Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:23])([C:13](=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3](=[O:12])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[Pd].C(OCC)(=O)C>[CH3:1][C:2]([CH3:23])([C:3](=[O:12])[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:13](=[O:22])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C(=O)C=Cc1ccccc1)C(=O)C=Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C(=O)CCc1ccccc1)C(=O)CCc1ccccc1
Yield: 77.8 %

Procedure:
4,4-Dimethyl-1,7-diphenyl-1, 6-heptadiene-3,5-dione (11b, 0.15 g, 0.5 mmol) and palladium on activated carbon (0.20 g, 10%) were combined in ethyl acetate (25 ml). The mixture was placed under a hydrogen atmosphere (60 psi) on a Parr apparatus for 1 hr at room temperature. The resulting mixture was filtered through celite and the filtrate was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford an oil. The crude oil was chromatographed on silica gel with ethyl acetate/hexane to give 0.12 g (80%) of a pale yellow oil; 1H NMR: δ 1.25 (s, 6H), 2.60 (t, 4H, J=7.4 Hz), 2.80 (t, 4H, J=7.0 Hz), 7.18 (m, 10H); 13C NMR: δ 21.1, 29.8, 40.2, 62.4, 126.1, 128.3, 140.7, 208.4; Exact mass calcd for C21H24O2: 308.1776, observed (M+H) 309.1843.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:16])=[CH:7][C:8]([C:12]([O:14]C)=[O:13])=[N:9]2)=[CH:4][CH:3]=1.[Li+].[OH-]>CO.O>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:16])=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(O)c2ccc(C)cc2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc2c(O)cc(C(=O)O)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
7-methyl-4-hydroxy-2-methoxycarbonylquinoline (6.45 g, 30.14 mmol) was suspended in MeOH (150 mL) and water (100 mL), and LiOH (3.08 g, 75.5 mmol) was added and stirred at ambient temperature for 2 hours. The methanol was evaporated in vacuo and residue was crystallized by addition of 2N hydrochloric acid. The resulting solid was filtered, washed with water and dried to afford 7-methyl-4-hydroxy-2-carboxyquinoline (6.0 g, 98%), NMR (DMSO-d6) 2.40 (s, 3), 6.68 (s, 1), 7.22 (d, 1), 7.68 (s, 1), 7.96 (d, 1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH:33][O:34][CH3:35])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][N:33]([O:34][CH3:35])[C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:20])[CH3:21])=[O:23])=[CH:30][CH:31]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: CONCc1ccc(F)cc1
Product: CON(Cc1ccc(F)cc1)C(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and (4-fluorophenyl)-N-methoxymethanamine. White crystals; mp 141° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.66 (6H, s, 2×CH3), 3.59 (3H, s, OCH3), 4.07 (4H, m, 2×CH2), 4.90 (2H, s, NCH2), 5.20 (2H, s, OCH2), 6.81 (2H, m, aromatics), 7.26–7.30 (3H, m, aromatics), 7.36 (2H, m, aromatics), 7.44 (2H, m, aromatics). HRMS (ESI+) calculated for C25H27FN3O5 [M+H+]: 468.1935. Found: 468.1916.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:10]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[N:9]1
Reactant: BrCCCCCCCCBr
Reactant: c1ccc(-c2nn[nH]c2-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: BrCCCCCCCCn1nnc(-c2ccccc2)c1-c1ccccc1

Procedure:
4,5-Diphenyl-1,2,3-triazole was treated with 1,8-dibromooctane and potassium carbonate in butanone to give after chromatographic work up the title compound, m.p. 90°-91° C., Found: C, 64.0; H, 6.5; N, 10.1; Br, 19.8%; C22H26BrN3 requires: C, 64.1;H, 6.4; N, 10.2; Br, 19.4%.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.CC(C)([O-])C.[K+].[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Cl>CN(C)C=O>[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][O:9][CH:6]1[CH2:7][CH2:8][C:3]([N:2]([CH3:16])[CH3:1])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH2:5]1
Reactant: Fc1cccc(CCl)c1
Reactant: CN(C)C1(c2ccccc2)CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C1(c2ccccc2)CCC(OCc2cccc(F)c2)CC1
Temperature: 0 °C
Yield: 33.4 %

Procedure:
2.00 g of 4-dimethylamino-4-phenylcyclohexanol were dissolved in 20 ml of dimethylformamide; 1.13 g of potassium tert.-butoxide were added and stirring was carried out for 45 minutes, before 1.45 g of 3-fluorobenzyl chloride were added dropwise in the course of 15 minutes. After stirring overnight, the mixture was added to 25 ml of ice-water and extracted repeatedly with ethyl acetate. The combined extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The resulting crude product (2.71 g) was separated on silica gel with hexane/diethyl ether (V:V=1:1). 996 mg of [4-(3-fluorobenzyloxy)-1-phenylcyclohexyl]dimethylamine were obtained and, as described for Example 1, were converted into 720 mg of the corresponding hydrochloride with chlorotrimethylsilane and water in 2-butanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@H:18]2[NH:22][CH2:21][C@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1.[C:30](O)(=[O:33])[CH2:31][OH:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@H:18]2[N:22]([C:31](=[O:32])[CH2:30][OH:33])[CH2:21][C@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc(OC[C@@H]2C[C@@H](O)CN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reactant: O=C(O)CO
Product: COc1cc(OC[C@@H]2C[C@@H](O)CN2C(=O)CO)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Yield: 53 %

Procedure:
The procedure described in Example 20 was repeated using (3R,5S)-5-[({4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidin-3-ol (209 mg) with glycolic acid (42 mg) to give the title compound as a white solid in 53% yield; NMR spectrum (DMSO-d6) 10.17 (s, 1H), 8.53 (s, 1H), 8.14 (dd, 1H), 7.74-7.69 (m, 1H), 7.47 (t, 1H), 6.92 (d, 1H), 6.83 (d, 1H), 5.14-5.10 (m, 1H), 4.71-4.67 (m, 1H), 4.50-4.44 (m, 1H), 4.40-4.38 (m, 1H), 4.28-4.23 (m, 1H), 4.06-4.03 (m, 2H), 3.95 (s, 3H), 3.53-3.48 (m, 3H), 2.05-2.02 (m, 2H); Mass spectrum MH+ 477.
Reaction SMILES: [C:1]([NH:8][C:9](=[NH:12])SC)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH2:35][CH2:36][C:37]1[CH:42]=[C:41]([Cl:43])[C:40]([NH:44][C:45](=[O:47])[CH3:46])=[C:39]([Cl:48])[CH:38]=1>C(Cl)Cl>[C:45]([NH:44][C:40]1[C:39]([Cl:48])=[CH:38][C:37]([CH2:36][NH:35]/[C:9](/[NH2:12])=[N:8]\[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[CH:42][C:41]=1[Cl:43])(=[O:47])[CH3:46]
Reactant: CSC(=N)NC(=O)OC(C)(C)C
Reactant: CC(=O)Nc1c(Cl)cc(CN)cc1Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1c(Cl)cc(CN/C(N)=N\C(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To a solution of mono-N-Boc-S-methylisothiourea (Preparation C, 764 mg, 4.0 mmol) and DIPEA (3.0 mL) in CH2Cl2 (8.0 mL) was added trifluoroacetic anhydride (924 mg, 4.4 mmol). The mixture was stirred at rt for 30 min, and then N-(4-(aminomethyl)-2,6-dichlorophenyl)acetamide (930 mg, 4.0 mmol) was added. The resulting mixture was stirred at rt overnight. The solvent was removed. Then 15 mL of MeOH and K2CO3 (1.2 g) were added. After stirring at rt for 30 min, the MeOH was removed. 50 mL of HCl (1 N) was added, and the mixture was washed with Et2O (50 mL) and then neutralized with 50% NaOH to pH=12. The aqueous layer was then extracted with EtOAc (2×100 mL). The organic layer was dried and concentrated to give 1.1 g (yield 73%) of the title compound. MS (ESI) (M+H)+=375.06. 1H NMR (500 MHz, CD3OD) δ 7.39 (s, 2 H), 4.41 (s, 2 H), 2.19 (s, 3 H), 1.45 (s, 9 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:10]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O.C(O)C>[N:21]1[CH:22]=[CH:23][C:18]([C:10](=[N:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(c1ccccc1)c1ccncc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NN=C(c1ccccc1)c1ccncc1
Yield: 11.9 %

Procedure:
To 6.61 gm (0.05 mole) of t-butylcarbazate dissolved in 100 ml of warm water is added 9.16 gm (0.05 mole) of 4-benzoylpyridine in 30 ml of ethanol. The mixture is refluxed 7 hr. Cooling several weeks yields 1.77 gm (12%) of the title compound having a melting point of 134.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:24](=O)[C:25]([CH3:28])([CH3:27])[CH3:26])[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=2)=[O:13])=[C:7]([N+:30]([O-])=O)[CH:6]=1)[CH3:2]>CO.[NH4+].[Cl-].[Zn]>[C:25]([C:24]1[NH:30][C:7]2[C:8]([C:11]=1[C:12](=[O:13])[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1)=[CH:9][CH:10]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:33])[CH:6]=2)([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)c1ccc(C(C(=O)NCc2ccc(F)c(F)c2)C(=O)C(C)(C)C)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CCOC(=O)c1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)(C)C)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
General Procedure R. To a solution of ethyl4-(1-(3,4-difluorobenzylamino)-4,4-dimethyl-1,3-dioxopentan-2-yl)-3-nitrobenzoate (Compound 114, 91 mg, 0.20 mmol) in MeOH (10 ml) and saturated aqueous NH4Cl (5 ml) was added zinc dust (320 mg, 4.9 mmol). The mixture was stirred at room temperature for 0.5 h, filtered and concentrated. The remaining aqueous suspension was extracted with EtOAc (×3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12]([NH:14][C:15](=[N:18][CH3:19])SC)#[N:13]>C(#N)C>[C:12]([NH:14][C:15]([NH:18][CH3:19])=[N:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])#[N:13]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CN=C(NC#N)SC
Solvent: CC#N
Product: CNC(=NCCSCc1[nH]cnc1C)NC#N

Procedure:
A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (17.0 g.) and N-cyano-N',S-dimethylisothiourea (11.2 g.) in acetonitrile (500 ml.) was heated under reflux for 24 hours. Following concentration, the residue was chromatographed on a column of silica gel with acetonitrile as eluant and the product obtained was finally recrystallised from acetonitrile-ether to yield N-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine, m.p. 141°-2°. (Found: C, 47.2; H, 6.4; N, 33.4; S, 12.4. C10H16N6S requires: C, 47.6; H, 6.4; N, 33.3 S, 12.7).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Br:20])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])C.O.C(Cl)Cl.Cl>C(O)C>[Br:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=[C:9]([S:12][CH3:13])[N:8]=1
Reactant: CCOC(=O)c1cnc(SC)nc1-c1ccccc1Br
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CSc1ncc(C(=O)O)c(-c2ccccc2Br)n1
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a solution of 5.10 g (14.4 mmol) 4-(2-bromo-phenyl)-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester in 10 ml ethanol 10 ml 2N NaOH-solution were added. After stirring for 1 hr. 50 ml H2O and 50 ml CH2Cl2 were added to the yellow solution.The pH of the aqueous phase was adjusted to 1 with 25% HCl the phases separated and the aqueous phase extracted twice with 200 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtrated and evaporated to give 4.60 g (98%) 4-(2-bromo-phenyl)-2-methylsulfanyl-pyrimidine-5-carboxylic acid as a off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:6]=[C:7]([C:12]([O:14]C)=[O:13])[NH:8]2)=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:6]=[C:7]([C:12]([OH:14])=[O:13])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2ccc(Cl)c(F)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc2ccc(Cl)c(F)c2[nH]1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A stirred solution of methyl 6-chloro-7-fluoroindole-2-carboxylate (2.3 g, 10 mmol), tetrahydrofuran (20 mL) and aqueous sodium hydroxide solution (2 N, 20 mL) was heated under reflux for 16 h. The mixture was cooled to room temperature and partitioned between aqueous sulfiuric acid (2 M, 30 mL) and ethyl acetate (3×30 mL). The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to give the product (2.1 g, 98% yield) as a white solid: IR νmax (Nujol)/cm−1 1681, 1557, 1263, 1206, 926 and 840; NMR δH (400 MHz, DMSO-d6) 7.01-7.12 (2H, m) and 7.31-7.34 (1H, m).
Reaction SMILES: [N:1]1([C:6]([O:8][C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[C:12](F)=[CH:11][C:10]=2[F:19])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]([O:24][CH3:25])(=[O:23])[CH2:21][OH:22].[H-].[Na+]>O1CCCC1>[N:1]1([C:6]([O:8][C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[C:12]([O:22][CH2:21][C:20]([O:24][CH3:25])=[O:23])=[CH:11][C:10]=2[F:19])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Oc1cc([N+](=O)[O-])c(F)cc1F)N1CCCC1
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COc1cc(F)c(OC(=O)N2CCCC2)cc1[N+](=O)[O-]
Temperature: -50 °C
Reaction time: 4 h
Yield: 51.2 %

Procedure:
To a stirred, cold (-50° ) mixture of 7.00 g (0.0257 mole) of (2,4-difluoro-5-nitrophenyl) 1-pyrrolidinecarboxylate and 1.60 g (0.0283 mole) of methyl glycolate in 200 mL of tetrahydrofuran was added 1.02 g (0.0424 mole) of sodium hydride. The reaction mixture was stirred at -50° C. for approximately four hours. The mixture was allowed to gradually warm to room temperature. The reaction mixture was poured into ice-water, and the resultant mixture was extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure to yield 4.5 g of (2-fluoro-4-methoxycarbonylmethoxy-5-nitrophenyl) 1-pyrrolidinecarboxylate. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])=[O:4].[CH3:25][N:26]1[C@@H:43]2[CH2:44][C:31]3[CH:32]=[CH:33][C:34]([O:45][CH3:46])=[C:35]4[O:36][C@H:37]5[C:38]([CH2:40][CH2:41][C@@H:42]2[C@:29]5([C:30]=34)[CH2:28][CH2:27]1)=[O:39].Cl>O1CCOCC1>[CH3:14][CH:12]([CH2:11][C@H:10]([NH:9][C:7]([CH2:6][NH:5][C:3]([CH2:2][NH2:1])=[O:4])=[O:8])[C:15]([OH:17])=[O:16])[CH3:13].[CH3:25][N:26]1[C@@H:43]2[CH2:44][C:31]3[CH:32]=[CH:33][C:34]([O:45][CH3:46])=[C:35]4[O:36][C@H:37]5[C:38]([CH2:40][CH2:41][C@@H:42]2[C@:29]5([C:30]=34)[CH2:28][CH2:27]1)=[O:39]
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(=O)O
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C[C@H](NC(=O)CNC(=O)CN)C(=O)O
Reaction time: 18 h

Procedure:
To the Boc-Gly-Gly-Leu-Hydrocodone (2.08 g) was added 50 ml of 4N HCl in dioxane. The resulting mixture was stirred at ambient temperatures for 18 hours. Solvent was removed and final product dried under vacuum. Solid was collected as a slightly yellow solid (1.72 g, 86% yield): 1H NMR (DMSO-d6) δ 0.89 (dd, 6H), 1.50-1.87 (m, 5H), 2.26 (m, 2H), 2.66 (m, 2H), 2.82-2.97 (m, 5H), 3.21 (m, 2H), 3.60 (m, 4H), 3.88 (m, 5H), 4.37 (m, 1H), 5.04 (s, 1H), 5.60 (s, 1H), 6.79 (d, 2H), 8.07 (br s, 3H), 8.54 (br s, 1H), 8.66 (br s, 1H), 11.29 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([S:18]([O-:20])=[O:19])[CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Na+].I[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C@@H:29]([OH:31])[CH3:30].N>[Cu]I.CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([S:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C@@H:29]([OH:31])[CH3:30])(=[O:20])=[O:19])[CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@H](O)c1ccccc1I
Reactant: O=S([O-])c1cnc2cc(-c3ccc(F)cc3)ccc2c1
Agent: [Cu]I
Agent: N
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@H](O)c1ccccc1S(=O)(=O)c1cnc2cc(-c3ccc(F)cc3)ccc2c1
Reaction time: 1 h
Yield: 41.3 %

Procedure:
Sodium 7-(4-fluorophenyl)quinoline-3-sulfinate (2.52 g, 8.15 mmol), (1S)-1-(2-iodophenyl)ethanol (2.18 g, 8.79 mmol) and copper(I) iodide (4.69 g, 24.6 mmol) were weighed into a 3-neck round-bottomed flask. A nitrogen atmosphere was established by evacuation and back-filling with nitrogen. Dimethyl sulfoxide (50 mL) was added and the flask placed in an oil bath at 110° C. The reaction mixture was stirred at this temperature for 1 hour. The cooled reaction mixture was poured into concentrated ammonia solution (250 mL) and extracted with ethyl acetate (2×250 ml). The extracts were washed with brine (250 mL), combined, dried (MgSO4) and evaporated to an off-white solid. Recrystallisation from methanol gave the title compound (1.37 g, 41%). 1H NMR (500 MHz, DMSO-d6) δ 9.16 (2H, s), 8.41 (1H, d, J 8.6 Hz), 8.39 (1H, s), 8.19 (1H, dd, J 1.0, 8.0 Hz), 8.15 (1H, dd, J 1.7, 8.5 Hz), 7.99-7.97 (2H, m), 7.84 (1H, dd, J 1.0, 7.8 Hz), 7.78 (1H, t, J 7.1 Hz), 7.62-7.58 (1H, m), 7.39 (2H, t, J 8.8 Hz), 5.52-5.46 (1H, m), 5.29 (1H, d, J 3.9 Hz), 1.20 (3H, d, J 6.2 Hz); m/z (ES+) 408 [MH+].
Reaction SMILES: S(Cl)(Cl)=O.CN(C=O)C.[CH3:10][C:11]1[N:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:13]=[C:14]2[C:23]=1[C:22]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:16][C:15]2=O.[Cl:31]CCl>C(#N)C>[Cl:31][C:15]1[C:14]2=[N:13][N:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:11]([CH3:10])=[C:23]2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: Cc1c2c(nn1-c1ccccc1)c(=O)[nH]c1ccccc12
Reactant: ClCCl
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cc1c2c(nn1-c1ccccc1)c(Cl)nc1ccccc12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Thionyl chloride (17 mL) and DMF (17 mL) were combined and added dropwise to a mixture of 1-methyl-2-phenyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one (9.78 g, 35.5 mmol) and dichloromethane (500 mL) at 0° C. The resulting suspension was stirred 5 minutes at 0° C. before warming to ambient temperature and stirring 2 hours. The suspension was concentrated under reduced pressure to afford a tan solid that was stirred in acetonitrile and filtered to obtain 8.8 g of 4-chloro-1-methyl-2-phenyl-2H-pyrazolo[3,4-c]quinoline as a tan solid, mp 208-209° C. MS (APCI) m/z 294 (M+H)+; Anal. calcd for C17H12ClN3.0.05 CH2Cl2: C, 68.72; H, 4.09; N, 14.10. Found: C, 68.85; H, 3.95; N, 14.09.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:14]#[N:15])[CH2:13][CH:12]=[CH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].B.C1C[O:20]CC1>>[NH2:15][CH2:14][C:9]1([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:13][CH2:12][CH:11]([OH:20])[CH2:10]1
Reactant: C1CCOC1
Reactant: N#CC1(c2ccc(Cl)c(Cl)c2)CC=CC1
Agent: B
Product: NCC1(c2ccc(Cl)c(Cl)c2)CCC(O)C1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(3,4-dichlorophenyl)cyclopent-3-enecarbonitrile (119 mg, 0.500 mmol) and borane-THF (2 mL, 1M in THF, 2 eq) was heated at 65° C. for 2 hours. The reaction was cautiously quenched with ethanol (0.5 mL), sodium hydroxide (lmL, 5M aqueous) and stirred for two hours. It was then extracted with MTBE and evaporated. The residue was purified by HPLC to give cis 167 and trans 167.
Reaction SMILES: [CH2:1]([N:8]([CH3:22])[C:9]([CH2:11][CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]=[O:21])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([Mg]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>C1COCC1>[C:23]1([CH:20]([C@@H:16]2[CH2:17][CH2:18][CH2:19][N:15]2[C:13](=[O:14])[CH2:12][CH2:11][C:9](=[O:10])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:22])[OH:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C=O
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(O)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of (2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-al (200 mg) in THF (5 ml) was cooled to -b 25° C. A solution of phenyl magnesium bromide in THF (2M, 0.49 ml) was added dropwise to the solution. The reaction solution was stirred for 30 mins, at the same temperature, and for 30 mins at 0° C. A saturated aq. solution of ammonium chloride was added to the reaction solution. The mixture was extracted with EtOAc. The extract was washed, dried, and evaporated. The residue was purified by column chromatography on silica gel (EtOAc-CH3OH) to give the title compound (45 mg) having the following physical data:
Reaction SMILES: C([O:5][C:6]1[C:7]([CH2:12][N:13]2[CH2:18][CH2:17][C:16]([C:20](=[O:29])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])([CH3:19])[CH2:15][CH2:14]2)=[N:8][CH:9]=[CH:10][N:11]=1)(C)(C)C.C(=O)(O)[O-].[Na+].ClCCl>C(OCC)(=O)C.Cl.C(OCC)(=O)C>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][C:20]([C:16]1([CH3:19])[CH2:15][CH2:14][N:13]([CH2:12][C:7]2[C:6](=[O:5])[NH:11][CH:10]=[CH:9][N:8]=2)[CH2:18][CH2:17]1)=[O:29]
Reactant: CC(C)(C)Oc1nccnc1CN1CCC(C)(C(=O)Cc2ccccc2F)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(C(=O)Cc2ccccc2F)CCN(Cc2ncc[nH]c2=O)CC1
Reaction time: 1 h
Yield: 81 %

Procedure:
After dissolving 135 mg of 1-[1-(3-tert-butoxy-2-pyrazinylmethyl)-4-methylpiperidin-4-yl]-2-(2-fluorophenyl)ethanone in 2 ml of ethyl acetate, 2 ml of 4N hydrogen chloride/ethyl acetate was added while stirring on ice. After 1 hour, saturated aqueous sodium bicarbonate solution was added to the reaction solution and extraction was performed with dichloromethane. The extract was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue and the mixture was filtered to obtain the title compound (94 mg, 86% yield).
Reaction SMILES: CO.Cl.[CH3:4][O:5][NH2:6].[CH3:7][CH:8]1[O:12][CH:11](O)[CH:10]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:9]1>C(N(CC)CC)C>[CH3:4][O:5][N:6]=[CH:11][CH:10]([S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH2:9][CH:8]([OH:12])[CH3:7]
Reactant: CC1CC(Sc2ccccn2)C(O)O1
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CON=CC(CC(C)O)Sc1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
8.0 mL of methanol and 712 mg of O-methylhydroxylamine hydrochloride were added to 1.5 g of 5-methyl-3-(pyridin-2-ylsulfanyl)oxolan-2-ol, and thereafter, 1.1 mL of triethylamine was added dropwise to the mixture. The thus obtained mixture was stirred at room temperature for 2 hours. Thereafter, the solvent was distilled away under reduced pressure, 50 mL of ethyl acetate and 50 mL of water were then added to the residue, and the water layer was then removed. The organic layer was washed with a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/acetone=4/1), so as to obtain 1.74 g of 5-(methoxyimino)-4-(pyridin-2-ylsulfanyl)pentan-2-ol in the form of a colorless oily product.