Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([Cl:15])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12].O.O.Cl[Sn]Cl>O.Cl>[ClH:15].[NH:5]([C:6]1[CH:7]=[CH:8][C:9]([Cl:15])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12])[NH2:1]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Cl)c(C(=O)O)c1
Temperature: -3 °C
Reaction time: 2 h
Yield: 123.1 %

Procedure:
A solution of 2.11 g of NaNO2 in 40 ml of water is added over 30 minutes to a suspension, cooled to -2° C., of 5 g of 5-amino-2-chlorobenzoic acid in 50 ml of concentrated HCl. The solution is stirred for 2 hours at -3° C. and cooled to -10° C., and a solution of 23 g of SnCl2.2H2O in 20 ml of concentrated HCl and 20 ml of water is added over 30 minutes. The mixture is stirred for one and a half hours at 0° C. and filtered, and the precipitate is dried to obtain 4 g of expected product.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)=[O:21]>>[CH3:18][O:19][C:20](=[O:21])[C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)[CH:27]=1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: COC(=O)c1cccc(-n2cnc(-c3c(-c4ccccc4)noc3C)c2)c1
Yield: 40 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 3-methoxycarbonylphenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (65 mg, 40%) which was obtained as a white solid. MS (ESI): m/e=360.0 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)=[CH:8][CH:9]=2)[N:4]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[C:10]3[C:5](=[CH:6][C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=4)=[CH:8][CH:9]=3)[N:4]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH:3]=2)=[CH:30][CH:29]=1
Reactant: O=[N+]([O-])c1cccc(-c2ccc3c(Br)cn(-c4ccncc4)c3c2)c1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cn(-c3ccncc3)c3cc(-c4cccc([N+](=O)[O-])c4)ccc23)cc1

Procedure:
The target compound was prepared as in Example 13 using 3-bromo-6-(3-nitrophenyl)-1-(pyridin-4-yl)-1H-indole (97 mg, 0.222 mmol) and 4-methoxyphenylboronic acid (37 mg, 0.244 mmol).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[CH:7]([CH2:8][C:9]4[C:18]([Cl:19])=[CH:17][C:16]([O:20][CH3:21])=[C:15]([O:22][CH2:23][C:24]([O:26]CC)=[O:25])[C:10]=4[CH2:11]3)[C:6]=2[CH:29]=1.[OH-].[Na+]>C(O)C>[OH:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[CH:7]([CH2:8][C:9]4[C:18]([Cl:19])=[CH:17][C:16]([O:20][CH3:21])=[C:15]([O:22][CH2:23][C:24]([OH:26])=[O:25])[C:10]=4[CH2:11]3)[C:6]=2[CH:29]=1
Reactant: CCOC(=O)COc1c(OC)cc(Cl)c2c1CN1CCc3cc(OC)c(O)cc3C1C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc2c(cc1O)C1Cc3c(Cl)cc(OC)c(OCC(=O)O)c3CN1CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
A product obtained in Example 55 (3.1 g, 6.9 mmol) was dissolved in ethanol (50 ml), adding 1 mol/L NaOH (13.9 ml). The mixture was stirred at room temperature for 2 hours. Then the mixture was concentrated under reduced pressure followed by adding water. The aqueous phase was washed with ethyl acetate and adjust to pH 5˜6 by 1 mol/L hydrochloric acid. The precipitated solid was collected by filtration and washed by water to give pale yellow powder. The solid was dissolved in alkali solution and adjust the pH again to give the refine product (2.6 g, 89.5%). mp 172˜174° C. 1HNMR (DMSO-d6) δ: 2.30˜2.49 (2H, m, CH2), 2.58˜2.63 (1H, d, CH2), 2.89˜2.95 (1H, m, CH2), 3.08 (1H, dd, CH2), 3.23 (1H, dd, N—CH), 3.38˜3.47 (2H, m, CH2), 3.74 (3H, s, Ar—OCH3), 3.79 (1H, s, Ar—OCH3), 4.25 (1H, d, CH2), 4.59 (2H, q, OCH2CO), 6.66 (1H, s, ArH), 6.73 (1H, s, ArH), 7.05 (1H, s, ArH).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:3].[CH3:13][S:14]([N:17]([CH2:32][CH2:33][Cl:34])[N:18]([S:28]([CH3:31])(=[O:30])=[O:29])C(OC1C=CC=CC=1)=O)(=[O:16])=[O:15]>>[CH3:13][S:14]([N:17]([CH2:32][CH2:33][Cl:34])[N:18]([S:28]([CH3:31])(=[O:30])=[O:29])[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:3])(=[O:15])=[O:16]
Reactant: CS(=O)(=O)N(CCCl)N(C(=O)Oc1ccccc1)S(C)(=O)=O
Reactant: COc1ccc(OC(=O)Cl)cc1
Product: COc1ccc(OC(=O)N(N(CCCl)S(C)(=O)=O)S(C)(=O)=O)cc1

Procedure:
1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(4-methoxyphenoxy)carbonyl]hydrazine (compound 10g) was prepared by reacting compound 2 with 4-methoxyphenyl chloroformate using a procedure similar to the one employed for compound 10d. The product was recrystallized from ethanol, and the yield was about 30.0% by weight. The Mp of the product was approximately 119-121° C. 1H NMR (CDCl3): δ 7.1 and 6.9 (4H, 2d, aromatic H), 3.6-4.2 (4H, m, CH2CH2Cl), 3.8 (3H, s, OCH3), 3.5 and 3.2 (6H, 2s, 2 CH3SO2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([Li])CCC.[CH3:14][C:15]([S:18]([N:20]=[C:21]1[CH2:24][O:23][CH2:22]1)=[O:19])([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:21]2([NH:20][S:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19])[CH2:24][O:23][CH2:22]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)(C)S(=O)N=C1COC1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)S(=O)NC1(c2ccc(Br)cn2)COC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 31.3 %

Procedure:
To a toluene (20 ml) solution of 2,5-dibromopyridine (1.93 g, 8.16 mmol) that is cooled to −78° C. in an atmosphere of nitrogen is added n-butyllithium (2.5 M in hexanes, 3.6 ml, 8.98 mmol) dropwise via syringe over a period of five minutes. The reaction mixture is stirred at −78° C. for ten minutes more before 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (1.43 g, 8.16 mmol) is added all at once as a concentrated solution in toluene. The reaction is stirred for 30 minutes at −78° C. and for 20 minutes at 0° C. before it is quenched with saturated aqueous ammonium chloride (5 ml). The volatiles were removed by rotary evaporation at reduced pressure. The residual material is partitioned between water (20 ml) and methylene chloride (50 ml). The aqueous is extracted once more with methylene chloride (30 ml). The combined extracts were concentrated and the residual material is subjected to flash column chromatography using a gradient of acetone in hexanes (20% to 75% over 5 column volumes) to provide N-(3-(5-bromopyridin-2-yl)oxetan-3-yl)-2-methylpropane-2-sulfinamide (850 mg): 1H NMR (400 MHz, CDCl3) 1.32 (s, 9 H) 4.91-4.97 (m, 2 H) 5.13 (d, 1 H) 5.34 (d, 1 H) 7.78 (d, 1 H) 8.04 (m, 1 H) 8.68 (d, 1 H); m/z (Cl) 333, 335 [m+H]+.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][CH2:12][O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(OCC)=O)C.[CH2:20]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[I:34])[CH:29]=O)[CH3:21].O>O1CCCC1>[CH2:20]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[C:28](/[CH:29]=[C:14](\[O:13][CH2:12][CH3:11])/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:31]=[CH:32][C:33]=1[I:34])[CH3:21]
Reactant: CCOCCOc1cc(C=O)ccc1I
Reactant: CCOC(=O)COCCP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCCOc1cc(/C=C(\OCC)C(=O)OCC)ccc1I
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 10 %

Procedure:
0.26 g (6.87 mmol) of sodium hydride is added portionwise to a solution at 0° C. of 1.75 g (6.87 mmol) of ethyl (diethoxyphosphoryl)ethoxyacetate (prepared according to Example 1b) in 20 mL of tetrahydrofuran. The reaction mixture is stirred for 45 minutes at room temperature and 2 g (6.25 mmol) of 3-(2-ethoxyethoxy)-4-iodobenzaldehyde in 10 mL of tetrahydrofuran are then added dropwise. The reaction is slightly exothermic, and the reaction mixture is maintained at a temperature of 25-30° C. with an ice-water bath. When the temperature has stabilized, the reaction mixture is stirred for 24 hours at room temperature. After addition of 50 mL of water, the reaction medium is extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and then dried over sodium sulfate. After evaporating under vacuum, the crude product obtained is purified by chromatography on a column of silica eluted with a 90/10 heptane/ethyl acetate mixture to give 61.2 mg of the (E) isomer of ethyl 3-[3-(2-ethoxyethoxy)-4-iodophenyl]-2-ethoxyacrylate, 1.56 g of a mixture of (Z) and (E) isomers and 270.3 mg of the isomer ethyl (Z)-3-[3-(2-ethoxyethoxy)-4-iodophenyl]-2-ethoxyacrylate in the form of yellow oils.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].[H-].[Na+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C)C=O>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccccc1Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccccc1Cc1ncc[nH]1

Procedure:
Treatment of 2-(1-imidazolylmethyl)phenol with sodium hydride in dry N,N-dimethylformamide followed by ethyl bromoacetate as described in Example 11B gave 2-(1-imidazolylmethyl)phenoxyacetic acid ethyl ester as an oil which was used without further characterisation.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[Cl:15]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)C>[Cl:15][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][C:7]=1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)Oc1cccc(CC(=O)O)c1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(Cl)c(CC(=O)O)c1
Reaction time: 8 h
Yield: 81.1 %

Procedure:
Dissolve 2-(3-isopropoxyphenyl)acetic acid (3.24 g, 16.6 mmol) in dimethylformamide (11.1 mL). Cool on an ice bath and add a solution N-chlorosuccinimide (2.44 g, 18.3 mmol) in dimethylformamide (12.2 mL). Stir overnight allowing the reaction to reach ambient temperature. Dilute the reaction mixture with diethyl ether. Wash with water. Extract the water wash with diethyl ether. Combine the diethyl ether extracts and wash with water and brine, dry over sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by silica gel chromatography eluting with acetone: hexanes (0-25% gradient) to give the title compound (3.08 g, 13.47 mmol). MS (m/z): 245.8 (M+18).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14][CH2:15][CH2:16]OS(C)(=O)=O)=[CH:10][C:9]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[CH:23]=3)=[N:8]2)=[CH:4][CH:3]=1.[N:33]1([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[C:42]([O:41][C:39]([N:33]1[CH2:38][CH2:37][N:36]([CH2:16][CH2:15][CH2:14][C:11]2[C:12](=[O:13])[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:32][CH:31]=3)[N:8]=[C:9]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[CH:23]=3)[CH:10]=2)[CH2:35][CH2:34]1)=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(-c2cc(CCCOS(C)(=O)=O)c(=O)n(Cc3ccc(F)cc3)n2)cc1F
Product: COc1ccc(-c2cc(CCCN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(Cc3ccc(F)cc3)n2)cc1F
Yield: 37.4 %

Procedure:
Following the procedure of Example 1(10), 2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a brown oil (yield: 37.4%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3](=[C:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=O)O.[CH:18]1[C:23]([NH:24][NH2:25])=[CH:22][CH:21]=[C:20]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:19]=1.Cl>C(O)C>[F:1][C:2]([F:17])([F:16])[C:3]1[C:5]2[C:6](=[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]3=[CH:13][CH:14]=2)[N:24]([CH:23]2[CH2:22][CH:21]=[C:20]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:19]=[CH:18]2)[N:25]=1
Reactant: O=C1C(=C(O)C(F)(F)F)CCc2ccccc21
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CCO
Product: NS(=O)(=O)C1=CCC(n2nc(C(F)(F)F)c3ccc4ccccc4c32)C=C1
Yield: 71.2 %

Procedure:
A 100 mL one neck round bottomed flask equipped with reflux condenser, nitrogen inlet and provisions for magnetic stirring was charged with 3,4-dihydro-2-[2,2,2-trifluoro-1-hydroxyethylidene]-1(2H)-naphthalenone from Step 1 (1.21 g, 5.0 mmol), 4-sulfonamidophenylhydrazine hydrochloride (1.12 g, 5.0 mmol) and 25 mL of absolute ethanol. The solution was warmed to reflux for 15 hours, cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water and with brine, dried over anhydrous MgSO4, filtered and reconcentrated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and isooctane to give 1.4 g (71%) of pure 4,5-dihydro-4-[3-(trifluoromethyl)-1H-benz[g]indazol-1-yl]benzenesulfonamide: mp 257°-258° C.; 1H NMR (CDCl3 /CD3OD, 4:1) δ 2.7 (m, 2H), 2.9 (m, 2H), 6.6 (m, 1H), 6.9 (m, 1H), 7.1 (m, 1H), 7.16 (m, 1H), 7.53 (m, 2H), 7.92 (m, 2H); 19F NMR CDCl3 δ-62.5. FAB-MS M+H=394.
Reaction SMILES: [CH2:1]([C:5]1([N:43]([CH3:45])[CH3:44])[CH2:10][CH2:9][C:8]([C:21]2[NH:22][C:23]3[C:28]([C:29]=2[CH2:30][CH2:31][N:32]2C(=O)C4C(=CC=CC=4)C2=O)=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH3:20])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].O.NN>CO.[OH-].[Na+]>[NH2:32][CH2:31][CH2:30][C:29]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][C:21]=1[C:8]1([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH3:20])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][CH2:10][C:5]([N:43]([CH3:45])[CH3:44])([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7]1
Reactant: CCCCC1(N(C)C)CCC(c2[nH]c3ccccc3c2C)(c2[nH]c3ccccc3c2CCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCC1(N(C)C)CCC(c2[nH]c3ccccc3c2C)(c2[nH]c3ccccc3c2CCN)CC1

Procedure:
2-(2-(2-(4-butyl-4-(dimethylamino)-1-(3-methyl-1H-indol-2-yl)cyclohexyl)-1H-indol-3-yl)ethyl)isoindolin-1,3-dione (450 mg, 0.749 mmol) and hydrazine monohydrate (2 ml, 41.2 mmol) were dissolved in methanol (20 ml) and then boiled with reflux for 45 min. For work up the batch was diluted with 1N NaOH (50 ml) and extracted with diethyl ether (3×20 ml). The combined organic phases were dried over Na2SO4 and then concentrated until dry. The product was obtained as a light beige-coloured solid with a yield of 302 mg (86%, melting point 105-112° C.). According to the NMR spectrum it was a mixture of the two possible diastereoisomers in a ratio of approx. 30:70.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])/[C:4](/[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[C:5](/[CH:10]([CH3:12])[CH3:11])\[C:6]([O:8][CH3:9])=[O:7].[C:22]([O:26][C:27]([NH:29][CH2:30][CH2:31]O)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[C:22]([O:26][C:27]([NH:29][CH2:30][CH2:31][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13]/[C:4](=[C:5](\[CH:10]([CH3:11])[CH3:12])/[C:6]([O:8][CH3:9])=[O:7])/[C:3]([O:2][CH3:1])=[O:21])=[CH:19][CH:18]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: COC(=O)/C(Cc1ccc(O)cc1)=C(\C(=O)OC)C(C)C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: COC(=O)/C(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)=C(\C(=O)OC)C(C)C
Temperature: 25 °C
Yield: 94.2 %

Procedure:
To a solution of 2-(4-hydroxybenzyl)-3-isopropylmaleic acid dimethyl ester (204.5 mg, 0.6996 mmol) in benzene (6 mL) were added N-(t-butoxycarbonyl)ethanolamine (343 mg, 2.13 mol), tributylphosphine (853 mg, 4.20 mmol) and 1,1′-(azodicarbonyl)dipiperidine (1.05 g, 4.20 mmol) with stirring at room temperature. After stirring at room temperature for 1 h, the reaction mixture was filtered, and the residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (hexane-ethyl acetate 2:1) to give 287 mg of dimethyl 2-{4-[2-(t-butoxycarbonylamino)ethoxy]benzyl}-3-isopropylmaleate as oil (yield: 98%).
Reaction SMILES: C(=O)([O-])[O:2][C:3](C1C2C=CC=CC=2C2C1=CC=CC=2)(C)[CH:4]1[N:8]2[C:9](=[O:18])[C:10]3[N:16]=[CH:15][C:14]([Br:17])=[CH:13][C:11]=3[N:12]=[C:7]2[CH2:6][CH2:5]1.CCN(CC)CC>C(Cl)Cl>[OH:2][CH2:3][CH:4]1[N:8]2[C:9](=[O:18])[C:10]3[N:16]=[CH:15][C:14]([Br:17])=[CH:13][C:11]=3[N:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: CC(OC(=O)[O-])(C1c2ccccc2-c2ccccc21)C1CCc2nc3cc(Br)cnc3c(=O)n21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1c2ncc(Br)cc2nc2n1C(CO)CC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 43.1 %

Procedure:
To a solution of (9H-fluoren-9-yl)methyl(3-bromo-10-oxo-6,7,8,10-tetrahydropyrido[3,2-d]pyrrolo[1,2-a]pyrimidin-8-yl)methyl carbonate (1.4 g, 4.7 mmol) in DCM (50 mL) was added Et3N (4 mL). The mixture was stirred for 5 h at room temperature. The reaction mixture was then concentrated and purified by column chromatography to give 0.6 g of the desired product. MS (ESI): 296, 298 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH3:9])[CH:3]=1.[Br:10]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][NH:5][C:4]([Br:10])([CH3:9])[CH:3]=1
Reactant: Cc1cc(Cl)c(F)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Solvent: ClCCl
Product: CC1(Br)C=C(Cl)C(F)=CN1
Temperature: 75 °C
Yield: 69 %

Procedure:
4-Chloro-5-fluoro-2-picoline (2.9 g, 20 mmol), the product of Example 66, was dissolved in 50 mL of 1,2-dichloroethane in a dry flask. The resultant solution was heated, with stirring, to 75° C. and 4.09 (23 mmol) of N-bromosuccinimide was added, followed by 100 mG (0.7 mmol) of 2,2-azobisisobutyronirile (AIBN), a free radical initiator. After the reaction mixture was stirred at 75° C. for 24 hours, it was diluted with 450 mL of methylene chloride and washed with 3 X 400 mL of water. The organic layer was separated and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dried in vacuo to give 3.5 g (69% yield) of the title compound as an amber oil; 1H NMR (CDCl3) d 4.50 (s, 2H), 7.54 (d, 1H), 8.44 (s, 1H).
Reaction SMILES: [CH2:1]([NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([CH2:20][CH2:21][CH3:22])=[C:18]([C:23]([OH:25])=O)[N:17]=[N:16]2)=[CH:11][CH:10]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].C1C=C[C:29]2N(O)N=[N:32][C:30]=2[CH:31]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:30]1([NH:32][C:23]([C:18]2[N:17]=[N:16][N:15]([C:12]3[CH:11]=[CH:10][C:9]([C:7]([NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[O:8])=[CH:14][CH:13]=3)[C:19]=2[CH2:20][CH2:21][CH3:22])=[O:25])[CH2:31][CH2:29]1
Reactant: On1nnc2ccccc21
Reactant: CCCCCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCCCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
1-{4-[(Pentylamino)carbonyl]phenyl}-5-propyl-1H-1,2,3-triazole-4-carboxylic acid (487 mg, 1.41 mmol) obtained in Example 57b), HOBt (193 mg, 1.41 mmol, 1.0 eq.) and cyclopropylamine (0.131 ml, 1.84 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (1:1, 7.5 ml), WSC (332 mg, 1.70 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (40 ml), and washed with 5% aqueous sodium hydrogen carbonate solution, 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane (2:1, 30 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give a white powder. This was crystallized from methanol-ethyl acetate to give the title compound as a white powder (298 mg, 0.777 mmol, 55.1%). The mother liquor was concentrated, and crystallized from diethyl ether to give the title compound as a white powder (225 mg, 0.587 mmol, 41.6%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:11]([CH3:13])=[O:12].[N-:14]=[N+]=[N-].[Na+].S(=O)(=O)(O)O.O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:11]([CH3:13])(=[NH:14])=[O:12]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc([N+](=O)[O-])ccc1S(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc([N+](=O)[O-])ccc1S(C)(=N)=O
Temperature: 25 °C

Procedure:
1.5 g (7.5 mmol) of (RS)-2-methyl-1-(methylsulfinyl)-4-nitrobenzene and 1.1 g (17.1 mmol) of sodium azide in 10.0 ml of CHCl3 are carefully mixed at 0° C. with 2.2 ml of concentrated sulfuric acid. The batch is heated first to room temperature and then to 45° C. while being stirred vigorously. It is stirred for 116 hours at this temperature. After cooling, it is mixed with water and extracted from DCM (2×). The aqueous phase is made basic with 2N NaOH solution and extracted from DCM. The combined organic phases are filtered through a Whatman filter and concentrated by evaporation. The crude product that is obtained is recrystallized from ethyl acetate. 1.3 g (6.1 mmol, corresponding to 81% of theory) of the product is obtained.
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][C:8](N(C)C)=[CH:7][C:6]=2[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1.Cl.C1C[O:20]CC1>>[F:1][C:2]1[C:10]2[S:9][C:8](=[O:20])[CH2:7][C:6]=2[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c2sc(N(C)C)cc12
Reactant: C1CCOC1
Agent: Cl
Product: COc1ccc(F)c2c1CC(=O)S2
Temperature: 80 °C
Yield: 84 %

Procedure:
To a solution of N-(7-fluoro-4-methoxy-1-benzothien-2-yl)-N,N-dimethylamine (1.73 g, 7.7 mmol) in THF (25 mL) was added aqueous hydrochloric acid (1 N, 25 mL) and this was heated to 80° C. for 3 h. After cooling to room temperature then extracted with ether (100 mL), dried (MgSO4) and the solvent evaporated in vacuo to give a yellow solid. The residue was purified by flash chromatography in 5% ethyl acetate in hexane to give (1.3 g, 84%) of the title compound; δH (300 MHz, CHCl3) 6.97-6.87 (1H, m, ArH), 6.62-6.55 (1H, m, ArH), 3.91 (2H, s, CH2) and 3.85 (3H, s, OCH3).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11]([O:13][C:14](=[O:28])[CH:15]([C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:16][C:17](=O)[CH3:18])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:16]=[C:17]([CH3:18])[N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[O:10])[CH3:9])[CH:3]=2)[C:20]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:28])[CH3:12]
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Reactant: CC(=O)c1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2cccc(C(C)=O)c2)c1-c1ccccc1

Procedure:
3′-Amino-acetophenone (5 mmol, 0.7 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The residual oil was purified over silica and yielded the named product (m.p. 100° C.-102° C.).