3-yl)pyrimidin-4-amine was replaced with 83 and 55, respectively
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:5]2[NH:10]/[C:9](=[N:11]/[NH2:12])/[CH2:8][O:7][C:6]=2[N:13]=1.C(O[C:23](OCC)(OCC)[CH2:24][CH3:25])C>>[Br:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:5]2[N:10]3[C:23]([CH2:24][CH3:25])=[N:12][N:11]=[C:9]3[CH2:8][O:7][C:6]=2[N:13]=1
Reactant: CCOC(CC)(OCC)OCC
Reactant: N/N=C1\COc2nc(Br)c(-c3ccccc3)cc2N1
Product: CCc1nnc2n1-c1cc(-c3ccccc3)c(Br)nc1OC2
Temperature: 120 °C
Yield: 40 %

Procedure:
In a 10 ml microwave vial was (E)-6-bromo-2-hydrazono-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (90 mg, 0.282 mmol) in 1,1,1-triethoxypropane to give a yellow suspension. The reaction mixture was heated to 120° C. for 20 minutes. The crude residue was concentrated under reduced pressure and purified by Biotage silica gel chromatography (gradient 100% to 100% n-hexane in ethyl acetate) to give the title compound (41 mg, 40%). 1H NMR (500 MHz, CDCl3): 7.73 (1H, s), 7.54-7.48 (3H, m), 7.45-7.41 (2H, m), 5.56 (2H, s), 3.10-3.00 (2H, q), 1.53-1.48 (3H, t). LCMS (Method D) RT 1.117 min, M+1=358.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:27][CH2:26][C:11]2([O:16][C:15](=[O:17])[NH:14][CH2:13][CH:12]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH2:10][CH2:9]1)=[O:7].CN(C)C=O.[H-].[Na+].Br[CH2:45][CH:46]([F:48])[F:47]>>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([O:16][C:15](=[O:17])[N:14]([CH2:45][CH:46]([F:48])[F:47])[CH2:13][CH:12]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH2:26][CH2:27]1)=[O:7]
Reactant: FC(F)CBr
Reactant: O=C1NCC(c2ccc(F)c(F)c2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1OC2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C(c2ccc(F)c(F)c2)CN1CC(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.7 %

Procedure:
To a solution of 261 mg (0.5 mmol) 9-(3,5-bis-trifluoromethyl-benzoyl)-5-(3,4-difluoro-phenyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one in dimethylformamide 24 mg (0.5 mmol) of a 55% sodium hydride suspension in mineral oil was added at room temperature under argon. After 15 min, 80 mg (0.55 mmol) of 2-bromo-1,1-difluoroethane was added. The reaction mixture was stirred at room temperature under argon overnight. After evaporation of the solvent in vacuum water (1 ml) was added and the mixture was extracted with ethyl acetate. The organic layer was dried over (Na2SO4) and concentrated. The residue was purified by column chromatography (SiO2, Hexane/ethylacetate=1:1) to yield 96 mg (33%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]([CH3:23])([CH3:22])[C:19](O)=[O:20].S(=O)(=O)(O)O>C(#N)C>[C:1]([C:5]1[CH:11]=[C:10]([O:12][C:19](=[O:20])[C:18]([CH3:23])([CH3:22])[CH3:17])[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C(=O)O
Reactant: CC(C)(C)c1cc(O)c(C(C)(C)C)cc1O
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: CC(C)(C)C(=O)Oc1cc(C(C)(C)C)c(O)cc1C(C)(C)C
Yield: 78 %

Procedure:
Under argon atmosphere, a solution of 11.12 g of 2,5-di-t-butylhydroquinone and 10.1 ml of anhydrous trimethylacetic acid in 200 ml of acetonitrile was stirred with a catalytic amount of sulfuric acid at room temperature for a whole day and night. After the reaction mixture was evaporated under reduced pressure, the concentrate was dissolved in diisopropyl ether. This solution was washed with a saturated aqueous sodium bicarbonate solution, then saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 5% ethyl acetate) to give 11.9 g of 2,5-di-t-butyl-4-trimethylacetoxyphenol as a white solid (yield 78%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]([O:9]CC)=[O:8]>Cl>[CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1cnoc1C
Agent: Cl
Product: Cc1oncc1C(=O)O
Yield: 78.9 %

Procedure:
Ethyl 5-methylisoxazol-4-yl carboxylate (65 g) was heated under reflux in 10 M HCl (500 ml) for 3 hours. On cooling the product crystallised out. This was filtered and dried giving 42 g of a white crystalline solid, m.p. 134°-136° C.
Reaction SMILES: [CH2:1]([CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Rh]>[CH:2]1([CH2:1][CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Reactant: [H][H]
Agent: [Rh]
Solvent: CO
Product: CCOC(=O)C(CC1CCCCC1)C(=O)OCC
Yield: 98.6 %

Procedure:
To a solution of 50.0 g of diethyl benzylmalonate in 100 ml of methanol under nitrogen is added 5.0 g of 5% rhodium on alumina. The mixture is hydrogenated in a Parr hydrogenator at 50 pounds per square inch of hydrogen for 16 hours. The mixture is filtered through diatomaceous earth and the filtrate concentrated under vacuum to give 50.5 g of diethyl (cyclohexylmethyl)propanedioate as a colorless oil. A 2.80 g sample of sodium hydride (60% in oil) is washed with hexane (decanted) under argon and 70 ml of dry tetrahydrofuran added. The mixture is cooled in an ice bath and 17.94 g of diethyl (cyclohexylmethyl)propanedioate added dropwise over 15 minutes. To the mixture (0° C. to 5° C.) is added dropwise 13.23 g of 2-bromo-1-(2-furanyl)ethanone in 40 ml of tetrahydrofuran. The cooling bath is removed and the mixture stirred at room temperature overnight. The solvent is removed under vacuum and 100 ml of ether added. The mixture is filtered through 240 g of silica gel in a 600 ml glass sintered funnel and the silica gel pad washed with 2 liters of ether. The filtrate is concentrated to 300 ml and is washed three times with 100 ml portions of 1M sodium bicarbonate and with 100 ml of brine. The organic layer is dried (MgSO4) and the solvent removed to give 26.0 g of a brown oil. This oil is chromatographed on silica by HPLC on a Waters-Prep 500 instrument with hexane-ethyl acetate (12:1) to give 16 g of diethyl(cyclohexylmethyl)[2-(2-furanyl)-2-oxoethyl]-propanedioate as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:28][CH2:27][CH2:26][CH:25]2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[OH-].[Na+].Cl>CO.O1CCCC1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:28][CH2:27][CH2:26][CH:25]2[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=2)[CH2:12][CH2:11]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCCC3c3ccccc3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCCC3c3ccccc3)CC2)cc1
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 60.6 %

Procedure:
To an ice cooled solution of methyl 4-(1-(5-chloro-2-(2-phenylpyrrolidin-1-yl)nicotinamido)cyclopropyl)benzoate (D142) (189 mg, 0.40 mmol). in a mixture methanol/tetrahydrofuran (10 ml/10 ml), 2N NaOH (10 ml) was added. The reaction mixture was heated to 40° C. for 2 hours then cooled to 0° C., acidified with 2.5N HCl (pH=1-2) and stirred at 0° C. for 10 min. The formed solid was collected by filtration and dried to provide title compound (E1) (112 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[S:14][CH:15]=2)=[O:9])[CH:3]=1.[CH:20]1([C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)[CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)CCC>[CH:20]1([C:23]2[N:24]=[CH:25][N:26]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]4[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[S:14][CH:15]=4)=[O:9])[CH:3]=3)[CH:27]=2)[CH2:22][CH2:21]1
Reactant: c1nc(C2CC2)c[nH]1
Reactant: COC(=O)c1cc(NC(=O)c2cc(F)ccn2)cs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCC#N
Product: COC(=O)c1cc(NC(=O)c2cc(-n3cnc(C4CC4)c3)ccn2)cs1
Temperature: 105 °C
Yield: 74.5 %

Procedure:
To a solution of methyl 4-(4-fluoropicolinamido)thiophene-2-carboxylate (400 mg, 1.4 mmol) in butyronitrile (5 mL), was added 4-cyclopropyl imidazole (310 mg, 2.9 mmol), and caesium carbonate (840 mg, 2.6 mmol) and the reaction was heated to 105° C. for 2 hours. The reaction was filtered and the solids were washed with acetonitrile, methylene chloride, and the filtrate was evaporated under reduced pressure. The residue was suspended in acetonitrile, and the solids were collected by filtration to provide 384 mg (73%) of methyl 4-(4-(4-cyclopropyl-1H-imidazol-1-yl)picolinamido)thiophene-2-carboxylate. M+1=369.1
Reaction SMILES: C(O[C:6](=O)[N:7](C)[CH:8]([CH3:42])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]3=[N:20][C:19]=2[CH3:27])=[C:14]([C:28]#[C:29][C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[N:36]([CH3:40])[C:35](=[O:41])[CH:34]=[CH:33]3)[N:13]=1)=[O:10])(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:6][NH:7][CH:8]([CH3:42])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]3=[N:20][C:19]=2[CH3:27])=[C:14]([C:28]#[C:29][C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[N:36]([CH3:40])[C:35](=[O:41])[CH:34]=[CH:33]3)[N:13]=1)=[O:10]
Reactant: Cc1nc2ccccn2c1-c1ccc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)nc1C#Cc1ccc2c(ccc(=O)n2C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(C)C(=O)Nc1ccc(-c2c(C)nc3ccccn23)c(C#Cc2ccc3c(ccc(=O)n3C)c2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl-N-methyl-N-[1-[[5-(2-methylimidazo[1,2-a]pyridin-3-yl)-6-[2-(1-methyl-2-oxoquinolin-6-yl)ethynyl]pyridin-2-yl]amino]-1-oxopropan-2-yl]carbamate G1b (17 mg, 0.03 mmol) and DCM:TFA (9:1, 2 ml) is stirred at RT for 2 h. The mixture is diluted with DCM and a saturated aqueous solution of NaHCO3 is added. The mixture is extracted with DCM. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 14 mg (99%). HPLC-MS: M+H=491; tR=0.97 min (*Method—1).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][N:17]4C(=O)C5=CC=CC=C5C4=O)=[CH:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:7]=2[CH:34]=1.O.NN>C(O)C>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][NH2:17])=[CH:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:7]=2[CH:34]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1)=NC2
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1cnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 28, 8-trifluoromethyl-1-(phthalimidomethyl)-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine is reacted at room temperature with hydrazine hydrate, dissolved in ethanol, to give 8-trifluoromethyl-1-(aminomethyl)-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4](Br)[C:3]1=[O:9].O.O.O.C([O-])(=O)C.[Na+].[CH2:18]([SH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CO>[CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4]([S:24][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:3]1=[O:9]
Reactant: CN1C(=O)C=C(Br)C1=O
Reactant: CCCCCCS
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCSC1=CC(=O)N(C)C1=O
Yield: 83 %

Procedure:
To N-methyl bromomaleimide (100 mg, 0.53 mmol) and sodium acetate trihydrate (70 mg, 0.53 mmol) in methanol (15 mL) was added hexanethiol (74 μL, 0.58 mmol) in methanol (100 mL) dropwise over 1 hour with vigorous stirring. After 5 minutes solvent was removed in vacuo. Purification by column chromatography (gradient elution in 10% ethyl acetate in petroleum ether to 30% ethyl acetate in petroleum ether) afforded the desired compound as a bright yellow solid (99 mg, 0.44 mmol) in 83% yield. δH (600 MHz, CDCl3) 6.03 (s, 1H, H-2), 3.01 (s, 3H, H3-5), 2.89 (t, 2H, J=7.6, 2H, H2-11), 1.76-1.71 (m, 2H, H2-10), 1.46-1.41 (m, 2H, H2-9), 1.33-1.27 (m, 4H, H2-7 and CH2-8), 0.89 (t, 3H, J=6.5, H3-6); δC (125 MHz, CDCl3) 171.47 (C═O), 169.94 (C═O), 151.84 (C3), 117.27 (C2), 31.92 (C11), 31.31 (CH2), 28.64 (CH2), 27.75 (CH2), 24.10 (C5), 24.10 (C7), 14.09 (C6); IR (oil, cm−1) 2727 (w), 1708 (s); MS (FAB+) m/z (relative intensity): 250 ([M+Na], 40), 228 (35), 199 (30), 176 (100); Exact Mass Calcd for [C11H17NO2S]+Na requires m/z 250.0878 Found 250.0880 (FAB+).
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[C:5](=[C:10]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].COCCNC1C=CC=C(C(O)=O)C=1C(O)=O>>[CH2:15]([NH:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:20])=[O:2])[C:5]=1[C:6]([OH:8])=[O:7])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCNc1cccc(C(=O)OC)c1C(=O)OC
Agent: COCCNc1cccc(C(=O)O)c1C(=O)O
Product: CCCCCNc1cccc(C(=O)O)c1C(=O)O

Procedure:
3-Pentylamino-phthalic acid dimethyl ester (4.19, 15 mmol) was treated in the same manner as described above for the synthesis of 3-(2-methoxy-ethylamino)-phthalic acid. The product of the reaction, which contained a mixture of diacid and monomethyl esters, was used without further purification.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[Br:22][Si](C)(C)C>ClCCl>[Br:22][CH2:13][C:12]([C:9]1[CH:8]=[CH:7][C:6]([C:5]2[O:1][CH:2]=[N:3][CH:4]=2)=[CH:11][CH:10]=1)=[O:14]
Reactant: C[Si](C)(C)Br
Reactant: CC(=O)c1ccc(-c2cnco2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CBr)c1ccc(-c2cnco2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[4-(1,3-Oxazol-5-yl)phenyl]-1-ethanone (2.81 g) and triethylamine (6.27 mL) were dissolved in dichloromethane mL), and bromotrimethylsilane (3.96 mL) was added dropwise to the solution under ice cooling. The mixture was stirred at room temperature overnight under argon. The reaction mixture was washed sequentially with water and saturated saline, followed by drying over magnesium sulfate. The solvent was evaporated under reduced pressure, and the formed brown oily matter was dissolved in tetrahydrofuran mL). Subsequently, N-bromosuccinimide (2.67 g) was added to the solution, followed by stirring at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was evaporated, and the residue was purified through flash column chromatography (dichloromethane), followed by concentration under reduced pressure. The obtained solid was recovered through filtration by use of n-hexane, to thereby yield the title compound (3.35 g).
Reaction SMILES: [O:1]=[C:2]1[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:5](=[O:12])[CH2:4][S:3]1.[Cl:13][C:14]1[CH:42]=[CH:41][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24](/[CH:29]=C4/C(=O)N(CC(O)=O)C(=O)S/4)=[C:25]([F:28])[CH:26]=3)[CH:21]=[N:20]2)=[C:16]([C:43]([F:46])([F:45])[F:44])[CH:15]=1>>[Cl:13][C:14]1[CH:42]=[CH:41][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24](/[CH:29]=[C:4]4/[C:5](=[O:12])[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:2](=[O:1])[S:3]/4)=[C:25]([F:28])[CH:26]=3)[CH:21]=[N:20]2)=[C:16]([C:43]([F:46])([F:45])[F:44])[CH:15]=1
Reactant: O=C(O)CN1C(=O)S/C(=C\c2cc3cnn(Cc4ccc(Cl)cc4C(F)(F)F)c3cc2F)C1=O
Reactant: CS(=O)(=O)NN1C(=O)CSC1=O
Product: CS(=O)(=O)NN1C(=O)S/C(=C\c2cc3cnn(Cc4ccc(Cl)cc4C(F)(F)F)c3cc2F)C1=O

Procedure:
N-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-6-fluoro-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methanesulfonamide was prepared from N-(2,4-dioxothiazolidin-3-yl)methanesulfonamide (from Example 360) and [4-chloro-2-(trifluoromethyl)benzyl]-6-fluoro-1H-indazol-5-carbaldehyde (from Example 348) following General Procedure E.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])[C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[OH:19])[CH2:15][CH2:14][CH2:13]2)=O)([CH3:4])([CH3:3])[CH3:2].[C:28](OCC)(=[O:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C1CCN2C(=NCCC2)CC1>>[C:24]([C:21]1[CH:20]=[C:7]([C:8]2[C:10]3[CH:11]=[C:12]4[CH2:13][CH2:14][CH2:15][C:16]4=[CH:17][C:18]=3[O:19][C:28](=[O:35])[C:29]=2[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:22]=1[OH:23])([CH3:26])([CH3:27])[CH3:25]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C)c1cc(C(=O)c2cc3c(cc2O)CCC3)cc(C(C)(C)C)c1O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1c(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cc3c(cc2oc1=O)CCC3
Yield: 87.7 %

Procedure:
A mixture of 5- (3,5-di-tert-butyl-4-hydroxybenzoyl)-6-hydroxyindan (2.8 g), diethyl malonate (3.6 g) and DBU (0.12 ml) was heated at 160°-170° C. for 2 hours. After cooling, the resulting crystals were collected by filtration and washed with ethanol to give ethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta [g] [1]benzopyran-3-carboxylate (3.1 g, 87.8%). Recrystallization from ethanol gave colorless prisms, m.p. 208°-209° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)O.S(Cl)([Cl:27])=O>ClC(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[CH:8]([Cl:27])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: O=c1cnn(-c2ccc(C(O)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=c1cnn(-c2ccc(C(Cl)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Reaction time: 3 h
Yield: 83.1 %

Procedure:
To a stirred mixture of 16 parts of 2-[3-chloro-4-[(4-chlorophenyl)hydroxymethyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione and 150 parts of trichloromethane were added dropwise, during a period of 5 minutes, 16 parts of thionyl chloride. Upon completion, stirring was continued for 3 hours at reflux temperature. The reaction mixture was evaporated in vacuo. Methylbenzene was added and the whole was evaporated again, yielding 14 parts (83.1%) of 2-[3-chloro-4-[chloro(4-chlorophenyl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione as a residue (intermediate 107).
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:12])=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.OS(O)(=O)=O.[CH3:18][CH2:19]O>CCOC(C)=O>[Cl:1][C:2]1[C:3]([I:12])=[C:4]([CH2:8][C:9]([O:11][CH2:18][CH3:19])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)Cc1cccc(Cl)c1I
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cccc(Cl)c1I
Temperature: 25 °C

Procedure:
A mixture of 2-(3-chloro-2-iodophenyl)acetic acid (3.2 g, 11 mmol) in 50 mL EtOH was treated with 2 mL con. H2SO4, and refluxed for 2 hours. The mixture was cooled to room temperature, diluted with 200 mL EtOAc, washed with water (3×50 mL), saturated NaCl (20 mL), dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by column chromatography (10-20% EtOAc/hexane) to give 3.62 g pale yellow oil. MS m/e: (M+H)+ 325.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[N+:4]([O-])[C:3]=1[C:10]#[N:11].C(=O)(O)[O-].[Na+].[C:17]([O:20]C(=O)C)(=[O:19])[CH3:18]>>[C:17]([O:20][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([C:10]#[N:11])[N:4]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(C)[n+]([O-])c1C#N
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)OCc1ccc(C)c(C#N)n1
Temperature: 0 °C
Yield: 67 %

Procedure:
To acetic anhydride (20 ml) at 120° was added 3,6-dimethyl-2-pyridine-carbonitrile 1-oxide (5.28 g) and the solution heated at 120° for 5 minutes then under reflux for 2 hours. After cooling the solution was added to ice (ca. 150 g) and the mixture neutralized with sodium bicarbonate. It was extracted with ether (170 ml then 2×75 ml) and the combined extracts washed with brine (60 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by Biotage chromatography eluting with 2:1 hexane:ethyl acetate to afford the title compound (3.62 g, 67%) as a pale yellow oil
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[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[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[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1cnc2ccccc2c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cnc4ccccc4c3)c2cc1OC
Temperature: 140 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (243 mg), 3-hydroxyquinoline (100 mg), and 4-dimethylaminopyridine (348 mg) were dissolved in o-dichlorobenzene (13 ml) to prepare a solution which was stirred at 140° 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 thin layer chromatography using acetone-chloroform to give the title compound (213 mg, yield 93%).