Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].OS(O)(=O)=O.O=S(=O)=O.[N+]([O:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)([O-])=O>>[N+:1]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:18]=1[OH:17])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])Oc1ccncc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=[N+]([O-])c1cnccc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A nitric acid solution (HNO3>90%, 13.3 ml) is slowly added to a solution of oleum (H2SO4 containing 20% SO3, d=1.9, 10.5 ml) cooled to 0° C. 4-Pyridol nitrate (10 g, 63 mmol) is added at 0° C. to the mixture which is then heated at 90° C. for 1 h 30 min. The reaction mixture is poured over 50 g of ice. The suspension is stirred for 30 min at 0° C. and is then filtered. The solid is washed with a few ml of water and then air-dried.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][N:41]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4CCC)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncn4CCC)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(4-propyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (826 mg) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.46 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 1 hour at −78° C. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethanol:ethyl acetate 1:5→1:3), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(4-propyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 139) (628.7 mg) as yellow amorphous.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][C:7]=1[CH3:11])=[O:5])[CH3:2].[H-].[Na+].Cl[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1>CN(C)C=O.O.[Cu]>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[C:7]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc[nH]c1C
Reactant: Clc1ccc2ccccc2n1
Agent: [Cu]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccn(-c2ccc3ccccc3n2)c1C
Temperature: 20 °C
Reaction time: 0.2 h

Procedure:
2.75 g (17.9 mmol) of 3-ethoxycarbonyl-2-methyl-1H-pyrrole are added at 20° C. under an argon atmosphere to 0.756 g (18.9 mmol) of sodium hydride, at 60% by weight in liquid petroleum jelly, suspended in 12 mL of dimethylformamide. After stirring at 20° C. for 0.2 hour, 0.114 g (1.79 mmol) of copper powder and 2.93 g (17.9 mmol) of. 2-chloroquinoline are added. After stirring at 140° C. for 48 hours, the reaction mixture is filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 100 mL of water and then extracted with 4 times 50 mL of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) to give 6 g of an oil, which oil is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (8/2 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa), 2.2 g of 3-ethoxycarbonyl-2-methyl-1-(quinol-2-yl)-1H-pyrrole are obtained in the form of a yellow oil. Mass spectrum (EI): m/e 280 (M+.), m/e 251, m/e 206.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:23]=[CH:22][C:8]2[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][CH2:19][C:7]=2[CH:6]=1)=[CH:15][CH:14]=[C:13](Cl)[C:12]=4[F:21])=[O:4].[CH3:24][C:25]1[CH:26]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:29]([CH3:35])[C:30]=1[O:31][CH2:32][CH2:33][CH3:34]>>[CH3:1][O:2][C:3]([C:5]1[CH:23]=[CH:22][C:8]2[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][CH2:19][C:7]=2[CH:6]=1)=[CH:15][CH:14]=[C:13]([C:27]1[CH:28]=[C:29]([CH3:35])[C:30]([O:31][CH2:32][CH2:33][CH3:34])=[C:25]([CH3:24])[CH:26]=1)[C:12]=4[F:21])=[O:4]
Reactant: CCCOc1c(C)cc(B2OC(C)(C)C(C)(C)O2)cc1C
Reactant: COC(=O)c1ccc2c(c1)CCc1c-2[nH]c2c(F)c(Cl)ccc12
Product: CCCOc1c(C)cc(-c2ccc3c4c([nH]c3c2F)-c2ccc(C(=O)OC)cc2CC4)cc1C

Procedure:
A sample of crude 9-Chloro-10-fluoro-5,11-dihydro-6H-benzo[a]carbazole-3-carboxylic acid methyl ester (prepared as in example 57, step 2) and 2-(3,5-Dimethyl-4-propoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane are coupled as in example 19, step 2 to afford the title material: ESMS m/z/z 458 (M+H+).
Reaction SMILES: Cl[C:2]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:12]=[C:13]([C:14]([O:16]C)=[O:15])[C:8]=2[N:7]=[C:6]1[CH:24]([F:26])[F:25].[Li+].[OH-].[CH2:34]1COCC1>>[Cl:31][C:30]1[C:2]([CH3:34])=[C:3]([CH2:4][N:5]2[C:9]3[CH:10]=[C:11]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:8]=3[N:7]=[C:6]2[CH:24]([F:26])[F:25])[CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)F)n2Cc1cccc(Cl)c1Cl
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Product: Cc1c(Cl)cccc1Cn1c(C(F)F)nc2c(C(=O)O)cc(N3CCOCC3)cc21
Temperature: 45 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A solution of methyl 1-(2,3-dichlorobenzyl)-2-(difluoromethyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate (1045 mg, 2.3 mmol) in THF (40 mL) was added into 2 N LiOH (20 mL) and the mixture was stirred at 45° C. for 4 h. It was filtered, the filter cake was added to water (100 mL) and formic acid was added to adjust pH=3. Then a filtration was performed, the filter cake was collected and washed with water (200 mL), dried under vacuum to give the desired product (800 mg, 80%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 2.46 (s, 3H), 3.13 (t, 4H, J=4.8 Hz), 3.73 (t, 4H, J=4.8 Hz), 3.92 (s, 3H), 5.70 (s, 2H), 6.00 (d, 1H, J=7.5 Hz), 7.04 (t, 1H, J=7.5 Hz), 7.23 (d, 1H, J=1.8 Hz), 7.34 (t, 1H, J=7.5 Hz), 7.36 (t, 1H, J=51.9 Hz), 7.57 (d, 1H, J=1.8 Hz), 12.96 (br s, 1H);
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([NH:10][NH2:11])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14](OC)(OC)(OC)[CH3:15]>>[CH3:14][C:15]1[O:9][C:8]([C:7]2[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:10][N:11]=1
Reactant: NNC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COC(C)(OC)OC
Product: Cc1nnc(-c2ccc([N+](=O)[O-])cc2)o1
Temperature: 25 °C

Procedure:
4-Nitro-benzoic acid hydrazide (1.0 g, 5.6 mmol) was heated to reflux in trimethyl orthoacetate for 4 days. After cooling to RT, the mixture was triturated with hexanes and the title compound collected by filtration (0.93 g). MS (ESI+) for m/z 206 (M+H)+.
Reaction SMILES: C([O:8][C:9](=[O:46])[CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:19]2[CH:28]=[C:27]3[C:22]([CH2:23][CH2:24][N:25]([C:29](=[N:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]3)=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1>O1CCCC1.CO.[C].[Pd]>[C:42]([O:41][C:39]([NH:38][C:29]([N:25]1[CH2:24][CH2:23][C:22]2[C:27](=[CH:28][C:19]([O:18][CH2:17][CH:14]3[CH2:13][CH2:12][N:11]([CH2:10][C:9]([OH:46])=[O:8])[CH2:16][CH2:15]3)=[CH:20][CH:21]=2)[CH2:26]1)=[N:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])=[O:40])([CH3:43])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCN(CC(=O)OCc4ccccc4)CC3)cc2C1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCN(CC(=O)O)CC3)cc2C1
Yield: 95.1 %

Procedure:
4-[2-(N,N′-Di-tert-butoxycarbonylamidino)-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl]piperidine-1-acetic acid benzyl ester (735 mg) was hydrogenated using 7.5% palladium carbon (220 mg) in a mixture of tetrahydrofuran (7 ml) and methanol (14 ml) at atmospheric pressure over 3 hours. After completion of the reaction, the reaction mixture was filtered through celite and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (600 mg).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH3:14])[C:9]([O:11][CH2:12]C)=[O:10])=[CH:6][N:5]=[CH:4][N:3]=1.[Na].[CH3:16][OH:17]>>[CH3:16][O:17][C:2]1[C:7]([CH:8]([CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)C(C)c1cncnc1Cl
Reactant: CO
Agent: [Na]
Product: COC(=O)C(C)c1cncnc1OC
Temperature: 120 °C
Yield: 93 %

Procedure:
To a solution of 0.250 g (1.17 mmol) of ethyl 2-(4-chloropyrimidin-5-yl)propanoate from step A above in 5 mL of absolute methanol was dissolved 0.054 g (2.34 mmol) of sodium metal. The resulting solution was heated under microwave conditions at 120° C. for 10 min. All volatiles were removed in vacuo and the residue was diluted with saturated sodium bicarbonate and extracted with dichloromethane (3×10 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo to afford the title compound as a clear gum (0.21 g, 93%). 1H-NMR (500 MHz, CD3OD) δ: 8.65 (s 1H), 8.36 (s, 1H), 4.0 (s, 3H), 3.9 (q, J=7 Hz, 2H), 3.66 (s, 3H), 1.58 (d, J=7 Hz, 3H). LC-MS: m/z (E/S) 197 (MH)+.
Reaction SMILES: [CH3:1][C:2]([CH3:56])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:55])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:54])=[CH:11]/[CH2:12][CH2:13]/[C:14](/[CH3:53])=[CH:15]/[CH2:16][CH2:17]/[C:18](/[CH3:52])=[CH:19]/[CH2:20][CH2:21]/[C:22](/[CH3:51])=[CH:23]/[CH2:24][CH2:25]/[C:26](/[CH3:50])=[CH:27]/[CH2:28][CH2:29]/[C:30](/[CH3:49])=[CH:31]/[CH2:32][CH2:33]/[C:34](/[CH3:48])=[CH:35]/[CH2:36][CH2:37]/[C:38](/[CH3:47])=[CH:39]/[CH2:40][CH2:41]/[C:42](/[CH3:46])=[CH:43]/[CH2:44][OH:45].[C:57](Cl)(=[O:64])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>N1C=CC=CC=1.CCCCCC>[C:57]([O:45][CH2:44][CH:43]=[C:42]([CH3:46])[CH2:41][CH2:40][CH:39]=[C:38]([CH3:47])[CH2:37][CH2:36][CH:35]=[C:34]([CH3:48])[CH2:33][CH2:32][CH:31]=[C:30]([CH3:49])[CH2:29][CH2:28][CH:27]=[C:26]([CH3:50])[CH2:25][CH2:24][CH:23]=[C:22]([CH3:51])[CH2:21][CH2:20][CH:19]=[C:18]([CH3:52])[CH2:17][CH2:16][CH:15]=[C:14]([CH3:53])[CH2:13][CH2:12][CH:11]=[C:10]([CH3:54])[CH2:9][CH2:8][CH:7]=[C:6]([CH3:55])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:56])[CH3:1])(=[O:64])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CO
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.5 Grams of undecaprenol were dissolved in 30 ml of pyridine and the solution was added with a solution of 1.3 g of benzoyl chloride in pyridine dropwise over 30 minutes. After completion of the addition, the mixture was stirred at room temperature for one hour to complete the reaction. The reaction product was diluted with n-hexane, washed with water and concentrated. The concentrate was purified by chromatography with 50 g of silica gel in n-hexane/benzene solvent mixture as elution solvent to obtain white waxy final product. Yield: 3.6 g.______________________________________Elementary analysis as C62H94O2 : C H______________________________________Theoretical (%): 85.45 10.87Found (%): 85.43 10.86______________________________________
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:9][CH:8]=1)[NH2:5].[CH3:25][C:26]([C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](O)=[O:32])([CH3:28])[CH3:27]>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:11][CH:12]=1)[NH:5][C:31]([C:30]1[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=1[C:26]([CH3:28])([CH3:27])[CH3:25])=[O:32]
Reactant: CC(C)(C)c1ccccc1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1ccccc1C(C)(C)C

Procedure:
4-[[(2,6-Dichlorophenyl)carbonyl]amino]-N-[[2-(1,1-dimethylethyl)phenyl]carbonyl]-L-phenylalanine methyl ester was prepared from 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester and 2-(1,1-dimethylethyl)benzoic acid using the general procedure described in example 3. HR MS: Obs. mass. 527.1523. Calcd. mass. 527.1573 (M+H).
Reaction SMILES: ClC1C=C(SC2C3C(=CC(C)=CC=3)[NH:12]C=2CCC(N)=O)C=C(Cl)C=1.[Cl:25][C:26]1[CH:27]=[C:28]([S:33][C:34]2[C:42]3[C:37](=[CH:38][C:39]([CH3:43])=[CH:40][CH:41]=3)[NH:36][C:35]=2[CH2:44][C:45]([OH:47])=O)[CH:29]=[C:30]([Cl:32])[CH:31]=1.C(Cl)(=O)C(Cl)=O.N>O1CCOCC1>[Cl:25][C:26]1[CH:27]=[C:28]([S:33][C:34]2[C:42]3[C:37](=[CH:38][C:39]([CH3:43])=[CH:40][CH:41]=3)[NH:36][C:35]=2[CH2:44][C:45]([NH2:12])=[O:47])[CH:29]=[C:30]([Cl:32])[CH:31]=1
Reactant: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CCC(N)=O)[nH]c2c1
Reactant: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CC(=O)O)[nH]c2c1
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1COCCO1
Product: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CC(N)=O)[nH]c2c1
Yield: 80 %

Procedure:
Following the method used to prepare 24a, the use of 53 (0.35 g, 0.96 mmol) and oxalyl chloride (120 μL, 1.44 mmol) followed by allowing the intermediate acid chloride to react with ammonia in dioxane provided 0.28 g (80%) of product 24b as an off white solid, mp 197° C. 1H NMR (300 MHz, DMSO-d6) δ 2.40 (s, 3H), 3.70 (s, 2H), 6.90 (d, J=8 Hz, 1H), 6.99-7.01 (m, 2H), 7.08 (brs, 1H), 7.20 (d, J=8 Hz, 1H), 7.25-7.28 (m, 2H), 7.54 (brs, 1H), 11.65 (brs, 1H). LC-MS (CI): m/z 365.0, 367.0 [(M+H)+ C17H14Cl2NO2S requires 364.0]. Purity (100%). Calcd for C17H14Cl2NO2S: C, 55.90; H, 3.86; N, 7.67; S, 8.78; Cl, 19.41. Found: C, 55.61; H, 3.90; N, 7.68; S, 8.59; Cl, 19.67.
Reaction SMILES: [CH3:1][C:2]1[C:10]([Sn](C)(C)C)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:15].[Br:16]Br.S([O-])([O-])(=O)=S>C(Cl)Cl>[Br:16][C:10]1[C:2]([CH3:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:15])[O:5][CH2:4]2
Reactant: Cc1c([Sn](C)(C)C)ccc2c1COC2=O
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: Cc1c(Br)ccc2c1COC2=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-methyl-5-(trimethylstannyl)isobenzofuran-1(3H)-one (4.37 g, 14.05 mmol) in DCM (20 mL) was added bromine (0.796 ml, 15.46 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h. Saturated thiosulfate solution was added and the mixture was extracted with methylene chloride (2×100 mL), the combined organic phase was dried over sodium sulfate, concentrated to give 5-bromo-4-methylisobenzofuran-1(3H)-one. LC/MS: (M+1)+: 226.89; 228.89.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][CH2:13][CH2:14]Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:17])=[C:7]([Cl:16])[CH:8]=2)[N:3]=1.[SH-:18].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:16][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:17])[N:3]=[C:2]1[C:11]([CH2:12][CH2:13][CH2:14][S:18]1)=[N:10]2
Reactant: [SH-]
Reactant: ClCCCc1nc2cc(Cl)c(Cl)cc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cc2nc3c(nc2cc1Cl)SCCC3
Temperature: 25 °C
Reaction time: 96 h
Yield: 100 %

Procedure:
To a solution of 2,6,7-trichloro-3-(3-chloropropyl)quinoxaline (0.15 g, 0.48 mmol) in dry DMF (50 ml) were added sodium hydrosulfide (0.11 g, 1.44 mmol) and potassium carbonate (0.20 g, 1.45 mmol). The reaction mixture was stirred for 4 days at room temperature. The solvent was evaporated in vacuo, followed by the addition of water. The resulting mixture was extracted with dichloromethane (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to yield 6,7-dichloro-3,4-dihydro-2H-1-thia-9,10-diaza-anthracene (>100%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[C:23]4=[O:29])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:37][CH2:38][OH:39]>CS(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:37][CH2:38][OH:39])[C:23]4=[O:29])=[CH:20][CH:21]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(-n3cccc(O)c3=O)cc2)nn1)c1ccc(Cl)s1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C(NCc1cn(-c2ccc(-n3cccc(OCCO)c3=O)cc2)nn1)c1ccc(Cl)s1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
5-Chloro-N-((1-(4-(3-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (30 mg, 0.07 mmol, prepared as shown in EXAMPLE 61) was dissolved in 2 mL DMSO. To it were added cesium carbonate (69 mg, 0.21 mmol) and 2-bromoethanol (10 μL, 0.14 mmol). The mixture was stirred in a sealed tube at 70° C. for 30 min, and was directly subjected to reverse phase prep HPLC to isolate the title compound. MS found for C21H18ClN5O4S (M+H)+ 472.1, 474.1 (Cl pattern).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[CH:9][N:10]=2)[N:7]=1.[NH2:11][CH2:12][CH2:13][CH2:14][OH:15]>C(O)C>[OH:15][CH2:14][CH2:13][CH2:12][NH:11][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: NCCCO
Reactant: Clc1ccc2ncnn2n1
Solvent: CCO
Product: OCCCNc1ccc2ncnn2n1
Yield: 72 %

Procedure:
6-Chloro[1,2,4]triazolo[1,5-b]pyridazine (928 mg) was dissolved in ethanol (10 ml). 3-Amino-1-propanol (1.23 g) was added to the solution. The mixture was refluxed under heating for 20 hours. After being cooled, the mixture was concentrated under reduced pressure to an half of its volume. The resulting precipitates were washed with ethanol and dried to yield the title compound (835 mg).
Reaction SMILES: [OH:1][CH:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19].[Br:20]Br>ClCCl>[Br:20][C:11]1[S:12][C:4]2[CH:3]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3=[O:19])[CH:2]([OH:1])[C:7]([CH3:8])([CH3:9])[O:6][C:5]=2[CH:10]=1
Reactant: CC1(C)Oc2ccsc2C(N2CCCCC2=O)C1O
Reactant: BrBr
Solvent: ClCCl
Product: CC1(C)Oc2cc(Br)sc2C(N2CCCCC2=O)C1O

Procedure:
The title compound was prepared as described in Example 4 starting with 5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopiperidin-1-yl)-7H-thieno[3,2-b]pyran (1.4 g, 5.0 mmol) and bromine (0.27 mL, 5.2 mmol) in dichloromethane (30 mL). Purification by flash chromatography using 1% methanol in dichloromethane as the eluant and recrystallization from dichloromethane/hexanes gave the product, 3.87 g (78%), as a colorless solid: mp 200°-202° C.; IR(KBr): 3442, 2942, 1616, 1571 and 1488 cm-1 ; MS: m/z 360 (MH+); 1H NMR(CDCl3): δ 1.29 (s, 3H), 1.46 (s, 3H), 1.82 (m, 4H), 2.51 (m, 2H), 3.12 (m, 1H), 3.27 (m, 1H), 3.46 (d, J=5.0 Hz, 1H, exchanges with D2O),3.78 (d,d, J=9.0 Hz, J=5.0 Hz,1H, simplifies to d, J=9.0 Hz, with D2O), 5.74 (d, J=9.0 Hz, 1H) and 7.58 (s, 1H).
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](Cl)(=O)[C:21]1C=CC=[CH:23][CH:22]=1>>[C:2]1([C:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:8])[C:7]2[C:6](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCCCCC(=O)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Product: CCOC(=O)CCCCCCC(=O)c1cccc2ccccc12
Yield: 58 %

Procedure:
Following a procedure analogous to that described above for 49a, but substituting 1-naphthoyl chloride for benzoyl chloride, the title compound was obtained as a white solid in 58% yield: 1H NMR (300 MHz, CDCl3) δ 8.56 (d, J=8.7 Hz, 1H), 7.42-7.92 (m, 6H), 4.10 (q, J=6.9 Hz, 2H), 2.98 (m, 2H), 2.26(t, J=7.5 Hz, 2H), 1.75 (m, 2H), 1.62 (m, 2H), 1.36 (m, 4H), 1.22 (t, J=6.9 Hz, 3H); 13C NMR (75.4 MHz, CDCl3) δ 14.02, 24.23, 24.55, 28.70(2), 33.98, 41.79, 59.89, 124.12, 125.51, 126.12, 126.99, 127.51, 128.14, 129.87, 132.06, 133.69, 136.00, 173.39, 204.44.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[CH:18]=[CH:19][C:20]([N+:32]([O-:34])=[O:33])=[C:21]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:22]=1.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:17]1[CH:18]=[CH:19][C:20]([N+:32]([O-:34])=[O:33])=[C:21]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccccc1OCc1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2OCc2ccccc2)ccc1[N+](=O)[O-]
Yield: 92.5 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 2-benzyloxyphenol (2.00 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (2.87 g), sodium hydride (55 wt. %, 0.44 g) and anhydrous N,N-dimethylformamide (20 ml) and the reaction mixture was purified to give the title compound (4.16 g).
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:9]Br>C(Cl)Cl>[Br:9][C:3]1[CH:2]=[C:1]([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=1
Reactant: BrBr
Reactant: Cc1ccccc1O
Solvent: ClCCl
Product: Cc1cc(Br)ccc1O
Temperature: 2 °C
Yield: 78 %

Procedure:
Into a 5-liter reaction flask was charged 324g of o-cresol (3 moles) and 1200 g of methylene chloride. The reaction was cooled to 2° C. and 480 g (3 moles) of bromine dissolved in 960 g of methylene chloride was run in slowly over a 7-hour period. The next day, the cooling bath was removed and a heating mantle was attached. 1 liter of Isopar G (trademark of Exxon for a hydrocarbon fraction) was added and distillation of the methylene chloride was begun under water aspirator vacuum. Eventually the distillation rate slowed and the pot temperature rose to 70° C. The still head temperature dropped from 35° C. to 28° C. The solution was poured into a beaker and cooled to room temperature without stirring. In the morning, the solution was cooled to -5° C. and filtered. There was recovered 440 g of 4-bromo-o-cresol melting at 61-64° C. in 78% yield.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]CC)=O.[CH3:13][C:14]([CH3:23])([CH2:17][CH:18]([CH3:22])[CH2:19][CH2:20][NH2:21])[CH2:15][NH2:16]>CO>[CH3:13][C:14]([CH3:23])([CH2:17][CH:18]([CH3:22])[CH2:19][CH:20]([C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[NH2:21])[CH:15]([C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[NH2:16]
Reactant: CC(CCN)CC(C)(C)CN
Reactant: CCOC(=O)CN1CCCC1=O
Solvent: CO
Product: CC(CC(N)C(=O)CN1CCCC1=O)CC(C)(C)C(N)C(=O)CN1CCCC1=O

Procedure:
8.55 g (0.05 mol) of ethyl 2-oxo-1-pyrrolidineacetate and 3.95 g (0.025 mol) of 2,2,4-trimethyl-1,6-diaminohexane are boiled in 5 ml of absolute methanol for 22 hours, moisture being excluded. After evaporating off the solvent, the residue is chromatographed on silica gel from methanol/water (80:30). Chromatography is then carried out a second time from methanol/water/acetic acid (20:7.5:2.5), and finally the water and the acetic acid are removed by chromatography on aluminium oxide. The product is syrupy with nD54 1.5095.