Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].CC(=CC)C.B(F)(F)F.CCOCC.[C:17]1([C:23]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:24][CH:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:26]#[CH:27])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[I:45]I>O1CCCC1.COCCOCCOC>[I:45]/[CH:27]=[CH:26]/[CH:25]([O:24][C:23]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: II
Reactant: C#CC(CCCCC)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC=C(C)C
Agent: FB(F)F
Agent: [BH4-]
Solvent: COCCOCCOC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCC(/C=C/I)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 0.650 g. (16.91 mmole) of sodium borohydride and 3.17 g. (45.2 mmoles) of 2-methyl-2-butene in 40 ml. of diglyme cooled to -5° C. under an inert atmosphere is added over 15 minutes 3.24 g. (22.6 mmoles) of boron trifluoride etherate and the resulting mixture is stirred at 0° C. for 2 hours. To this mixture is then added over 5 minutes 8.32 g. (22.6 mmoles) of 3-triphenylmethoxyl-1-octyne (Example 127) in 10 ml. diglyme, the cooling bath is removed, and the mixture is stirred at ambient temperature for 1.5 hours. The mixture is cooled to 0° C. and 6.0 g. of finely divided anhydrous trimethylamine oxide is added over 10 minutes. The cooling bath is removed and the mixture is stirred at ambient temperatures for 0.5 hour. The mixture is then poured into 200 ml. of 15 % sodium hydroxide solution, a solution of 16 g. (63 mmoles) of iodine in 20 ml. of tetrahydrofuran is added immediately, and the resulting mixture is stirred for 0.5 hour. The organic phase is separated and the aqueous phase is washed with ether. The combined organic phase and washings are decolorized with 5% sodium thiosulfate solution, washed with saturated brine, dried (Na2SO4), and evaporated. The residue is dry-columned chromatographed upon alumina using hexane as eluent and the title compound is isolated as an oil.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:17][O:18][C:19](=[O:45])[C:20]([CH3:44])([CH3:43])[CH2:21][O:22][C:23]1[N:28]=[CH:27][C:26]([C:29]2[CH:38]=[C:37]3[C:32]([C:33]([C:40](O)=[O:41])=[CH:34][C:35]([CH3:39])=[N:36]3)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1>CN(C)C=O>[CH3:44][C:20]([CH3:43])([CH2:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:38]=[C:37]3[C:32]([C:33]([C:40](=[O:41])[NH:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:34][C:35]([CH3:39])=[N:36]3)=[CH:31][CH:30]=2)=[CH:27][N:28]=1)[C:19]([O:18][CH3:17])=[O:45]
Reactant: Nc1ccccc1
Reactant: COC(=O)C(C)(C)COc1ccc(-c2ccc3c(C(=O)O)cc(C)nc3c2)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)COc1ccc(-c2ccc3c(C(=O)Nc4ccccc4)cc(C)nc3c2)cn1
Reaction time: 8 h
Yield: 88 %

Procedure:
N-Ethyl-N,N-diisopropylamine (64.5 mg, 0.50 mmol) was added at room temperature to a solution of aniline (465.0 mg, 0.50 mmol), 7-(6-(3-methoxy-2,2-dimethyl-3-oxopropoxy)pyridin-3-yl)-2-methylquinoline-4-carboxylic acid B-15 (98.8 mg, 0.25 mmol) and N,N,N′N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (190.0 mg, 0.50 mmol) in anhydrous N,N-dimethylformamide (5.0 mL) under an atmosphere of nitrogen. The reaction mixture was stirred overnight, then partitioned between methylene chloride (30 mL) and an aqueous solution of pH 7 phosphate buffer (30 mL). The aqueous layer was extracted with methylene chloride (3×30 mL); the combined extracts were successively washed with water (30 mL), brine (30 mL), then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (hexanes:ethyl acetate gradient) to give methyl 2,2-dimethyl-3-(5-(2-methyl-4-(phenylcarbamoyl)quinolin-7-yl)pyridin-2-yloxy)propanoate B-16 (103.4 mg, Yield=88%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.37 (s, 6H), 2.83 (s, 3H), 3.73 (s, 3H), 4.42 (s, 2H), 6.90 (d, J=8.5 Hz, 1H), 7.26-7.29 (m, 1H), 7.45-7.48 (m, 3H), 7.73-7.77 (m, 2H), 7.88 (s, 1H), 7.95 (q, J=6.0 Hz, 1H), 8.23 (s, 1H), 8.32 (d, J=8.5 Hz, 1H), 8.54 (s, 1H); MS (ESI) [M+1]+ 470.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH2:15].[C:17]([CH:20]1[CH2:25][CH2:24][O:23][C:21]1=[O:22])(=O)[CH3:18]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]1([CH3:16])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][C:17](=[C:20]1[CH2:25][CH2:24][O:23][C:21]1=[O:22])[CH3:18]
Reactant: Cc1cc(C)c(-c2ccncc2N)c(C)c1
Reactant: CC(=O)C1CCOC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(Nc1cnccc1-c1c(C)cc(C)cc1C)=C1CCOC1=O
Yield: 77.5 %

Procedure:
p-Toluenesulfonic acid monohydrate (0.2 g, 1.18 mmol) was added to a solution of 4-mesityl-3-pyridinamine (5.0 g, 24 mmol) and α-acetyl-γ-butyrolactone (6.0 g, 47 mmol) in toluene (100 mL), followed by heating under reflux for three days while removing water using a Dean-Stark apparatus. The mixture was evaporated, and the resulting crystals were washed with 60% diethyl ether/ethyl acetate, to give the title compound (6.0 g) as white crystals.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([NH:16][C:17]([C:19]2[CH:20]=[C:21]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[F:33])[CH:22]=[CH:23]C=2O)=[O:18])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].Cl>O1CCCC1.N1C=CC=CC=1>[F:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[C:21]1[CH:22]=[CH:23][C:5]2[O:4][C:2](=[O:3])[N:16]([C:10]3[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([O:7][CH3:6])[CH:9]=3)[C:17](=[O:18])[C:19]=2[CH:20]=1
Reactant: COc1ccc(NC(=O)c2cc(-c3ccc(F)cc3F)ccc2O)cc1OC
Reactant: COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(-n2c(=O)oc3ccc(-c4ccc(F)cc4F)cc3c2=O)cc1OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 43 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 11 (1.54 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 23.
Reaction SMILES: [CH:1]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:45](=[O:58])[NH:46][CH2:47][CH2:48][C:49](=[O:57])[O:50]CC[Si](C)(C)C)[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:44])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[CH:16]([C:29]1[CH:43]=[CH:42][C:32]([C:33]([O:35]CC[Si](C)(C)C)=[O:34])=[CH:31][CH:30]=1)[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:49]([CH2:48][CH2:47][NH:46][C:45]([C@:7]12[CH2:6][CH2:5][C@@H:4]([CH:1]([CH3:3])[CH3:2])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:44])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:28])([CH3:27])[CH:16]([C:29]2[CH:43]=[CH:42][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)=[O:58])([OH:57])=[O:50]
Reactant: CC(C)[C@@H]1CC[C@]2(C(=O)NCCC(=O)OCC[Si](C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(c6ccc(C(=O)OCC[Si](C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)[C@@H]1CC[C@]2(C(=O)NCCC(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 52882.4 %

Procedure:
2-(trimethylsilyl)ethyl 4-((1S,3aS,5aR,5bR,7aS,11aS,11bR,13aR,13bR)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3a-(3-oxo-3-(2-(trimethylsilyl)ethoxy)propylcarbamoyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (14 mg, 0.017 mmol) was dissolved in THF (Volume: 0.5 mL) and treated with TBAF (0.5 mL, 0.500 mmol). The mixture was stirred at rt for 1 h. The solvent was removed in vacuo and the residue was dissolved in DMF and purified using reverse phase prep HPLC to afford 4-((1S,3aS,5aR,5bR,7aS,11aS,11bR,13aR,13bR)-3a-(2-carboxyethylcarbamoyl)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (6 mg, 8.99 mmol, 53.6% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.82 (d, J=8.28 Hz, 2H), 7.56 (t, J=5.52 Hz, 1H), 7.29 (d, J=8.28 Hz, 2H), 3.37-3.11 (m, 2H), 2.65-2.56 (m, 1H), 2.47-2.39 (m, 1H), 2.39-2.31 (m, 2H), 2.28-2.18 (m, 1H), 2.18-2.08 (m, 2H), 1.84-0.97 (m, 22H), 0.94 (s, 6H), 0.91 (s, 3H), 0.83 (d, J=6.78 Hz, 3H), 0.74 (d, J=6.78 Hz, 3H), 0.72 (s, 3H), 0.67 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[C:4]([F:18])[C:3]=1[F:19].[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([C:27](O)=[O:28])[C:23](=[O:30])[N:22]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([C:27]([NH:1][C:2]2[CH:17]=[CH:16][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=3)=[C:4]([F:18])[C:3]=2[F:19])=[O:28])[C:23](=[O:30])[N:22]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NC(=O)c1cc(Oc2ccc(N)c(F)c2F)ccn1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)c(F)c2F)c(=O)n(-c2ccccc2)n1C
Temperature: 45 °C
Reaction time: 12 h
Yield: 33.1 %

Procedure:
To a suspension of 4-(4-amino-2,3-difluorophenoxy)picolinamide (180 mg, 0.68 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (161 mg, 0.69 mmol) in DCM (4 mL) was added EDCI (157 mg, 0.82 mmol) and HOAT (19 mg, 0.14 mmol). The mixture was stirred at 45° C. for 12 hours, then more 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (87 mg, 0.37 mmol) was added and the reaction was further stirred at 45° C. for 5 hours. The mixture was cooled to rt, quenched with 5 mL of water, and extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (10 mL×3), dried over Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc 100%) to give the title compound as an orange solid (108 mg, 33.2%).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].C(N(CC)CC)C.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:30]>O1CCCC1>[CH:9]1([C:7]2[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH3:19])[C:3](=[O:20])[CH:2]([NH:1][C:29]([O:31][C:32]3[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=3)=[O:30])[N:8]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: CN1C(=O)C(N)N=C(C2CCCCC2)c2ccccc21
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1C(=O)C(NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(C2CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.6 %

Procedure:
A solution of 3(R,S)-amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (1.0 g) in anhydrous tetrahydrofuran (20 ml) under an atmosphere of nitrogen at 0° C. was treated with triethylamine (0.51 ml), followed by a solution of 4-nitrophenyl chloroformate (0.75 g) in anhydrous tetrahydrofuran (10 ml) dropwise. After stirring at ambient temperature for 20 min, the solid which precipitated from the mixture was filtered and the filtrate was evaporated in vacuo. The residue was triturated with diethyl ether to give the title compound (1.2 g, 75%) as a colourless solid. Mp 165°-168° C. 1H NMR (360 MHz, CDCl3) δ 1.05 (1H, m), 1.18-1.42 (3H, m), 1.55 (1H, m), 1.65 (3H, m), 1.87 (1H, m), 2.05 (1H, m), 2.80 (1H, m), 3.43 (3H, s), 5.18 (1H, d, J=8.3 Hz), 6.90 (1H, d, J=8.2 Hz), 7.30 (4H, m), 7.57 (2H, m), 8.23 (2H, d, J=7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([N:14]2[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]2)[N:5]=[C:4]([NH:21][C:22]#[N:23])[N:3]=1.O.[C:25](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:6]([N:14]2[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]2)[N:5]=[C:4]([N:21]([C:22]#[N:23])[CH3:25])[N:3]=1
Reactant: CC1CCN(c2nc(NC#N)nc(Cl)c2-c2ccccc2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1CCN(c2nc(N(C)C#N)nc(Cl)c2-c2ccccc2)CC1
Reaction time: 0.08 h
Yield: 86.3 %

Procedure:
To a solution of 4-chloro-2-(N-cyanoamino)-6-[(4-methyl)-piperidin-1-yl]-5-phenylpyrimidine (0.1 g, 0.305 mmol) in dimethylformamide (4 ml) at room temperature was added water (2 ml) followed by potassium carbonate (0.084 g, 0.61 mmol) and the resulting suspension was warmed gently to afford a clear solution. To the cooled solution was then added methyl iodide (0.076 ml, 1.22 mmol) and the reaction mixture stirred at room temperature for 2.5 hours. The reaction was then quenched by the addition of saturated aqueous ammonium chloride solution (40 ml). After adding ethyl acetate (40 ml) the biphasic mixture was stirred for 5 minutes. The organic phase was then separated, washed with saturated brine (50 ml), dried over magnesium sulfate and concentrated in vacuo to afford a yellow syrup. The crude product was chromatographed an silica gel eluting with 90:10 v/v hexane: ethyl acetate to afford 0.09 g (87% yield) of the title compound as a colorless syrup.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>ClCCl>[CH3:19][C:18]([CH3:21])([CH3:20])[C:17]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:22]
Reactant: Nc1cccnc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution containing 50 g (531 mmol) of 3-aminopyridine and 139 mL (797 mmol) of N,N-diisopropylethylamine in 800 mL of dichloromethane at 0° C. was carefully added through an addition funnel 72 mL (584 mmol) of pivaloyl chloride. The reaction mixture was stirred at 0° C. for 30 min then concentrated in vacuo. To the residue was added 600 mL of ethyl acetate and the organic solution was washed sequentially with water, 0.5N aqueous sodium bicarbonate solution and saturated aqueous brine (300 mL each). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. To the crude solid was added 150 mL of ethyl acetate. The mixture was stirred vigourously for 30 min, then 300 mL of hexane was added and the mixture was stirred for an additional 30 min. The resultant crystalline solid was filtered and washed with 400 mL of 10% ethyl acetate/hexane to give the title compound. 1H NMR (500 MHz, CDCl3): δ 8.57 (d, J=2.5 Hz, 1H), 8.36 (dd, J=4.8, 1.4 Hz, 1H), 8.21-8.19 (m, 1H), 7.47 (br s, 1H), 7.30-7.27 (m, 1H), 1.36 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.C([Li])CCC.[F:15][C:16]([F:24])([F:23])[C:17]([C:19]([F:22])([F:21])[F:20])=[O:18].Cl>CCCCCC.C(OCC)C>[F:15][C:16]([F:24])([F:23])[C:17]([C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1)([OH:18])[C:19]([F:22])([F:21])[F:20]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: Brc1cc(Br)cc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OC(c1cc(Br)cc(Br)c1)(C(F)(F)F)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
Under nitrogen atmosphere, a 500 mL glass flask was charged with 30.0 g (95.0 mmol) of 1,3,5-tribromobenzene and 400 mL of diethyl ether, followed by cooling to −78° C. At −78° C., 60 mL of a 1.6M solution containing 96.0 mmol of n-butyllithium in hexane was added dropwise by spending 1 hr, followed by aging at −78° C. for 1 hr. After confirming lithiation by gas chromatography, 16.6 g (100.0 mmol) of hexafluoroacetone was bubbled at −78° C., followed by stirring for 1 hr. After stirring, the reaction liquid was added to 400 mL of 2N hydrochloric acid to separate it into an organic layer and an aqueous layer. The aqueous layer was extracted with 100 mL of isopropyl ether. The combined organic layer was dried with anhydrous magnesium sulfate, followed by concentration with an evaporator and then solid distillation, thereby obtaining 23.0 g of 1-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-3,5-dibromobenzene (yield: 60%) represented by the following formula.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(O)CCCC.[OH-].[Na+].[CH3:22][C:23]1[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25]>[Cu]>[N+:11]([C:8]1[CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]([NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:29]([C:30]([F:31])([F:32])[F:33])[C:23]=2[CH3:22])=[CH:10][CH:9]=1)([O-:13])=[O:12]
Reactant: Cc1c(N)cccc1C(F)(F)F
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Cu]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCO
Product: Cc1c(Nc2ccc([N+](=O)[O-])cc2C(=O)O)cccc1C(F)(F)F

Procedure:
To a solution of 25 g. of 2-chloro-5-nitro-benzoic acid in 125 ml. of n-pentyl alcohol add 4.8 g. of sodium hydroxide pellets, 25 g. of 2-methyl-3-trifluoromethylaniline and 2 g. of copper powder. With constant stirring, reflux the reaction mixture for 18 hours. Concentrate the mixture to one half volume and dilute with water and ether. Acidify the aqueous layer to obtain a crude product which is recrystallized to yield 5-nitro-N-(2-methyl-3-trifluoromethylphenyl) anthranilic acid, m.p. 244°-245° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[C:15](F)[CH:16]=3)[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH:7]=1.[CH3:28][NH2:29]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[C:15]([NH:29][CH3:28])[CH:16]=3)[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH:7]=1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc([N+](=O)[O-])c(F)cc32)c(F)cc1F
Reactant: CN
Solvent: c1ccncc1
Product: CNc1cc2c(cc1[N+](=O)[O-])c(=O)c(C(=O)O)cn2-c1cc(N)c(F)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(5-Amino-2,4-difluorophenyl)-7-fluoro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg) was added to a mixed liquid of a 40% aqueous solution (120 mg) of methylamine and pyridine (3 ml), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure. The residue was acidified with 3% citric acid, and solids formed were collected by filtration. The solids were washed with water, ethanol and hexane to obtain the title compound (70 mg) as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][C:11](=[O:21])[C:12]2[N:13]([N:15]=[C:16]([C:18](O)=[O:19])[CH:17]=2)[CH:14]=1.C(Cl)CCl.C1C=CC2N(O)N=[N:32]C=2C=1.N.O1CCOCC1>ClCCl.CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][C:11](=[O:21])[C:12]2[N:13]([N:15]=[C:16]([C:18]([NH2:32])=[O:19])[CH:17]=2)[CH:14]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc2c(=O)[nH]c(-c3ccc(Cl)cc3Cl)cn2n1
Agent: CN(C)c1ccncc1
Agent: N
Solvent: ClCCCl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: NC(=O)c1cc2c(=O)[nH]c(-c3ccc(Cl)cc3Cl)cn2n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
360 mg (1.11 mmol) of 6-(2,4-dichlorophenyl)-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazine-2-carboxylic acid (Example 55A) were initially charged in dichloromethane (30 ml) and DMF (10 ml), and 320 mg (1.67 mmol) of EDC, 225 mg (1.67 mg) HOBt and 407 mg (3.33 mmol) of DMAP were added, followed by 0.5M ammonia in dioxane (2.44 ml, 1.22 mmol). The reaction mixture was stirred at RT for 20 h, the solvent was concentrated, the residue was poured into water (25 ml) and the precipitate was filtered off and washed with water and acetonitrile and dried. Drying gave 260 mg (72% of theory) of the product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:21])[N:12]([C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)[N:13]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27].CC([O-])(C)C.[Na+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:21])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[C:24]([C:23]([F:22])([F:31])[F:32])[CH:25]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(I)cc1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(Nc2cccc(C(F)(F)F)c2)cc1

Procedure:
To a solution of 5-(2-chloro-6-fluorophenyl)-2-(4-iodophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (step-4 of Intermediate-2, 0.100 g, 0.242 mmol) in toluene (5.0 mL) was added 3-(trifluoromethyl)aniline (0.076 g, 0.292 mmol), NaOtBu (0.035 g, 0.360 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.022 g, 0.024 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.021 g, 0.036 mmol). The reaction mixture was refluxed for 12 h. The reaction mass was quenched in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.N1C=CC=CC=1C1C=CC=CN=1.C([Li])CCC.[N+:27]([C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1C(Cl)=O)([O-:29])=[O:28].Cl>CCCCCC.O1CCCC1.C(OCC)C>[N+:27]([C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:3]([CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[O:5])([O-:29])=[O:28]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: [Li]CCCC
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CC(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The starting material is prepared as follows: The solution of 39.6 g of monoethyl malonate, 50 mg of 2,2-bipyridyl (indicator) and 650 ml of tetrahydrofuran is cooled to -70°, whereupon 305 ml of 1.97 M n-butyl lithium in hexane are added slowly under nitrogen while stirring. The temperature is allowed to rise to about -5° near the end of addition, after the pink color of the indicator persists. The mixture is recooled to -65°, and the solution of 31.7 g of o-nitrobenzoyl chloride in 50 ml of tetrahydrofuran is added dropwise within 10 minutes. The resultant mixture is stirred at room temperature for 1 hour and then poured onto a mixture of 650 ml of 1 N hydrochloric acid and 1100 ml of diethyl ether. The organic layer is separated, washed successively with 350 ml of saturated aqueous sodium bicarbonate, 400 ml of water and 200 ml of brine, dried and evaporated, to yield the ethyl 2-(o-nitrobenzoyl)-acetate, as an oil.