Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:2]1.FC(F)(F)S(O[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Si](C)(C)C)(=O)=O.[F-].[Cs+].C(OCC)(=O)C>C(#N)C>[C:25]1([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:2]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2C1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1Cc2ccccc2N(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 102.7 %

Procedure:
To a solution of tert-butyl 1,2,3,4-tetrahydroquinolin-3-ylcarbamate (0.3 g, 1.2 mmol) in acetonitrile (5 mL) was added 2-(trimethylsilyl)phenyl trifluoromethane sulfonate (397 mg, 1.33 mmol, 1.1 eq) and cesium fluoride (365 mg, 2.4 mmol, 2.0 eq). The mixture was stirred at room temperature for 3 days. Ethyl acetate was then added and the organic layer washed with brine, dried over sodium sulfate and evaporated. The residue was purified by flash column (eluted with 10% ethyl acetate in hexane) to give tert-butyl 1-phenyl-1,2,3,4-tetrahydroquinolin-3-ylcarbamate as a white solid (400 mg, 99%). M.p.=139-141° C. 1H NMR (DMSO) 400 MHz δ 7.33 (m, 2H), 7.18 (dd, J=1.2 and 7.6 Hz, 2H), 7.09-6.87 (m, 4H), 6.68-6.58 (m, 2H), 3.80 (s, br, 1H), 3.64 (m, 1H), 3.29 (m, 1H), 2.94 (dd, J=5.2 and 10.8 Hz, 1H), 2.72 (m, 1H), 1.34 (s, 9H). LCMS m/e 325 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([O:10][C:11]3[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16]=3[O:17][C:6]=2[C:5]([CH:24]=[O:25])=[C:4]([OH:26])[CH:3]=1)=[O:9].[BH4-].[Na+].O.Cl>C(O)C>[OH:26][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]2[C:8](=[O:9])[O:10][C:11]3[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16]=3[O:17][C:6]=2[C:5]=1[CH2:24][OH:25]
Reactant: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(C=O)c1O2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(CO)c1O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of psoromic acid (1 mmol) in ethanol (25 mL) was added sodium borohydride (4 mmol). The reaction was stirred overnight at room temperature. Water (3 mL) was added to the reaction. The solution was acidified to a pH of 6 with dilute HCl. All of the solvent was removed by rotatory evaporation. The residue was redissolved in ethanol and dried over magnesium sulfate, filtered, and evaporated by a rotatory evaporator to give a white solid product.
Reaction SMILES: [CH2:1]([N:3]([CH:7](C)C)[CH:4](C)C)C.BrC1[S:12][C:13]([Br:16])=[CH:14][N:15]=1.CNC>C(O)C>[Br:16][C:13]1[S:12][C:7]([N:3]([CH3:1])[CH3:4])=[N:15][CH:14]=1
Reactant: Brc1cnc(Br)s1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Solvent: CCO
Product: CN(C)c1ncc(Br)s1
Temperature: 140 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
To a microwave vial was added N-ethyl-N-isopropylpropan-2-amine (0.72 mL, 4.1 mmol), 2,5-dibromothiazole (1.00 g, 4.1 mmol) and dimethylamine (40% in water, 0.52 mL, 4.1 mmol) in ethanol (10 mL). The vial was sealed and stirred at 140° C. under microwave irradiation for one hour, then was concentrated and purified by MPLC (eluted with a gradient of 0-50% ethyl acetate in hexanes) to yield the product as a white, crystalline solid (0.25 g, 29%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16]C(=O)CC)[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.[CH2:38]([O:45][CH2:46][C:47](Cl)=[O:48])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:38]([O:45][CH2:46][C:47]([NH:16][C@H:14]1[CH2:15][C@@H:11]([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([Cl:1])=[N:3][C:4]=3[NH:23][CH2:24][CH:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:12]([OH:22])[C@@H:13]1[OH:21])=[O:48])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Product: O=C(COCc1ccccc1)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Intermediate J) by replacing propionyl chloride with benzyloxy-acetyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[C:12]([NH:14][C@H:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=1)[CH3:16])=[O:13].O[Li:31].O>>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[C:12]([NH:14][C@H:15]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([O-:23])=[O:22])=[CH:25][CH:26]=1)[CH3:16])=[O:13].[Li+:31]
Reactant: [Li]O
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2Cc2cccc(F)c2)cc1
Solvent: O
Product: C[C@H](NC(=O)[C@H]1CCCCN1Cc1cccc(F)c1)c1ccc(C(=O)[O-])cc1
Product: [Li+]

Procedure:
The title compound (E6) (36 mg) was prepared according to the general procedure for esters hydrolysis starting from methyl 4-((S)-1-((R)-1-(3-fluorobenzyl)piperidine-2-carboxamido)ethyl)benzoate (D23 (40 mg). (LiOH H2O: 3 eq; reaction time: 3 hrs)
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[N:18][C:17]([C:20](=O)[CH3:21])=[C:16](Cl)[N:15]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:25][NH2:26]>CC(O)C.O>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]3[NH:25][N:26]=[C:20]([CH3:21])[C:17]3=[N:18][CH:19]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1ncc(-c2ccc(NC(=O)OC(C)(C)C)cc2)nc1Cl
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: Cc1n[nH]c2nc(-c3ccc(NC(=O)OC(C)(C)C)cc3)cnc12
Temperature: 120 °C

Procedure:
[4-(5-Acetyl-6-chloro-pyrazin-2-yl)-phenyl]-carbamic acid tert-butyl ester (2.18 g) was suspended in a mixture of 21 ml iPrOH and 21 ml 35% hydrazine in water at RT and heated to 120° C. by microwave irradiation for 20 min under stirring in a sealed vessel. The reaction mixture was left to cool to RT, quenched with a saturated aqueous sodium bicarbonate solution (10 ml) and extracted with EtOAc (3×30 ml). The combined organic phases were dried over sodium sulfate, filtered and evaporated to afford the crude product. Purification by trituration in boiling EtOAc and subsequent filtration afforded [4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-carbamic acid tert-butyl ester as a yellow solid. Yield: 1.42 g (70%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:5]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:6])[CH3:2].P([O-])([O-])([O-])=O.C([O-])(=O)C>>[CH2:1]([O:3][C@@H:4]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)[C:5]([OH:7])=[O:6])[CH3:2].[CH2:1]([O:3][C@H:4]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)[C:5]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:6])[CH3:2]
Reactant: CCCCCCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Product: CCCCCCOC(=O)[C@@H](Cc1ccc(O)cc1)OCC
Product: CCO[C@@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 25 °C

Procedure:
To hexyl (2RS) (+/−) 2-ethoxy-3-(4-hydroxyphenyl)propanoate (0.5 ml of a solution containing 2 mg/ml in a phosphate, pH 7; 0.1M, or acetate buffer, pH 5; 0.1 M) was added the enzyme (0.5 ml enzyme solution). The reaction mixture was shaken at room temperature and analysed at different times (maximum 30 h). The reaction mixture was analysed by the gradient HPLC method 1, and the chiral CE method 1.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O.C([CH2:22][C:23]([NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)=[O:24])(O)=O.Cl>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:22]/[C:23]([NH:25][C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=2)=[O:24])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: O=C(O)CC(=O)Nc1ccc(C(=O)O)cc1
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1ccc(/C=C/C(=O)Nc2ccc(C(=O)O)cc2)cc1OC
Yield: 53.7 %

Procedure:
Piperidine (0.39 mL, 4.0 mmol) was added to a suspension of 3,4-dimethoxybenzaldehyde (0.66 g, 4.0 mmol) and 4-[(carboxyacetyl)amino]benzoic acid (0.74 g, 3.3 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. The crude product was recrystallised from EtOH providing (E)-4-[[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.58 g, 53%) as a yellow crystalline solid; mp 258-259° C., lit. [24] 267-269° C.; δH (400 MHz, DMSO-d6) 3.80 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 6.72 (d, J=15.6 Hz, 1H, CH═CHCO), 7.01 (d, J5′,6′=8.2 Hz, 1H, H5′), 7.20 (d, J5′,6′=8.2 Hz, 1H, H6′), 7.22 (s, 1H, H2′), 7.56 (d, J=15.6 Hz, 1H, CH═CHCO), 7.80 (d, J2,3=J5,6=8.4 Hz, 2H, H3, H5), 7.90 (d, J2,3=J5,6=8.4 Hz, 1H, H2, H6), 10.43 (s, 1H, NH), 12.68 (br s, 1H, CO2H).
Reaction SMILES: [N+](C1C2C(=O)C3C(=C([N+]([O-])=O)C=CC=3O)C(=O)C=2C(O)=CC=1)([O-])=O.[N+:25]([C:28]1[C:41]2[C:40](=[O:42])[C:39]3[C:34](=[C:35]([OH:46])[CH:36]=[CH:37][C:38]=3[N+:43]([O-])=O)[C:33](=[O:47])[C:32]=2[C:31]([OH:48])=[CH:30][CH:29]=1)([O-:27])=[O:26].C1(O)C=CC=CC=1>CO>[NH2:43][C:38]1[C:39]2[C:40](=[O:42])[C:41]3[C:32](=[C:31]([OH:48])[CH:30]=[CH:29][C:28]=3[N+:25]([O-:27])=[O:26])[C:33](=[O:47])[C:34]=2[C:35]([OH:46])=[CH:36][CH:37]=1
Reactant: O=C1c2c(O)ccc([N+](=O)[O-])c2C(=O)c2c([N+](=O)[O-])ccc(O)c21
Agent: O=C1c2c(O)ccc([N+](=O)[O-])c2C(=O)c2c(O)ccc([N+](=O)[O-])c21
Solvent: CO
Solvent: Oc1ccccc1
Product: Nc1ccc(O)c2c1C(=O)c1c([N+](=O)[O-])ccc(O)c1C2=O

Procedure:
16.5 parts of a mixture of 1,5-dinitro-4,8-dihydroxyanthraquinone and 1,8-dinitro-4,5-dihydroxyanthraquinone (about 1:1 parts) is heated with 50 parts of phenol for eight hours at 180° C while stirring. After cooling 100 parts by volume of methanol is added, the precipitate is suction filtered and the residue is washed with methanol and then with hot water. After drying 13 parts of a mixture of 1-amino-5-nitro-4,8-dihydroxyanthraquinone and 1-amino-8-nitro-4,5-dihydroxyanthraquinone is obtained; this is equivalent to 87% of the calculated yield.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1.[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2=[N:23][N:24]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:15]2[N:14]=1>CN(C)C=O>[CH3:9][C:5]1[N:4]=[C:3]([CH2:2][O:1][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]3=[N:23][N:24]=[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:15]3[N:14]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: Cc1cccc(CO)n1
Reactant: Clc1nn2c(-c3ccccc3)nnc2c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(COc2nn3c(-c4ccccc4)nnc3c3ccccc23)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-hydroxymethyl-6-methylpyridine (Example 67 part b, 0.5 g), in anhydrous dimethylformamide (20 ml) under nitrogen was added sodium hydride (107 mg of 60% in oil) and the reaction mixture was stirred at room temperature for 0.5 hours. To this mixture was added 6-chloro-3-phenyl-1,2,4-triazolo[3,4-a]phthalazine (Example 67 part d, 330 mg) and the solution was heated to 80° C. for 0.25 hours. After cooling the solvent was removed under vacuum, and the residue was dissolved in dichloromethane (30 ml) and washed with water and brine. After drying (MgSO4), the solution was filtered and evaporated to give the required product which was recrystallised from a mixture of ethyl acetate and hexane to give the title compound (210 mg, m.p. 186-187° C.). 1H NMR (360 MHz, DMSO) δ 2.52 (3H, s), 5.65 (2H, s), 7.25 (1H, d, J=7.7Hz), 7.49 (1H, d, J=7.7Hz), 7.58 (3H, m), 7.76 (1H, t, J=7.7Hz), 7.94 (1H, t, J=7.6Hz), 8.08 (1H, t, J=7.7Hz), 8.30 (3H, m), 8.58 (1H, d, J=7.6Hz); MS (ES+) m/e 368 [MH]+. Anal. Found C, 71.32; H, 4.44; N. 18.53. C22H17N5O. H2O requires C, 71.22; H, 4.73; N, 18.88%.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15]Cl)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=1>[Ti](Cl)(Cl)(Cl)Cl.C(O)C>[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:4]3[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=3[CH3:2])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(C)cc1
Reactant: ClCc1ccc(-c2ccc(CCl)cc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCO
Product: Cc1ccc(C)c(Cc2ccc(-c3ccc(Cc4cc(C)ccc4C)cc3)cc2)c1
Temperature: 25 °C

Procedure:
A 100mL flask was charged with 4,4′-bis(chloromethyl)-1,1′-biphenyl (1.0 g) and p-xylene (25 mL). To the clear solution stirring at room temperature was added titanium tetrachloride (6 drops) and the mixture instantly became dark brown. After stirring overnight at room temperature, ethanol (2mL) was added to kill the catalyst, and the mixture became a light, cream colored suspension. The mixture was transferred to a separatory funnel and washed with dilute aqueous HCl followed by saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, and concentrated to dryness under vacuum on a rotary evaporator. The tan solid was recrystallized from toluene yielding a white crystalline product, mp=144.6 C. GC/MS, HNMR, CNMR and IR were all consistent with the desired product.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].[C:5]([C:8]1[CH:9]=[C:10]([NH:15][C:16]([C:18]2N(C)[N:21]=[C:20]([C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[C:19]=2[C:31]([F:34])([F:33])[F:32])=[O:17])[CH:11]=[CH:12][C:13]=1[Cl:14])(=O)[CH3:6].C([O-])(=O)C.[NH4+:39].[Cl-].[Na+]>CO>[NH2:39][CH:5]([C:8]1[CH:9]=[C:10]([NH:15][C:16]([C:18]2[N:2]([CH3:1])[N:21]=[C:20]([C:24]([F:30])([F:29])[C:25]([F:28])([F:26])[F:27])[C:19]=2[C:31]([F:32])([F:34])[F:33])=[O:17])[CH:11]=[CH:12][C:13]=1[Cl:14])[CH3:6]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(NC(=O)c2c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn2C)ccc1Cl
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(N)c1cc(NC(=O)c2c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn2C)ccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.4 %

Procedure:
Sodium cyanoborohydride (163 mg, 2.59 mmol, 3.0 eq.) was added to a solution of N-(3-acetyl-4-chlorophenyl)-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (400 mg, 0.863 mmol) and ammonium acetate (1.33 g, 17.3 mmol, 20 eq.) in methanol (15 ml). The mixture was stirred at room temperature for 4 h and then heated to 80° C. and kept at this temperature for 3 h. The mixture was cooled to room temperature and left overnight. Sat. aq. sodium chloride solution was added, the mixture was extracted with ethyl acetate and the extract was washed with sat. aq. sodium chloride solution and dried over MgSO4. After concentration under reduced pressure, the product was purified by column chromatography (hexane/ethyl acetate) to give N-[3-(1-aminoethyl)-4-chlorophenyl]-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (186 mg, 46%).
Reaction SMILES: [CH2:1]([C:4]1([C:17](=[O:26])[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].O1CCOCC1>CO>[CH2:1]([C:4]1([C:17]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[O:26])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(C(=O)Nc2cccc(Cl)c2)CCN(C(=O)OC(C)(C)C)CC1
Solvent: CO
Solvent: C1COCCO1
Product: C=CCC1(C(=O)Nc2cccc(Cl)c2)CCNCC1
Temperature: 50 °C

Procedure:
To a solution of tert-butyl 4-allyl-4-(3-chlorophenylcarbamoyl)piperidine-1-carboxylate from step A (0.172 g, 0.453 mmol) in MeOH (10 mL) was added 4 MHCl in dioxane (0.340 mL, 1.36 mmol). The reaction was heated at 50° C. for 30 min, and then concentrated under vacuum, re-dissolved in MeOH and re-concentrated twice to give the title compound as the hydrochloride salt. MS (ES+) [M+H]+=279.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[C:26]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C:30]1=O)(=[O:28])[CH3:27].[O:36]1CCCC1>CCOCC.O>[C:26]([N:29]1[CH2:34][CH2:33][C:32]([OH:36])([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: C1CCOC1
Reactant: CC(=O)N1CCCCC1=O
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)C1(O)CCN(C(C)=O)CC1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
Under an inert atmosphere, 0.32 mmol of n-butyllithium (1.6M in hexane) is added over a period of 5 minutes to a solution of 0.32 mmol of diisopropylamine in 750 ml of tetrahydrofuran at 0° C. After stirring the mixture for 15 minutes, 0.32 mmol of tri-n-butyltin hydride is added. After 1 hour 30 minutes at 0° C., the reaction mixture is cooled to −70° C. and 0.26 mmol of N-acetylpiperidone in 225 ml of tetrahydrofuran is added and the reaction mixture is then diluted by adding 380 ml of tetrahydrofuran. After stirring for 2 hours 30 minutes, the reaction mixture is hydrolysed by the addition of 200 ml of an aqueous 10% solution of NaH2PO4, brought to 0° C., and then diluted with 2 litres of ether and 1 litre of water. After decanting and washing with a saturated NaCl solution, the organic phase is dried and filtered and then concentrated under reduced pressure. Chromatography on silica gel (dichloromethane) enables the expected product to be isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)=[C:4]([N+:20]([O-])=O)[CH:3]=1.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[NH2:20][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(CNc2ccc(Cl)cc2[N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CNc2ccc(Cl)cc2N)cc1

Procedure:
The title compound of Example 12, Step A (3.6 mmol, 1.2 g) and SnCl2.2H2O (18 mmol, 4 g) were heated in DMP (10 mL) at 40° C. for 3 hr. The reaction mixture was poured into EtOAc and concentrated NaHCO3 and stirred. The resulting mixture was filtered over celite, and the filter cake was washed with EtOAc. The organic phase was collected, dried with Na2SO4 and reduced in vacuo. Flash chromatography on silica eluting with 20% and 30% EtOAc in hexanes afforded the product as a pale white solid. 1H NMR (500 MHz, d6-DMSO) δ 7.94 (d, J=8.2 Hz, 2H), 7.49 (d, J=8.2 Hz, 2H), 6.70 (s, 1H), 6.32 (s, 1H), 5.68 (t, J=5.8 Hz, 1H), 5.07 (s, 2H), 4.41 (d, J=5.7 Hz, 2H), 3.85 (s, 3H). LC-MS (ESI, Method C) 3.33 min, 291.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23](O)=[O:24])=[CH:13][C:12]=2[N:11]=1.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.[H-].[Na+]>C1C=CC=CC=1.S(Cl)(Cl)=O.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([NH:31][C:30]3[CH:32]=[CH:33][C:27]([F:26])=[CH:28][CH:29]=3)=[O:24])=[CH:13][C:12]=2[N:11]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1nc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: Cc1nc2c(o1)c(C(=O)Nc1ccc(F)cc1)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Reaction time: 0.5 h
Yield: 15.4 %

Procedure:
To a solution of 7-[(2,6-dichlorophenyl)amino]-2-methyl-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylic acid (Intermediate-55, 0.100 g, 0.276 mmol) in benzene (4 mL), thionyl chloride (5.0 mL) was added at 5-10° C. The reaction mass was refluxed for 3 h. Thionyl chloride was removed under vacuum and stripped out with benzene. The solution of 4-fluoroaniline (0.091 g, 0.828 mmol) in THF (5.0 mL) was added 60% NaH (0.033 g, 0.825 mmol) under N2-atmosphere at 0-5° C. The solution was stirred for 30 minutes at same temperature and above prepared solution was added to reaction mixture. The reaction mass was stirred at RT for 1 h. The reaction mass was quenched in ice water and extracted with ethyl acetate. The obtained product was further purified by column chromatography on neutral alumina eluting with 1.5-2.0% MeOH:DCM to afford 0.020 g of the desired product. 1HNMR (DMSO-d6): δ 2.65 (s, 3H), 7.17-7.20 (m, 4H), 7.38-7.50 (m, 1H), 7.61 (s, 2H), 7.79 (s, 1H), 8.96-9.04 (m, 1H), 9.40-9.60 (s, 1H), 11-12 (s, 1H); MS [M+H]+: 470.23.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:17])[CH:14]([CH3:16])[CH3:15].[Cl:18][CH2:19][CH2:20][N:21]=[C:22]=[O:23]>>[Cl:18][CH2:19][CH2:20][NH:21][C:22]([N:17]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])=[O:23]
Reactant: CC(C)CN
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: O=C=NCCCl
Product: CC(C)CN(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 80.8 %

Procedure:
A mixture of 3.6 g of D-galactose, 2.0 g of isobutylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 5-(1). 5.5 g of 1-(2-chloroethyl)-3-isobutyl-3-D-galactopyranosylurea are thereby obtained as colorless caramel.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][SH:10].[OH-].[K+].Cl[CH:15]([CH3:19])[C:16]([OH:18])=[O:17].Cl>O>[CH3:1][C:2]1([CH3:11])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][S:10][CH:15]([CH3:19])[C:16]([OH:18])=[O:17]
Reactant: CC(Cl)C(=O)O
Reactant: CC1(C)[C@H]2CC[C@@H](CS)[C@@H]1C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(SC[C@@H]1CC[C@H]2C[C@@H]1C2(C)C)C(=O)O
Temperature: 100 °C

Procedure:
To a solution of ((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methanethiol (Eisen, Moris; et al. Inorg. Chim. Acta 1991, 188, 167-176) (52.0 g, 0.30 mmol) and potassium hydroxide (41.2 g, 0.62 mmol) in water (200 mL) was added α-chloro-propionic acid (33.2 g, 0.306 mmol) drop wise. The mixture was heated at 100° C. for 1 hour. The mixture was cooled and acidified to pH=1 with 6N HCl (100 mL). The product was extracted with ether, dried with magnesium sulfate and concentrated. The residue was distilled at reduced pressure (143-147° C., 0.5 mm of Hg) to obtain the title compound.
Reaction SMILES: C[O:2][C:3]1([C:42]2[CH:58]=[CH:57][CH:56]=[CH:55][C:43]=2[O:44][CH2:45]CCC2(C(O)=O)CCC2)[CH2:8][CH2:7][N:6]([C:9]([C@]2(OC3C=C(C(F)(F)F)SC=3)CCCN(C(=O)C3C(C(F)(F)F)=CC=CN=3)[C@@H]2CCC)=[O:10])[CH2:5][CH2:4]1.[OH-:59].[Na+].OO.[CH2:63]1C[O:66][CH2:65][CH2:64]1>B1C2CCCC1CCC2>[OH:2][C:3]1([C:42]2[CH:58]=[CH:57][CH:56]=[CH:55][C:43]=2[O:44][CH3:45])[CH2:4][CH2:5][N:6]([C:9]([O:10][CH2:3][C:42]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:43]=2)=[O:59])[CH:7]([CH2:63][CH2:64][CH2:65][OH:66])[CH2:8]1
Reactant: CCC[C@H]1N(C(=O)c2ncccc2C(F)(F)F)CCC[C@@]1(Oc1csc(C(F)(F)F)c1)C(=O)N1CCC(OC)(c2ccccc2OCCCC2(C(=O)O)CCC2)CC1
Reactant: C1CCOC1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Product: COc1ccccc1C1(O)CCN(C(=O)OCc2ccccc2)C(CCCO)C1
Reaction time: 16 h

Procedure:
To a solution of benzyl 2-allyl-4-hydroxy-4-(2-methoxyphenyl)piperidine-1-carboxylate 131 (220 mg, 0.58 mmol) in THF (2 mL), 0.5 M of 9-BBN in THF (3.5 mL) was added. The reaction solution was stirred at r.t for 16 hr and then 10% NaOH (3 mL) and H2O2 (3 mL) were added. After stirring for 30 mins, the reaction mixture was extracted with ethyl acetate. After removal of solvent, the crude product was purified by silica gel chromatography (gradient, 30% to 75% EtOAc/hexanes) to give benzyl 4-hydroxy-2-(3-hydroxypropyl)-4-(2-methoxyphenyl)piperidine-1-carboxylate 132. LC/MS RT (2.25 min method)=1.228 min. Mass observed: 400.2 (M+H).