Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:14][CH2:13][CH2:12][O:11][CH:10]([CH3:15])[CH2:9]2)=CC=1.[Cl:18]C(OC(Cl)C)=O.CO>ClCCCl>[ClH:18].[CH3:15][CH:10]1[CH2:9][NH:8][CH2:14][CH2:13][CH2:12][O:11]1
Reactant: COc1ccc(CN2CCCOC(C)C2)cc1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CO
Product: CC1CNCCCO1
Product: Cl
Temperature: 25 °C
Yield: 90.2 %

Procedure:
To a solution of 4-(4-methoxy-benzyl)-2-methyl-[1,4]oxazepane (1.66 g, 7.05 mmol) in 1,2-dichloroethane (12 ml) was added 1-chloroethyl chloroformate (2.52 g, 17.6 mmol) at room temperature. The mixture was refluxed for 5 hours and cooled to room temperature. After the addition of methanol (15 ml), the mixture was refluxed for 3 hours and concentrated in vacuo to afford the crude product. This crude product was partitioned between ether and 1N hydrochloric acid, and washed with ether. The water phase was basified with saturated aqueous sodium hydrogen carbonate. The product was extracted with dichloromethane. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure carefully to avoid evaporating the product. To the resulting solution was added 4N hydrochloric acid in ethyl acetate. The solution was concentrated in vacuo to afford 2-methyl-[1,4]oxazepane hydrochloride as pale yellow oil (964 mg, 90%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][C:20]#[CH:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:28]([O-])([N+]([O-])=O)=[O:29]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:28]=[O:29])[C:5]([N:7]([CH2:19][C:20]#[CH:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: C#CCN(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#CCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 71.7 %

Procedure:
3.2 g of 1-(2-chloroethyl)-3-(2-propynyl)-3-D-galactopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling and stirring. The mixture is treated in the same manner as described in Example 2. 2.5 g of 1-(2-chloroethyl)-1-nitroso-3-(2-propynyl)-3-D-galactopyranosylurea are thereby obtained as a pale yellow powder.
Reaction SMILES: [N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=[O:20].[CH2:23]([N:30]1[C:38]2[C:33](=[N:34][CH:35]=[CH:36][C:37]=2[N:39]2[CH2:48][CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40]2)[C:32]([CH3:49])=[C:31]1[CH3:50])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)(=O)C.O>[CH2:23]([N:30]1[C:38]2[C:33](=[N:34][CH:35]=[CH:36][C:37]=2[N:39]2[CH2:48][CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40]2)[C:32]([CH2:49][OH:20])=[C:31]1[CH3:50])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(C)n(Cc2ccccc2)c2c(N3CCc4ccccc4C3)ccnc12
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(CO)c2nccc(N3CCc4ccccc4C3)c2n1Cc1ccccc1
Temperature: 55 °C
Reaction time: 4 h

Procedure:
The compound prepared in Example 6 (501.1 mg, 1.23 mmol) was treated with a saturated sodium bicarbonate solution to obtain 1-benzyl-7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[3,2-b]pyridine (433.6 mg, 1.18 mmol). Ammonium cerium (IV) nitrate (1.94 g, 3.54 mmol) was added at room temperature to a solution of 1-benzyl-7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[3,2-b]pyridine (433.6 mg, 1.18 mmol) in acetic acid (10 ml). The reaction mixture was stirred for 4 hours at 55° C., cooled to room temperature, poured in water, and then extracted with ethyl acetate. The resulting organic layer was washed with a saturated sodium chloride solution, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was dissolved in methanol (20 ml). 2N Lithium hydroxide (5.0 ml) was added to the solution, which was then stirred for 1 hour at room temperature. The reaction mixture was neutralized with 1N hydrochloric acid, concentrated under reduced pressure to discard methanol, and then extracted with ethyl acetate. The resulting organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography to give 1-benzyl-7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-3-hydroxymethyl-2-methyl-1H-pyrrolo[3,2-b]pyridine, which was then dissolved in ethyl acetate. The solution was saturated with hydrochloric acid gas and then filtered to give the titled compound as a white solid (69 mg, 13.9%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[C:13]1[N:14]=[C:15]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[C:16]2[S:21][C:20]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([N:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]3)=[CH:19][C:17]=2[N:18]=1>CN(C=O)C.O>[N:1]1([C:13]2[N:14]=[C:15]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[C:16]3[S:21][C:20]([CH2:22][N:23]4[CH2:24][CH2:25][CH:26]([N:29]([CH3:31])[CH3:30])[CH2:27][CH2:28]4)=[CH:19][C:17]=3[N:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: c1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C1CCN(Cc2cc3nc(-n4ncc5ccccc54)nc(N4CCOCC4)c3s2)CC1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 48.9 %

Procedure:
A solution of indazole (0.118 g) in DMF (8 mL) was cooled to 0° C. then sodium hydride (0.06 g) added. After 15 min, [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.395 g) was added and the reaction vessel sealed and heated at 150° C. After 1 h the reaction mixture was cooled to room temperature then diluted with water. The resulting precipitate was collected by filtration then purified by chromatography (silica, 0 to 20% of a 49:1 MeOH:NH4OH mixture in dichloromethane) to furnish 116 (0.233 g, 49%) as a white solid after trituration with ethyl acetate. MS m/e 478 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.41 (dd, J=11.68, 3.39 Hz, 2 H) 1.73 (d, J=10.93 Hz, 2 H) 2.07 (t, J=10.74 Hz, 3 H) 2.17 (s, 6 H) 2.94 (d, J=11.68 Hz, 2 H) 3.75-3.90 (m, 6 H) 3.93-4.13 (m, 4 H) 7.31 (t, J=7.54 Hz, 1 H) 7.39 (s, 1 H) 7.56 (dd, J=7.91, 6.40 Hz, 1 H) 7.88 (d, J=7.91 Hz, 1 H) 8.39 (s, 1 H) 8.68 (d, J=8.67 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[C:4]([O:11][CH3:12])[CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(Cl)Cl>>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([O:10][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(Br)cc(OC)c1O
Solvent: ClCCl
Product: COc1cc(Br)cc(OC)c1Oc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-bromo-2,6-dimethoxyphenol (500 mg, 0.002 mol), phenylboronic acid (0.65 g, 0.0054 mol), TEA (1.8 mL, 0.013 mol), cupric acetate (0.62 g, 0.0034 mol) and DCM (30 mL, 0.4 mol) were added to a 100 mL oven dried flask and the reaction was stirred at rt for 48 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=3.77 (s, 6H), 6.82 (s, 2H), 6.86 (d, J=7.83 Hz, 2H), 6.96-7.04 (m, 1H), 7.22-7.27 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:8]=1[Cl:34])[CH3:6])=[O:4].[CH3:35][O:36][C:37]([NH:39][C:40]1[N:45]=[CH:44][C:43]([CH2:46][CH2:47][C:48](O)=[O:49])=[CH:42][CH:41]=1)=[O:38].ClC1C(COC2C3N=C(OC)N(CC4C=CC=CN=4)C=3C=CC=2)=C(Cl)C=CC=1N(C)C(=O)CNC(=O)CCC1C=CC(C(NCCOC)=O)=CC=1>>[Cl:34][C:8]1[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:48](=[O:49])[CH2:47][CH2:46][C:43]1[CH:42]=[CH:41][C:40]([NH:39][C:37](=[O:38])[O:36][CH3:35])=[N:45][CH:44]=1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Reactant: COC(=O)Nc1ccc(CCC(=O)O)cn1
Agent: COCCNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)cc1
Product: COC(=O)Nc1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)cn1

Procedure:
2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide and 3-(6-((methoxycarbonyl)amino)pyridin-3-yl)propanoic acid were combined as previously described for compound 1 to give 2. LCMS (+APCI) 706 (M+). 1H-NMR (CDCl3, δ ppm): 8.58 (m, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.72 (bs, 1H), 7.58 (dt, J=1.6, 7.6 Hz, 1H), 7.51 (2.0, 8.4 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.19 (m, 1H), 7.04 (t, J=8.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.83 (d, J=7.6 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 6.40 (bt, 1H), 5.67 (d, J=1.6 Hz, 2H), 5.28 (s, 2H), 4.21 (s, 3H), 3.78 (s, 3H), 3.75 (m, 1H), 3.50 (dd, J=4.0, 17.6 Hz, 1H), 3.23 (s, 3H), 2.88 (dd, J=7.6 Hz, 2H), 2.49 (t, J=7.6 Hz, 2H). Calcd. for C34H33Cl2N7O6+1H2O: C, 56.36; H, 4.87; N, 13.53. Found: C, 56.34; H, 4.68; N, 13.24.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([OH:21])=O)=[CH:5]2.[NH2:22][C:23]1[CH:24]=[C:25]2[NH:31][CH:30]=[CH:29][C:26]2=[N:27][CH:28]=1>>[NH:31]1[C:25]2[C:26](=[N:27][CH:28]=[C:23]([NH:22][C:19]([C:6]3[N:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=4)[C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)=[O:21])[CH:24]=2)[CH:29]=[CH:30]1
Reactant: Nc1cnc2cc[nH]c2c1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Product: O=C(Nc1cnc2cc[nH]c2c1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Yield: 39.3 %

Procedure:
The process is performed according to a method similar to that of Example 1.3 starting with 0.4 g (1.39 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid prepared in step 1.1 and 0.22 g (1.67 mmol) of 6-amino-1H-pyrrolo[3,2-b]pyridine (Adesis). 0.22 g of the expected product is thus isolated in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:14])[N:8]=1)=[O:5].[CH:27]1([CH:30]=O)[CH2:29][CH2:28]1.C(O)(=O)C.[Na].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Cl:50]CCl>CO>[ClH:50].[ClH:50].[F:26][C:21]1[CH:22]=[C:23]([F:25])[CH:24]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH:15]2[CH2:16][CH2:17][N:18]([CH2:30][CH:27]3[CH2:29][CH2:28]3)[CH2:19][CH2:20]2)=[O:14])[N:8]=1)=[O:5]
Reactant: O=C(Nc1cccc(C(=O)C2CCNCC2)n1)c1c(F)cc(F)cc1F
Reactant: ClCCl
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Product: Cl
Product: O=C(Nc1cccc(C(=O)C2CCN(CC3CC3)CC2)n1)c1c(F)cc(F)cc1F
Reaction time: 0.25 h
Yield: 77 %

Procedure:
Combine 2,4,6-trifluoro-N-[6-(piperidin-4-ylcarbonyl)pyridin-2-yl]benzamide (0.05 g, 0.138 mmol), cyclopropylmethanal (0.10 g, 1.38 mmol) and dichloromethane (5 mL), and stir at ambient temperature. After 15 minutes, add glacial acetic acid (0.02 mL, 0.35 mmol) followed by sodium-triacetoxyborohydride (0.038 g, 0.18 mmol) with stirring. After 3 hrs., dilute the reaction mixture with methanol (5 mL) and load on an SCX column (10 g). Wash the column with methanol, elute with 2M ammonia/methanol, and concentrate the eluent. Purify the residue by flash chromatography, eluting with 10% ammonia/methanol in dichloromethane, to obtain the free base of the title compound (0.045 g, 77%). Dissolve the free base in dichloromethane (5 mL), treat with 1M hydrogen chloride in diethylether (0.25 mL), and concentrate the mixture to obtain the dihydrochloride salt. M.p.=140° C.; HRMS: Obs. m/z 418.1743; Calc. m/z 418.1742; 1H NMR (CDCl3): 11.51 (bs, 1H), 10.34 (bs, 1H), 8.38 (m, 1H), 8.11 (m, 1H), 7.78 (d, 1H), 7.42 (m, 2H), 3.79 (m, 1H), 3.64 (m, 2H), 2.98 (m, 4H), 2.17 (m, 2H), 1.99 (m, 2H), 1.13 (m, 1H), 0.65 (m, 2H), 0.39 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([NH2:12])[CH:5]=1.Cl.C(O)CCC.[C:20]1(Cl)[C:26](=O)[C:25](Cl)=[C:24](Cl)[C:22](=O)[C:21]=1Cl>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3]([C:4]1[C:5]2[CH:26]=[CH:20][C:21]([CH2:22][CH2:24][CH3:25])=[N:12][C:6]=2[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)=[O:13]
Reactant: COC(=O)c1ccc(OC)c(N)c1
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCCCO
Product: CCCc1ccc2c(C(=O)OC)ccc(OC)c2n1
Temperature: 25 °C
Yield: 10.5 %

Procedure:
Methyl-3-amino-4-methoxybenzoate (10.0 g) was treated with concentrated hydrochloric acid (14 ml) and n-butanol (10 ml), under nitrogen, with stirring. The stirred mixture was treated with p-chloranil (13.65 g) and then heated at reflux whilst a mixture of trans-2-hexanal (8 ml) and n-butanol (5 ml) was added dropwise over 2 hours using a syringe pump. After heating at reflux for a further 30 minutes the mixture was treated with a solution of anhydrous zinc chloride (7.52 g) in tetrahydrofuran (60 ml), then allowed to cool slowly to room temperature and then cooled to 0° C. for 18 hours. The reaction mixture was evaporated, then diluted with hydrochloric acid (1M) and then washed with diethyl ether. The pH of the solution was adjusted to 6 and the resulting emulsion was treated with ammonium hydroxide and the solution extracted with diethyl ether. The combined dark green extracts were dried over magnesium sulphate then evaporated. The resulting dark green oil was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (3:7, v/v) to give the title compound (1.5 g) as an orange oil. NMR(CDCl3): δ9.36(d,J=8.9 Hz,1 H), 8.26(d,J=8.4 Hz,1 H), 7.47(d,J=8.9 Hz,1 H), 7.03(d,J=8.4 Hz,1 H), 4.14(s,3 H), 3.97(s,3 H), 3.02(m,2 H), 1.86(m,2 H), 1.03(t,J=7.3 Hz,3 H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][NH:14][C@H:13]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:18]1([C@H:13]2[C:12](=[O:11])[CH2:17][CH2:16][CH2:15][NH:14]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O[C@H]1CCCN[C@H]1c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C1CCCN[C@H]1c1ccccc1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
A solution of dimethyl sulfoxide (4.2 ml, 59 mmol) in dichloromethane (10 ml) was added dropwise to a stirred solution of oxalyl chloride ( 4.4 ml, 51 mmol) in dichloromethane (100 ml) at −70° C. over 10 min. After 10 min a solution of (2S,3S)-3-hydroxy-2-phenylpiperidine (10.5 g, 38.5 mmol) in dichloromethane (30 ml) was added dropwise at −70° C. over 10 min. The mixture was stirred an additional 10 min and triethylamine (15 ml, 108 mmol) added dropwise over 15 min. The reaction mixture was allowed to warm to −10° C. over 90 min and poured into a 10% aqueous solution of citric acid (200 ml). The phases were separated and the aqueous layer was extracted with dichloromethane (2×50 ml). The combined organic extracts were dried (Na2SO4) and concentrated to give crude (2S)-2-phenyl-3-piperidone which was immediately used in the next step.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:17])[N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.C(N(C(C)C)CC)(C)C.[C:27]([O:30][CH2:31][C:32](Cl)=O)(=[O:29])[CH3:28]>C1COCC1.O>[C:27]([O:30][CH2:31][C:32]1[O:1][N:2]=[C:3]([N:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:8][CH2:9]2)[N:17]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(C(=N)NO)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OCc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)no1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
1,1-Dimethylethyl 4-[(hydroxyamino)(imino)methyl]piperazine-1-carboxylate (3.58 g, 14.6 mmol) was suspended in THF (50 mL) followed by the addition of diisopropylethylamine (3.0 mL, 17.5 mmol) and the mixture was cooled to 0° C. Acetoxyacetyl chloride (1.6 mL, 14.6 mmol) was added by syringe and the mixture was allowed to stir an additional 30 minutes at 0° C. The resulting homogeneous solution was allowed to warm to room temperature then concentrated in vacuo to afford a white solid residue. The material was suspended in water (50 ml) and the solid product was collected by filtration, washed with additional water then hexanes and dried in vacuo. The intermediate O-acyl derivative was then suspended in THF (50 mL) followed by addition of TBAF (1.0M in THF, 3.5 mL) and the mixture was stirred for 30 minutes at room temperature. The homogeneous solution obtained was concentrated in vacuo and the residue partitioned with ethyl ether and water. The organic layer was washed twice with additional water then with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. Filtration and concentration gave 1,1-dimethylethyl 4-{5-[(acetoxy)methyl]-1,2,4-oxadiazol-3-yl}piperazine-1-carboxylate (3.6 g, 76% yield) as a colorless crystalline solid. 1H-NMR (400 MHz, CDCl3): 5.14 (s, 2H), 3.51 (tr, 4H), 3.42 (tr, 4H), 2.18 (s, 3H), 1.48 (s, 9H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:18])=[CH:15][C:16]=1O>N1C=CC=CC=1>[CH3:18][C:14]1[CH:13]=[CH:12][C:11]2[N:10]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:8][C:16]=2[CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(N)c(O)c1
Solvent: c1ccncc1
Product: Cc1ccc2nc(-c3ccccc3)oc2c1

Procedure:
Benzoyl chloride (79 ml) was slowly added to a stirred suspension of 6-amino-m-cresol (83 gm) in pyridine (600 ml). The temperature was kept below 5°C. The solution was heated under reflux for 2 hr., then was evaporated to dryness to give an oil. This oil was extracted with aqueous 2N sodium hydroxide solution. The aqueous layer was made acid with concentrated hydrochloric acid. The solid, N-(2'-hydroxy-4'-methylbenzanilide), m.p. 170°C, was filtered off. This product was heated until no more water was evolved. The resulting liquid was allowed to cool and the solid produced was powdered and taken up in petroleum ether. The solution was treated with carbon and the filtrate evaporated to dryness to yield 6-methyl-2-phenylbenzoxazole, m.p. 93°C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[CH3:12])#[N:2].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-:22].[K+].[K+]>CO>[N+:9]([C:7]1[CH:8]=[C:3]([C:4]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:6]=1)[C:1]([NH2:2])=[O:22])([O-:11])=[O:10]
Reactant: Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: O=Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: NC(=O)c1cc([N+](=O)[O-])ccc1C=Cc1ccccc1
Temperature: 25 °C
Yield: 785.4 %

Procedure:
A mixture of 2-cyano-4-nitrotoluene (10 g, 6.17 mmol), benzaldehyde (6.51 g, 6.17 mmol) and potassium carbonate (20 g) in MeOH (200 mL) was heated at reflux for 10 min. The mixture was cooled to ambient temperature over 30 min, whereupon precipitation of the product was complete. The product was isolated by filtration and washed successively with 1N HCl, water and MeOH then air dried. There was obtained 13.0 g of the benzamide (mp 269.8° C.) as evident from the lack of a nitrile adsorption in the IR and the appearance of peaks at 3357.1, 3193.6 (—NH2) and 1648.7 cm−1 (H2NC(═O)—); LRMS (M−NO)+ m/z=238.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[NH:8][N:7]=1)=[O:5])[CH3:2].[F:22][C:23]([F:34])([F:33])[CH2:24]OS(C(F)(F)F)(=O)=O>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:24][C:23]([F:34])([F:33])[F:22])[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)[nH]n1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Product: CCOC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)nn1CC(F)(F)F

Procedure:
In analogy to the procedure described for example 13 a], 5-(4-trifluoromethoxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (example 11 b]) was reacted with trifluoroethyltriflate to give 2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazole-3-carboxylic acid ethyl ester as colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)#[N:2].[NH2:9][C:10]1[S:11][C:12]([N+:20]([O-:22])=[O:21])=[CH:13][C:14]=1[C:15](OCC)=O.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:15]1[C:14]2[CH:13]=[C:12]([N+:20]([O-:22])=[O:21])[S:11][C:10]=2[N:9]=[C:1]([C:3]2[CH:8]=[N:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc([N+](=O)[O-])sc1N
Reactant: N#Cc1cnccn1
Product: O=[N+]([O-])c1cc2c(Cl)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 477, the reaction of 2-cyanopyrazine and 2-amino-5-nitro-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(pyrazin-2-yl)-6-nitro-thieno-[2,3-d]-pyrimidine
Reaction SMILES: [CH:1]1[C:10]2CCCC[C:5]=2[CH:4]=[CH:3][C:2]=1[C:11](=[O:13])[CH3:12].[C:14]([OH:17])(=O)C.[Br:18]Br>>[Br:18][CH2:12][C:11]([C:2]1[CH:3]=[CH:4][CH:5]=[C:10]([O:17][CH3:14])[CH:1]=1)=[O:13]
Reactant: BrBr
Reactant: CC(=O)c1ccc2c(c1)CCCC2
Reactant: CC(=O)O
Product: COc1cccc(C(=O)CBr)c1
Yield: 28.9 %

Procedure:
Reaction of 1-(5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone (5 g, 28.70 mmol), acetic acid (1.6 mL, 28.70 mmol), and bromine (1.7 mL, 33.00 mmol) followed by recrystallisation from cold EtOAc/Hexane gave the title compound (1.9 g, 26%) as a yellow powder. 1H NMR (300 MHz, CD3OD) δ 1.84 (t, 4H, J=6.6 Hz), 2.80-2.85 (m, 4H), 4.61 (s, 2H), 7.19 (d, 1H, J=8.7 Hz), 7.70-7.78 (m, 2H). ES-MS m/z 253 (M+H).
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]1[CH:14]=[C:15]([NH:24][C:25](=[O:50])[N:26]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]([NH:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([C:47](=[O:49])[NH2:48])[CH:42]=3)[C:37]([OH:39])=[O:38])=[CH:32][CH:31]=2)[CH3:27])[CH:16]=[CH:17][C:18]=1[S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])=O)C1C=CC=CC=1>C1COCC1.CO.CCOC(C)=O.Cl.[Pd]>[NH2:11][CH2:12][C:13]1[CH:14]=[C:15]([NH:24][C:25](=[O:50])[N:26]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]([NH:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([C:47](=[O:49])[NH2:48])[CH:42]=3)[C:37]([OH:39])=[O:38])=[CH:32][CH:31]=2)[CH3:27])[CH:16]=[CH:17][C:18]=1[S:19]([CH2:22][CH3:23])(=[O:21])=[O:20]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)N(C)CCc2ccc(C(Nc3cccc(C(N)=O)c3)C(=O)O)cc2)cc1CNC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1ccc(NC(=O)N(C)CCc2ccc(C(Nc3cccc(C(N)=O)c3)C(=O)O)cc2)cc1CN

Procedure:
A solution of 28G (225 mg, 0.32 mmol) in THF/MeOH/EtOAc (1:1:1) and HCl (1.0 M, 1.5 mL) with Pd/C (50 mg, 10%) was stirred under H2 (60 psi) for 20 h. The mixture was filtered through Celite and concentrated in vacuo to yield 28H (160 mg, 83%). MS (ESI) m/z 568.3 (M+H)+.