Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[N:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[N:10]=[C:11]([CH3:12])[C:3]=12.N[C@@H](CC)CO.[C:28]1([OH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:12][C:11]1[C:3]2[C:4](=[N:5][C:6]([CH3:8])=[CH:7][C:2]=2[O:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:9]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[N:10]=1
Reactant: Oc1ccccc1
Reactant: Cc1cc(C)c(-n2nc(C)c3c(Cl)cc(C)nc32)c(C)c1
Agent: CC[C@H](N)CO
Product: Cc1cc(C)c(-n2nc(C)c3c(Oc4ccccc4)cc(C)nc32)c(C)c1
Temperature: 190 °C
Yield: 14.5 %

Procedure:
A mixture of 4-chloro-3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-b]pyridine (300 mg, 1 mmol), (S)-2-amino-1-butanol (107 mg, 1.2 mmol) and phenol (188 mg, 2 mmol) was heated in 190° C. oil bath for 15 hours. The mixture was cooled, quenched with 2 N sodium hydroxide and extracted with chloroform. The organic layer was separated and neutralized with 2 N hydrochloride and water. The organic layer was dried and concentrated to give an oil residue. The residue was purified through silica gel column chromatography using chloroform as eluent to give 157 mg of starting material, and 52 mg of 3,6-dimethyl-4-phenoxy-1-(2,4,6-trimethylphenyl)-1H-pyrazolo-[3,4-b]pyridine as beige crystals. 1H NMR (CDCl3): 7.1-7.45 (m, 5H), 6.95 (s, 2H), 6.06 (s, 1H), 2.71 (s, 3H), 2.38 (s, 3H), 2.29 (S, 3H), 1.94 (s, 6H) ppm; and 30 mg of 2-[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1-H-pyrazolo[3,4-b]pyridin4-ylamino]-butan-1-olasa yellow glass.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].Cl.[CH3:19]O>>[CH3:19][O:4][C:3](=[O:5])[CH:2]([NH2:1])[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CO
Reactant: NC(CCCc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: Cl
Product: COC(=O)C(N)CCCc1ccc([N+](=O)[O-])cc1
Reaction time: 24 h
Yield: 98 %

Procedure:
A solution of Compound 4 (7.1 g, 29.8 mmol) in MeOH (120 mL) at 0-5° C. was saturated with HCl (g) for 2 h, at which time the mixture was allowed to ambient temperature and then was stirred for 24 h. The resulting mixture was concentrated in vacuo to provide technically pure product 5 (7.4 g, 98%) as an acidic salt. 1H NMR (D2O, 300 MHz) δ 1.50-1.93 (m, 4H), 2.67 (t, J=7.1 Hz, 2H), 3.68 (s, 3H), 4.03 (t, J=5.9 Hz, 1H), 7.30 (d, J=8.4 Hz, 2H), 8.03 (d, 2H, J=8.2 Hz, 2H); 13C NMR (D2O, 300 MHz) δ 25.50, 29.26, 34.16, 52.66, 53.50, 123.30, 129.18, 145.50, 149.96, 170.37.
Reaction SMILES: [CH:1]1([C:7]([CH3:12])=[CH:8][C:9](O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)=CC[C@H]1O[C@@]1([C@@H]1[C@]2(OC2)CC[C@@H](OC(/C=C/C=C/C=C/C=C/C(O)=O)=O)[C@H]1OC)C.[N+:46]([C:49]1[CH:50]=[C:51]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[C:62]([F:65])([F:64])[F:63])[CH:52]=[CH:53][C:54]=1[NH2:55])([O-])=O>>[CH:1]1(/[C:7](/[CH3:12])=[CH:8]/[C:9]2[NH:55][C:54]3[CH:53]=[CH:52][C:51]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=4[C:62]([F:63])([F:64])[F:65])=[CH:50][C:49]=3[N:46]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CC(=CC(=O)O)C1CCCCC1
Agent: CO[C@@H]1[C@H](OC(=O)/C=C/C=C/C=C/C=C/C(=O)O)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Product: C/C(=C\c1nc2cc(-c3ccccc3C(F)(F)F)ccc2[nH]1)C1CCCCC1

Procedure:
(E)-2-(2-Cyclohexyl-propenyl)-5-(2-trifluoromethyl-phenyl)-1H-benzimidazole was prepared from the acid chloride of 3-cyclohexyl-but-2-enoic acid (prepared as described in YOUNG, S. T. et al., “Synthetic Studies in the Fumagillin Series”, J. Org. Chem., 1963, pp 928-932, Vol. 28) and 3-nitro-2′-trifluoromethyl-biphenyl-4-ylamine (prepared as described in Example 3, STEP A) according to the procedures s described in Example 3, STEPS B, C and D.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[CH3:36][N:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[C:42](O)=[O:43]>C(Cl)CCl>[CH3:36][N:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[C:42]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1)=[O:43]
Reactant: Cn1cccc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Solvent: ClCCCl
Product: Cn1cccc1C(=O)OCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1

Procedure:
In an analogous manner to that described in Example 9(c), by esterifying tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 53(c)] with 1-methyl-pyrrole-2-carboxylic acid in the presence of EDC there was obtained tert-butyl (3RS,4RS)-4-[4-[2-(1-methyl-1H-pyrrol-2-carbonyloxy)-ethoxy]-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 585 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([NH:24][C@H:25]([CH2:29][CH3:30])[C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][N:11]([C:26](=[O:27])[C@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:29][CH3:30])[CH2:10][C:9]2([CH3:14])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC1(C)CNCC[C@]1(O)c1ccc(Cl)cc1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1

Procedure:
(S)-4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol (100 mg, 0.42 mmol), (R)-2-(tert-butoxycarbonylamino)butanoic acid (102 mg, 0.50 mmol), HOBT (68 mg, 0.5 mmol), EDC (155 mg, 1 mmol), DIPEA (129 mg, 1 mmol), and chlororform (2 mL) was stirred overnight at rt. The reaction mixture was then partitioned between methylene chloride and saturated sodium bicarbonate solution, the layers were separated and the organic extracts were dried over magnesium sulfate, filtered, and concentrated to yield the product, which was used in next step without further purification.
Reaction SMILES: CS(C)=O.Cl[C:6]1[CH:19]=[C:18]([NH2:20])[C:17]2[C:16](=[O:21])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:22])[C:8]=2[C:7]=1[NH2:23].[OH-:24].[Na+].[OH2:26]>>[OH:24][CH2:10][CH2:9][C:8]1[CH:17]=[CH:18][C:19]([O:26][C:6]2[CH:19]=[C:18]([NH2:20])[C:17]3[C:16](=[O:21])[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9](=[O:22])[C:8]=3[C:7]=2[NH2:23])=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: Nc1cc(Cl)c(N)c2c1C(=O)c1ccccc1C2=O
Reactant: O
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1cc(Oc2ccc(CCO)cc2)c(N)c2c1C(=O)c1ccccc1C2=O
Yield: 24 %

Procedure:
A solution of dimethylsulfoxide (50 ml), water (5.0 ml), 2-chloro-1,4-diamino anthraquinone (5.0 g) and sodium hydroxide (1.0 g) is heated to 100° C. for 4 hours. The mixture is cooled and diluted with water until a precipitate forms. The precipitate is collected, washed, dried and recrystallized from carbon tetrachloride. The yield is 24 percent 2-(p-hydroxy ethyl phenoxy)-1,4-diamino anthraquinone with a melting point of 224° C. to 227° C.
Reaction SMILES: [O:1]1[C:5]2[CH2:6][N:7]([C:10](=[O:27])[CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:14]=3)[CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29].[CH2:33]=O>C(O)(=O)C>[CH2:28]([N:30]([CH2:33][C:2]1[O:1][C:5]2[CH2:6][N:7]([C:10](=[O:27])[CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:14]=3)[CH2:8][CH2:9][C:4]=2[CH:3]=1)[CH2:31][CH3:32])[CH3:29]
Reactant: O=C(CCc1cccc(CCc2ccccc2)c1)N1CCc2ccoc2C1
Reactant: CCNCC
Reactant: C=O
Solvent: CC(=O)O
Product: CCN(CC)Cc1cc2c(o1)CN(C(=O)CCc1cccc(CCc3ccccc3)c1)CC2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.393 g (1.093 mmol) of 1-(5,7-dihydro-4H-furo[2,3-c]pyridin-6-yl)-3-(3-phenethylphenyl) propan-1-one in 20 ml of acetic acid, 0.14 ml (1.3 mmol) of diethylamine and 0.11 g (1.3 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 1 hour. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=9/1) to yield the desired product.
Reaction SMILES: [O-]CC.[Na+].[Na].[OH:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[N:11][CH:12]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH2:14]([O:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[N:11][CH:12]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(O)cn1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: Cc1ccc(OCc2ccccc2)cn1

Procedure:
To a solution of sodium ethoxide prepared from 1.3 g. (0.0565 g. -atom) of sodium and 30 ml. of absolute ethanol is added a solution of 5-hydroxy-2-methylpyridine (5.0 g., 0.0458 mol) in 15 ml. of ethanol, followed by 8.6 g. (0.05 mol) of benzyl bromide. The mixture is refluxed for three hours, poured into 150 ml. of water and extracted with ether. The extract is dried and then treated with ethereal hydrogen chloride. The hydrochloride salt is dissolved in water and the aqueous solution is washed with ether, basified and extracted with ether. The dried extract is treated with charcoal and evaporated to give 5-benzyloxy-2-methylpyridine as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:17]([NH2:19])=[N:16][CH:15]=[N:14][C:13]=3[S:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.C(O)C>C1COCC1.O.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:18]3[C:17]([NH2:19])=[N:16][CH:15]=[N:14][C:13]=3[S:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: Nc1ncnc2scc(-c3ccc([N+](=O)[O-])cc3)c12
Agent: [Fe]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2csc3ncnc(N)c23)cc1
Yield: 97.4 %

Procedure:
A suspension of Example 58C (0.5 g, 1.83 mmol) in THF (30 mL), water (15 mL), and ethanol (40 mL) was heated to 50° C., treated with iron powder (0.616 g, 11.02 mmol), heated to between 70 and 80° C. for two hours, and filtered while hot through diatomaceous earth (Celite®). The pad was washed with TBF (10 mL) and ethanol and the combined filtrates were concentrated. The residue was partitioned between water and ethyl acetate and the aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated to give 0.432 g of the desired product. MS (CI) m/e 243 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.30 (s, 1H); 7.28 (s, 1H); 7.11 (d, J=8.4 Hz, 2H); 6.68 (d, J=8.4 Hz, 2H); 5.39 (br s, 2H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=1)[C:14]([O:16]CC)=[O:15].[OH-].[Na+].C(O)(=O)C>O1CCOCC1>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=1)[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)c1cccc(N2CCc3ccncc3C2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=C(O)c1cccc(N2CCc3ccncc3C2)c1
Temperature: 70 °C

Procedure:
A mixture of ethyl 3-(3,4-dihydro-2,7-naphthyridin-2(1H)-yl)benzoate (51 mg, 0.18 mmol) and 0.5 mL 1.0 M NaOH in 2.0 mL dioxane was heated at 70° C. for 2.3 hours. The pH of the reaction was adjusted to pH 5 using glacial acetic acid. The mixture was evaporated and then chased with MeOH to give a yellow solid film. An impure lot from a previous reaction was combined, and this material triturated with EtOAc. The remaining solid was dissolved in MeOH, and then Bio-rad AG1-X8 basic resin (hydroxide form) was added. The mixture was filtered and the resin rinsed with MeOH and CH2Cl2. The product was eluted from the resin using 10% formic acid in MeOH. The solvent was evaporated, chased with MeOH and EtOAc to give the title compound (used as is for the next step) as a yellow solid (49 mg). 1H NMR (CD3OD) δ: 8.42 (s, 1H), 8.29 (d, J=5.3 Hz, 1H), 7.68-7.70 (m, 1H), 7.48-7.51 (m, 1H), 7.33-7.39 (m, 1H), 7.30 (dd, J=2.5, 1.3 Hz, 1H), 7.26 (d, J=4.7 Hz, 1H), 4.48 (s, 2H), 3.64 (t, J=5.9 Hz, 2H), 3.04 (t, J=5.6 Hz, 2H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)([O:3]C(C)(C)C)=O.O[C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[C:21]([O:23]CC)=[O:22].N1CCC(CCOC2[CH:39]=[C:40]([CH:46]=CC=2)[C:41](OCC)=[O:42])CC1>>[OH:42][CH2:41][C:40]([CH3:46])([CH3:39])[C:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][O:16][C:27]2[CH:26]=[C:20]([CH:19]=[CH:18][CH:28]=2)[C:21]([OH:23])=[O:22])[CH2:12][CH2:13]1)=[O:3]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: CCOC(=O)c1cccc(OCCC2CCNCC2)c1
Product: CC(C)(CO)C(=O)N1CCC(CCOc2cccc(C(=O)O)c2)CC1

Procedure:
Prepared from N-Boc-4-piperidine ethanol and ethyl 3-hydroxybenzoate, with the exception that ethyl 3-(2-piperidin-4-yl-ethoxy)-benzoate was converted to its corresponding carboxamide as described below before the final alkaline hydrolysis to give the title compound. LC-MS (m/z): 351 (M+2).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)\[CH3:7])[CH3:2].[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:23])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)\[CH2:7][Br:24])[CH3:2]
Reactant: CCOC(=O)/C=C(\C)Oc1ccccc1OCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1ccccc1OCc1ccccc1
Yield: 65.3 %

Procedure:
To a stirred mixture of (E)-3-(2-benzyloxy-phenoxy)-but-2-enoic acid ethyl ester (5.70 g, 0.018 mol) in carbon tetrachloride (35 mL) under a nitrogen atmosphere was added N-bromosuccinimide (4.90 g, 0.028 mol) and benzoyl peroxide (440 mg, 0.002 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-3-(2-benzyloxy-phenoxy)-4-bromo-but-2-enoic acid ethyl ester (4.60 g, 64%) as a yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]=[CH:8]1)C.[OH-].[Na+].CCOC(C)=O>C(O)C>[C:12]1([C:10]2[N:9]=[CH:8][N:7]([CH2:6][CH2:5][C:4]([OH:18])=[O:3])[CH:11]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCn1cnc(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)CCn1cnc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
3-(4-phenylimidazol-1-yl)propionic acid ethyl ester (2.442 g, 10 mmol) was dissolved in 50 mL of ethanol, added with 0.5N-NaOH (20 mL) and then stirred at room temperature. Initiation and termination of the reaction was confirmed with TLC (EtOAc). Upon completion of the reaction, ethanol was removed by distillation under reduced pressure to obtain the target compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O.[F:14][C:15]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:16]=1[C:17](=[S:20])[NH:18][NH2:19]>C(O)C.ClCCl>[F:14][C:15]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:16]=1[C:17]1[S:20][C:6]([CH2:5][O:4][CH2:3][O:2][CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:19][N:18]=1
Reactant: COCOCC(=O)c1ccccc1
Reactant: NNC(=S)c1cc(F)ccc1F
Solvent: ClCCl
Solvent: CCO
Product: COCOCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.9 %

Procedure:
To a solution of 2-(methoxymethoxy)-1-phenylethanone (600 mg, 3.33 mmol) in ethanol/dichloromethane (12 mL, 3:1) was added 2,5-difluorobenzothiohydrazide (627 mg, 3.33 mmol). After stirring at room temperature for 16 hours, the mixture was concentrated under reduced pressure and chromatographed (9:1 hexanes/ethyl acetate) to afford the product (734 mg, 63%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[C:6]([CH3:19])[CH:5]=1.FC(F)(F)S(O[C:27]1[CH:32]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:31][CH2:30][CH2:29][CH:28]=1)(=O)=O>>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:31]2[CH:32]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:27][CH2:28][CH2:29][CH:30]=2)=[C:6]([CH3:19])[CH:5]=1
Reactant: CC(C)(C)C1CCCC=C1OS(=O)(=O)C(F)(F)F
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Product: COC(=O)c1ccc(C2=CCCCC2C(C)(C)C)c(C)c1
Yield: 84.9 %

Procedure:
3-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester of Example 28, Step A (1.00 g, 3.62 mmol) and 6-tert-butyl-cyclohex-1-en-1-yl trifluoromethanesulfonate (1.24 g, 4.34 mmol) were reacted in the manner of Example 1, Step F. Purification by flash column chromatography on silica gel, eluting with a solvent gradient of from 0 to 5% ethyl acetate in hexane, afforded the title compound (0.880 g) as a light yellow oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:13][C:14]1([CH3:22])[O:21][C:19](=[O:20])[CH2:18][C:16](=[O:17])[O:15]1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O.N1CCC[C@H]1C(O)=O>CCO>[CH3:13][C:14]1([CH3:22])[O:21][C:19](=[O:20])[CH:18]([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=2)[C:16](=[O:17])[O:15]1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CC1(C)OC(=O)C(Cc2ccc(C(F)(F)F)cc2)C(=O)O1
Temperature: 25 °C

Procedure:
Similar procedures to those referenced in Tett. Lett. (2006), 651, D. Ramachary; Eur. J. Org. Chem. (2008), 975, D. Ramachary were employed. To a 5 L 3-necked flask fitted with an overhead mechanical stirrer was charged with 4-(trifluoromethyl)benzaldehyde (43.5 g, 250 mmol) followed by the addition of anhydrous EtOH (3,000 mL), Meldrum's acid (37.5 g, 260 mmol), diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (67.5 g, 266 mmol) and L-proline (6.0 g, 51 mmol) at room temperature. The yellowish reaction mixture was stirred at room temperature under N2. An aliquot was removed after 4 hours and rinsed with EtOH and then Et2O, and air dried. The 1H NMR of this aliquot showed the reaction to be complete. The full reaction was stopped and the white precipitate from the reaction was collected by filtration and rinsed with EtOH and then Et2O and dried under vacuum to afford the title compound in the first crop as a fine white solid. The yellowish mother liquors were concentrated and allowed to crystallize overnight from EtOH and the solid material was collected as before to provide the title compound.
Reaction SMILES: [OH:1][C@H:2]([C@H:5]([CH3:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>C([Sn](=O)CCCC)CCC.C(Cl)Cl>[S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)([O:4][CH2:3][C@H:2]([OH:1])[C@H:5]([CH3:14])[CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:23])=[O:22]
Reactant: C[C@H](CCc1ccccc1)[C@@H](O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H](O)[C@H](C)CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a 2 L 3-neck round-bottom flask equipped with a mechanical stirrer and nitrogen inlet was added diol 17 (58 g, 0.30 mol), dibutyltin oxide (1.5 g, 0.006 mol, 2 mol %), p-toluenesulfonyl chloride (57.5 g, 0.30 mol), CH2Cl2 (580 mL) and triethylamine (42.0 mL, 0.30 mol). The resulting mixture was stirred at room temperature for 2 h (although the reaction was complete within 1 h), filtered, washed with water and dried over MgSO4. Concentration of the volatiles in vacuo afforded the title compound (104.1 g) as a slightly amber oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@:9]2([OH:17])[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][CH3:16])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.O.[Br:26][CH:27]([CH3:31])[C:28](Br)=[O:29]>ClCCl>[Br:26][CH:27]([CH3:31])[C:28]([N:15]([C@@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@:9]1([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[OH:17])[CH3:16])=[O:29]
Reactant: CN[C@@H]1CCCC[C@@]1(O)c1cccc(OC)c1
Reactant: CC(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1cccc([C@]2(O)CCCC[C@H]2N(C)C(=O)C(C)Br)c1
Reaction time: 1 h
Yield: 104.1 %

Procedure:
Crude (1R*,2R*)-1-(3-methoxyphenyl)-2-methylaminocyclohexanol (4.7 g, from Example 6) was dissolved in dichloromethane (50 cm3) containing triethylamine (2.8 cm3, 2.02 g). The solution was cooled to 10° in a bath of cold water and treated dropwise with 2-bromopropionyl bromide (2.33 cm3, 4.32 g). The mixture was stirred for 1 hr. while cooling and was then concentrated under reduced pressure to an oily solid. This was partitioned between N hydrochloric acid (50 cm3) and ether (50 cm3), and the aqueous phase was extracted with further ether (3×20 cm3). The ether extracts were dried (Na2SO4) and evaporated, leaving crude (1R*,2R*)-2-(2-bromopropionyl-N-methylamino)-1-(3-methoxyphenyl)cyclohexanol as a yellow oil (7.7 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([CH:8]=1)[NH2:7].ClC(Cl)(O[C:16](=[O:22])OC(Cl)(Cl)Cl)Cl.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>ClCCl>[NH2:9][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:8][C:6]=1[NH:7][C:16]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:22]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C1CCNC1
Reactant: Nc1cc(Br)ccc1[N+](=O)[O-]
Solvent: ClCCl
Product: Nc1ccc(Br)cc1NC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.4 %

Procedure:
To a solution of 5-bromo-2-nitroaniline (1 g, 4.61 mmol) in dichloromethane (15 mL) were added TEA (8.35 mL, 59.9 mmol, 1.3 eq.) and triphosgene (1.37 g, 4.61 mmol, 1 equiv.) at 0° C. The mixture was stirred for three hours at room temperature and the pyrrolidine (0.39 g, 5.53 mmol, 1.2 equiv.) was added slowly. The reaction was stirred for an additional two hours. The reaction crude was diluted with dichloromethane and washed with water and brine. The organic layers were dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography on eluting ethyl acetate and hexane to allow N-(2-amino-5-bromophenyl)pyrrolidine-1-carboxamide (0.45 g, 31% yield).