Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([Mg]Br)C.C(OCC)C.IC>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CI
Product: Cc1c[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
To a solution of 5-benzyloxyindole (19.8 g, 88.68•mmol) in THF (200 mL) pre-cooled with an ice bath, was added a 3.0 M solution of ethyl magnesium bromide in diethyl ether (44.3 mL, 133.02 mmol). The ice bath was removed and the resulting mixture was gradually warmed to rt over 5 h. The reaction mixture was cooled to 0° C. and iodomethane (37.8 g, 266.04 mmol) was added. The mixture was warmed to rt and stirred for 12 h. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride solution (50 mL). The reaction mixture was diluted with diethyl ether (150 mL), and then washed with water and a brine solution consecutively. The combined organic layers were dried over magnesium sulfate, filtered, and then concentrated via rotary evaporation to give a dark brownish solid. The crude mixture was purified on silica gel (95:5 hexane:dichloromethane) to give the title compound (12.6 g, 60%) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 7.79 (br s, 1H), 7.50 (d, 2H), 7.45 (m, 3H), 7.32 (s, 1H), 7.11 (d, 1H), 6.95 (m, 2H), 5.13 (s, 2H), 2.31 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14]S(C1C=CC(C)=CC=1)(=O)=O)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)=[O:35].[OH-].[Na+]>CN(C)C(=O)C>[Cl:13][C:10]1[CH:9]=[C:8]2[C:7]([C:6]([CH2:5][C:4]([OH:3])=[O:25])=[C:33]([C:34](=[O:35])[C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)[NH:14]2)=[CH:12][CH:11]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CCOC(=O)C=Cc1ccc(Cl)cc1NS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(O)Cc1c(C(=O)c2ccc(Cl)cc2)[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.7 %

Procedure:
To a solution of 3-[4-chloro-2-(toluene-4-sulfonylamino)-phenyl]-acrylic acid ethyl ester (13.0g, 34.2 mmol) in N,N-dimethylacetamide (120 ml) was added potassium carbonate (9.45 g, 68.4 mmol) and 2-bromo-4′-chloroacetophenone (8.78 g, 37.6 mmol) and the reaction was stirred at room temperature for 15 minutes. 1N Sodium hydroxide (130 ml) was added and the reaction mixture was heated to 100° C. for 8 hours. The reaction mixture was cooled to room temperature and poured into a separatory funnel and washed with methyl t-butyl ether (2×200 ml). The aqueous layer was acidified to pH 1 with 6N hydrochloric acid and was extracted with ethyl acetate (150 ml). The solvent was removed under reduced pressure and to the resulting oil was added isopropyl alcohol (24 ml) and water (48 ml). A solid precipitated and the slurry was stirred 12 hours. The precipitate was filtered, washed with water, and dried to provide [6-chloro-2-(4-chloro-benzoyl)-1H-indol-3-yl]-acetic acid (9.73 g, 82%). mp 181-183° C. 1H NMR (400 MHz, d6-DMSO) d 3.79 (s, 2), 7.08 (dd, 1, J=8.5, 1.9), 7.42 (d, 1, J=1.9), 7.60 (d, 2, J=8.5), 7.62-7.73 (m, 3), 11.74 (bs, 1), 12.22 (bs, 1). 13C NMR (75 MHz, d6-DMSO) d 31.74, 113.25, 118.00, 121.93, 123.96, 127.69, 130.10, 131.30, 132.02, 133.59, 138.02, 138.37, 138.58, 173.20, 188.29. IR 3314, 1710, 1700, 1618, 1522, 1323, 1227, 1093, 941 cm−1. Analysis calculated for C17H11Cl2NO3: C, 58.64; H, 3.18; N, 4.02. Found: C, 58.58; H, 3.22; N, 3.93.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>C(O)C.[Pd]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:3][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1ccc(-n2cncn2)cc1F
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(-n2cncn2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
1-(3-Fluoro-4-nitrophenyl)-1H-1,2,4-triazole (3.06 g) was dissolved in ethanol (100 ml) and admixed with 10% Pd/C (50% water, 612 mg) and then stirred under a hydrogen atmosphere at room temperature for 1 hour. After filtering the catalyst off, the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and the resultant solution as washed successively with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1:2). A desired fraction was concentrated under reduced pressure and the residue was crystallized from a mixture of ethyl acetate and diisopropyl ether to yield 1-(4-amino-3-fluorophenyl)-1H-1,2,4-triazole (1.68 g) as yellow powdery crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([NH:18][C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][N:21]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:20]1)=[O:17].[H-].[Na+].[CH3:42]I>CN(C=O)C.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][N:21]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:20]1)=[O:17]
Reactant: COCCCCn1c(C(=O)N[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Reactant: CI
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCCn1c(C(=O)N(C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl (3S,5R)-3-({[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}amino)-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (290 mg) was dissolved in DMF (5 ml), sodium hydride (60% in oil) (880 mg) was added, and the mixture was stirred at room temperature for 1 hr. Methyl iodide (98 μl) was added and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9-7:3) was concentrated under reduced pressure to give the object product (225 mg).
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][N:20]=2)[C:10]([O:12]C2C=CC=CC=2)=O)C=CC=CC=1.[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32][NH2:33])[CH3:28]>CN(C)C=O>[Cl:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:10]([NH:33][CH2:32][CH2:31][CH2:30][N:29]([CH2:34][CH3:35])[CH2:27][CH3:28])=[O:12])[CH:24]=1
Reactant: CCN(CC)CCCN
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Cl)ccn1
Solvent: CN(C)C=O
Product: CCN(CC)CCCNC(=O)Nc1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
Phenyl(4-chloropyridin-2-yl)-N-(phenoxycarbonyl)carbamate (738 mg, 2.00 mmol) was dissolved in N,N-dimethylformamide (8.0 ml); N,N-diethyl-1,3-diaminopropane (1.57 ml, 10.0 mmol) was added thereto; and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between water and ethyl acetate; and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia NH, hexane-ethyl acetate-methanol system) to yield the title compound (309 mg, 1.09 mmol, 54.3%) as a pale brown oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([C:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](O)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1>[C:23]1([C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:14][OH:15])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 49.3 %

Procedure:
To a suspension of LAH (3.9 g, 0.104 mol) in dry THF (200 mL) was stirred at 0° C. for 20 min. A solution of 2,2,2-triphenylacetic acid (10 g, 0.034 mol) in dry THF (50 mL) was added in a drop-wise manner. The reaction mixture was stirred at RT overnight. Excess LAH was quenched with 1.5 N HCl and the reaction mixture was further stirred for 2 h at RT. The reaction mixture was filtered through celite, washed with ethyl acetate and the filtrate was concentrated under vacuum. The crude product was purified by column chromatography on silica gel (4% ethyl acetate in pet ether) to give the title compound (4.6 g, 48%). TLC: Pet. ether/EtOAc, 7:3, Rf=0.2
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24](O)=[O:25])[CH2:9]2)=[O:7])[CH2:3]1.O[N:28]=[C:29]([CH:31]1[CH2:33][CH2:32]1)[NH2:30]>>[CH:31]1([C:29]2[N:30]=[C:24]([CH:10]3[CH2:11][CH:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:16][CH:15]=4)[CH2:13][N:8]([C:6]([N:4]4[CH2:5][CH:2]([OH:1])[CH2:3]4)=[O:7])[CH2:9]3)[O:25][N:28]=2)[CH2:33][CH2:32]1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Reactant: NC(=NO)C1CC1
Product: O=C(N1CC(O)C1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1

Procedure:
100 mg (0.269 mmol) of 1-[(3-hydroxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 101A) and 29.6 mg (0.295 mmol) of N′-hydroxycyclopropanecarboximidamide (Example 78A) were reacted according to the General Method 1. Yield: 54 mg (44% of theory).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=O.[Cl:13][C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH2:22][C:23]#[N:24])[CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:25])[C:22]([C:23]#[N:24])=[CH:7][C:6]2[CH:5]=[C:4]([O:10][CH3:11])[C:3]([OH:12])=[C:2]([Br:1])[CH:9]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: N#CCC(=O)Nc1cccc(Cl)c1
Reactant: COc1cc(C=O)cc(Br)c1O
Product: COc1cc(C=C(C#N)C(=O)Nc2cccc(Cl)c2)cc(Br)c1O
Yield: 64.9 %

Procedure:
The reaction was performed in the same manner as in Example 1 with 5-bromovanillin (1.38 g, 5.97 mmol) and N-(3-chlorophenyl) cyanoacetamide (1.16 g, 5.97 mmol) to give the objective N-(3-chlorophenyl)-2-cyano-3-(3-bromo-4-hydroxy-5-methoxyphenyl) propenamide (1.58 g, 65% in yield).
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([O:9][P:10]([CH2:15][CH2:16][NH2:17])(=[O:14])[O:11][CH2:12][CH3:13])[CH3:8].[C:18]([CH:22]1[CH2:27][CH2:26][CH:25]([O:28][C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[CH:35]=[C:34]([CH:39]=O)[CH:33]=[CH:32]3)[CH2:24][CH2:23]1)([CH3:21])([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:12]([O:11][P:10]([CH2:15][CH2:16][NH:17][CH2:39][C:34]1[CH:33]=[CH:32][C:31]2[C:36](=[CH:37][CH:38]=[C:29]([O:28][C@H:25]3[CH2:26][CH2:27][C@H:22]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:23][CH2:24]3)[CH:30]=2)[CH:35]=1)(=[O:14])[O:9][CH2:7][CH3:8])[CH3:13]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Reactant: CCOP(=O)(CCN)OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOP(=O)(CCNCc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2-amino-ethyl)-phosphonic acid diethyl ester oxalic acid salt (200 mg, 0.74 mmol) in 1,2-dichloroethane (3 mL) was added 6-(4-tert-butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (343 mg, 1.1 mmol). The mixture was stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (329 mg, 1.5 mmol) was added. After being stirred at room temperature overnight, the reaction mixture was quenched with water, stirred at room temperature for 30 min, then diluted with ethyl acetate, and washed with aqueous NaHCO3. The organic layer was dried over MgSO4 and purified with a silica gel column eluted with ethyl acetate (100%), then eluted with methanol in dichloromethane from 0 to 15% to give sticky oil (130 mg, yield: 25%). ESI-MS: 476.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[CH:14][C:13]=2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[ClH:37].CCOCC>CO.C(OCC)(=O)C>[ClH:37].[N:18]1([C:15]2[CH:16]=[CH:17][C:12]([NH:11][S:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)(=[O:9])=[O:10])=[C:13]([NH:32][S:33]([CH3:36])(=[O:34])=[O:35])[CH:14]=2)[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(N3CCCN(C(=O)OC(C)(C)C)CC3)cc2NS(C)(=O)=O)cc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)Nc2ccc(N3CCCNCC3)cc2NS(C)(=O)=O)cc1
Reaction time: 2 h

Procedure:
tert-Butyl 4-{4-{[(4-methylphenyl)sulfonyl]amino}-3-[(methylsulfonyl)amino]phenyl}-1,4-diazepane-1-carboxylate (0.5 g) was dissolved in methanol (15 mL). A solution of HCl in ethyl acetate (1N, 25 mL) was added and the mixture stirred for 2 hours. Ether (200 mL) was added and the mixture stirred for 3 hours to allow full precipitation. The product was collected by filtration, washed with ether and dried. Yield 0.43 g (98%) 1H NMR (400 MHz, DMSO-d6) δ 2.03 (m, 2 H), 2.36 (s, 3 H), 2.9 (s, 3 H), 3.02-3.09 (br m, 2 H), 3.11-3.19 (br m, 2 H), 3.41 (br t, J=7.08 Hz, 2 H), 3.63 (br m, 2 H), 6.46 (d ab, J=2.8 Hz, 8.8 Hz, 1 H), 6.62 (ab, J=8.8 Hz, 1 H), 6.71 (d, J=2.8 Hz, 1 H), 7.36 (ab, J=8.3 Hz, 2 H), 7.58 (ab, J=8.3 Hz, 2 H), 8.39 (s, 1 H), 9.2 (br, 2 H), 9.8 (s, 1 H);
Reaction SMILES: [CH3:1][C:2]([CH2:15][CH2:16][C:17]([CH3:21])=[C:18]([CH3:20])[CH3:19])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[O:30]1[C:18]([CH3:20])([CH3:19])[C:17]1([CH3:21])[CH2:16][CH2:15][C:2]([CH3:1])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1
Reactant: CC(=CCOc1ccc2c(c1)OCO2)CCC(C)=C(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=CCOc1ccc2c(c1)OCO2)CCC1(C)OC1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice cold solution containing 10.4 g. of 3,6,7-trimethyl-1-[3,4-(methylenedioxy)-phenoxy]-2,6-octadiene in 100 ml. of methylenechloride, 7 g. of m-chloroperbenzoic acid were added portionwise. After this addition, the reaction mixture was allowed to stand for 2 hours at 0° to 3°C. under constant stirring. After this period, the reaction mixture was diluted with 250 ml. of diethylether, and washed with ice cold 1N sodium hydroxide and saturated aqueous sodium chloride solution. After washing, the reaction mixture was dried over sodium sulfate and evaporated. By chromatography on Kieselgel with hexane-diethylether (4:1 parts by volume) and distillation under vcuum, there was obtained pure 6,7-epoxy-3,6,7-trimethyl-1-[3,4-(methylenedioxy)-phenoxy]-2-octene; b.p. 120°-122°C./0.004 mmHg; nD20 = 1.5277.
Reaction SMILES: [CH:1]1([NH:6][CH2:7][C:8]([F:14])([F:13])[C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[Cl:21][C:22]1[N:27]=[C:26](Cl)[C:25]([N+:29]([O-:31])=[O:30])=[CH:24][N:23]=1>CC(C)=O.CCOC(C)=O>[Cl:21][C:22]1[N:27]=[C:26]([N:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:7][C:8]([F:13])([F:14])[C:9]([O:11][CH3:12])=[O:10])[C:25]([N+:29]([O-:31])=[O:30])=[CH:24][N:23]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: COC(=O)C(F)(F)CNC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Compound methyl 3-(cyclopentylamino)-2,2-difluoropropanoate (400 mg, 2 mmol) was solubilized in acetone (20 mL, dry). The solution was cooled in an ice water bath under a nitrogen atmosphere and K2CO3 (552 mg, 4 mmol) added. To this, a solution of 2,4-dichloro-5-nitropyrimidine (407 mg, 2.1 mmol) in acetone (5 mL, dry) was added dropwise. The reaction mixture was warmed up to room temperature and stirred for 4 hr. After that, it was diluted with EtOAc and washed by brine and water. The organic extracts were dried over MgSO4, filtered and concentrated to yield the desired product which was used directly for next step without further purification. [M+H] calc'd for C13H15ClF2N4O4, 365; found 365.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)=[O:11])=[N:7][CH:8]=1.Br[CH2:25][C:26](=O)[CH2:27][CH3:28].C([O-])(O)=O.[Na+]>CC(C)=O>[CH2:27]([C:26]1[C:9]([C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)=[O:11])=[C:6]2[N:7]([CH:25]=1)[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5]2)[CH3:28]
Reactant: CCC(=O)CBr
Reactant: COc1ccc(CC(=O)c2cc(OC)c(OC)c(OC)c2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCc1cn2cc(OC)ccc2c1C(=O)c1cc(OC)c(OC)c(OC)c1
Yield: 91.4 %

Procedure:
A mixture of A mixture of 2-(5-methoxypyridin-2-yl)-1-(3,4,5-trimethoxyphenyl)ethanone (0.200 g, 0.631 mmol), 1-bromo-2-butanone (0.190 g, 1.3 mmol), and NaHCO3 (0.212 g, 2.6 mmol) in acetone (5 mL) was heated under reflux for 20 h. The precipitate was removed by filtration. The filtrate was concentrated to give a residue, which was purified on a silica gel column eluting with CH2Cl2 to afford compound 6 (0.213 g, 92%).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:25])[N:3]=1.C([Sn](CCCC)(CCCC)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)CCC.CCOC(C)=O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:25][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[C:11]([CH:12]([N:14]1[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]1=[O:24])[CH3:13])[C:2]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)=[N:3]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CC(c1cc2c(Cl)cccc2nc1Cl)N1C(=O)c2ccccc2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(c1cc2c(Cl)cccc2nc1-c1ccccn1)N1C(=O)c2ccccc2C1=O
Temperature: 110 °C
Reaction time: 0.01 h

Procedure:
Transferred 2-(1-(2,5-dichloroquinolin-3-yl)ethyl)isoindoline-1,3-dione (197 mg, 531 μmol) from 100 mL flask to 10 mL flask by dissolving/slurrying in toluene and concentrating. Added Pd(Ph3P)4 (61 mg, 53 μmol) and 2-tri-n-butylstannylpyridine (955 μl, 2653 μmol). Bubbled argon through mixture for 30 sec. Equipped with condensor and nitrogen inlet. Heated at 110° C. for ˜16 h. The reaction mixture was concentrated and chromatographed on 12 g silica gel column with 0-60% EtOAc. The desired fractions were combined and concentrated to yield an oil. NMR indicates residual EtOAc. LC. 1H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 1.98 (d, J=7.04 Hz, 3 H) 6.38 (q, J=7.04 Hz, 1 H) 7.24-7.37 (m, 1 H) 7.62-7.76 (m, 8 H) 8.01 (dd, J=8.61, 1.96 Hz, 1 H) 8.56-8.66 (m, 1 H) 9.02 (s, 1 H).−MS (+esi, M+H+=414.1)
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH2:12][C:13]3[N:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([CH3:19])[CH:18]=3)[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>>[CH3:19][C:17]1[CH:18]=[C:13]([CH2:12][N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:26]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:27])[C:7]=3[CH2:8]2)[N:14]=[N:15][C:16]=1[O:20][CH2:21][C:22]([F:25])([F:24])[F:23]
Reactant: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)nnc1OCC(F)(F)F
Reactant: O=COc1ccccc1
Product: Cc1cc(CN2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)nnc1OCC(F)(F)F
Yield: 64 %

Procedure:
The title compound is prepared in 64% yield (130 mg, colorless solid) from 4-chloro-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (170 mg, 0.46 mmol, Intermediate-67) and phenyl formate (110 mg, 0.91 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][C:9]=3[NH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BrH:19].[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl.O1CCCC1>[Br:19][C:11]1[NH:10][C:9]2[CH:12]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[S:14][C:8]=2[C:7]=1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1cc2[nH]cc(C3CCCCC3)c2s1
Reactant: Br
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)c1cc2[nH]c(Br)c(C3CCCCC3)c2s1
Yield: 73 %

Procedure:
To a solution of methyl 6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate obtained in Step 7 in chloroform (90 ml) and tetrahydrofuran (90 ml) was added pyridinium hydrobromide perbromide (21.7 g, 68 mmol) under ice-cooling. The mixture was stirred under ice-cooling for 2 hr and concentrated under reduced pressure at room temperature. Ethyl acetate (300 ml) was added to the residue, and the mixture was washed successively with 1M aqueous sodium hydrogen sulfite solution (100 ml×3), water (100 ml), saturated aqueous sodium hydrogen carbonate solution (100 ml×2) and saturated brine (100 ml), and dried over magnesium sulfate. The mixture was filtered and concentrated under reduced pressure, and the obtained solid was washed with a mixed solvent (100 ml) of n-hexane:ethyl acetate (25:1). The solid was collected by filtration, and dried under reduced pressure to give methyl 5-bromo-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (17 g, yield 73%).
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[OH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[OH:21])[CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.O>C(Cl)(Cl)Cl.S(=O)(=O)(O)O>[C:2]([C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][C:12]3[C:17](=[C:16]([OH:21])[CH:15]=[CH:14][CH:13]=3)[C:18](=[O:20])[C:19]=2[C:6]=1[OH:5])([CH3:3])([CH3:1])[CH3:4]
Reactant: C=C(C)C
Reactant: O=C1c2c(O)cccc2Cc2cccc(O)c21
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)c1ccc2c(c1O)C(=O)c1c(O)cccc1C2
Yield: 27.7 %

Procedure:
About 7 gm of isobutylene were introduced into a refluxing solution of 11.3 gm of 1,8-dihydroxy-9-(10H)anthracenone in 100 ml of chloroform and 6 ml of sulfuric acid. The resulting mixture was poured into water, and the organic phase was separated and worked up as described in Example 2. 3.9 gm of 2-tert. butyl-1,8-dihydroxy-9-(10H)anthracenone, m.p. 126°-127° C., corresponding to 27% of theory, were obtained.