Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][CH:18]=3)[CH:13]=2)[N:3]=1.[CH3:24][O:25][C:26]1[CH:35]=[C:34]2[C:29]([CH:30]=[CH:31][C:32]([O:36][CH2:37][CH2:38][OH:39])=[CH:33]2)=[CH:28][CH:27]=1.[NH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C([O-])([O-])=O.[K+].[K+].COC1C=C2C(C=CC(O)=C2)=CC=1.C1(=O)OCCO1>>[CH3:23][O:22][C:16]1[CH:15]=[C:14]2[C:19]([CH:20]=[CH:21][C:12]([O:11][CH2:10][CH2:9][O:8][C:4]3[CH:5]=[N:6][CH:7]=[C:2]([N:40]4[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]4)[N:3]=3)=[CH:13]2)=[CH:18][CH:17]=1.[CH3:24][O:25][C:26]1[CH:35]=[C:34]2[C:29]([CH:30]=[CH:31][C:32]([O:36][CH2:37][CH2:38][OH:39])=[CH:33]2)=[CH:28][CH:27]=1
Reactant: C1CNCCN1
Reactant: COc1ccc2ccc(OCCOc3cncc(Cl)n3)cc2c1
Agent: COc1ccc2ccc(O)cc2c1
Agent: COc1ccc2ccc(OCCO)cc2c1
Agent: O=C([O-])[O-]
Solvent: O=C1OCCO1
Product: COc1ccc2ccc(OCCOc3cncc(N4CCNCC4)n3)cc2c1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-[2-(7-methoxy-naphthalen-2-yloxy)-ethoxy]pyrazine [1.19 g, 3.60 mmol; obtained according to the procedure of example 50, step 1, starting from 2-(7-methoxy-naphthalen-2-yloxy)ethanol*], piperazine (1.25 g, 14.5 mmol) and K2CO3 (0.60 g, 4.3 mmol) with the exception that the final filtration through alumina was omitted. The yield of the of the title compound was 0.98 g (71%) which was obtained as an oil that solidified when refrigerated. Purity 100% (HPLC). MS m/z 380 (M)+. HRMS m/z calcd for C21H24N4O3 (M)+0 380.1848, found 380.1851. *Prepared from 7-methoxy-2-naphthol and ethylene carbonat according to the procedure of Example 134, step 1, in WO 00/76984. The reaction mixture was refluxed for 2 h. Pure 2-(7methoxy-naphthalen-2-yloxy)ethanol was obtained after column chromatography on silica gel using n-hexane/ethyl acetate (6:4) as eluent.
Reaction SMILES: C([O:3][C:4]1[C:13]2[CH:12]=[N:11][C:10]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[N:9][C:8]=2[N:7]=[CH:6][C:5]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])C.[CH2:26](I)[CH3:27]>>[CH2:26]([N:7]1[C:8]2[N:9]=[C:10]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[N:11]=[CH:12][C:13]=2[C:4](=[O:3])[C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:6]1)[CH3:27]
Reactant: CCI
Reactant: CCOC(=O)c1cnc2nc(N3CCN(C)CC3)ncc2c1OCC
Product: CCOC(=O)c1cn(CC)c2nc(N3CCN(C)CC3)ncc2c1=O

Procedure:
A mixture containing 1.0 g of ethyl 5-ethoxy-2-(4-methyl-1-piperazinyl)pyrido[2,3-d]pyrimidine-6-carboxylate and 5.0 ml of ethyl iodide was heated to reflux for one hour. After ethyl iodide was recovered by distillation, the resulting solid was crystallized from water to give 0.69 g of the product, m.p. 146° - 147°C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.C[O-].[Na+].CO.[C:30](OCC)(=[O:32])C>CO.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([O:32][CH3:30])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Product: COc1cc(C)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
A mixture of 7-methyl-5-bromo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.100 g, 0.25 mmol), 30% sodium methoxide-methanol (0.5 mL), and CuBr (0.005 g, 0.04 mmol) in methanol (4 mL) was stirred at 100° C. for 1 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-methyl-5-methoxy-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.035 g, 41%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.80 (s, 3H), 3.91 (s, 3H), 4.26 (s, 2H), 4.83 (s, 2H), 6.82 (d, 2H), 7.26 (d, 2H), 7.42 (d, 2H).
Reaction SMILES: [C:1]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[N:13]([C:31](Cl)=[O:32])[C@H:14]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:16]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[N:38]1([CH2:44][CH2:45][NH:46][C:47](=[O:49])[CH3:48])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[ClH:11].[C:1]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[N:13]([C:31]([N:41]3[CH2:40][CH2:39][N:38]([CH2:44][CH2:45][NH:46][C:47](=[O:49])[CH3:48])[CH2:43][CH2:42]3)=[O:32])[C@H:14]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:16]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(=O)NCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCNC(C)=O)CC1

Procedure:
N-(2-{4-[(4S,5R)-2-(4-tert-Butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-ethyl)-acetamide hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12h) and N-(2-piperazin-1-yl-ethyl)-acetamide hydrochloride (example 23) in an analogous manner as described in example 25. LR-MS: 700.4 [(M+H)+]
Reaction SMILES: F[C:2]1[C:12]([F:13])=[CH:11][C:10]([I:14])=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[NH2:15][CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[F:13][C:12]1[C:2]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[C:3]([CH:9]=[C:10]([I:14])[CH:11]=1)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5]
Reactant: CN(C)C(=O)c1cc(I)cc(F)c1F
Reactant: NCc1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN(C)C(=O)c1cc(I)cc(F)c1NCc1ccncc1
Temperature: 75 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
2,3-Difluoro-5-iodo-N,N-dimethyl-benzamide (507, 1.63 mmol), 4-(aminomethyl)-pyridine (1.8 ml, 17.73 mmol), di-iso-propylethylamine (0.31 ml, 1.78 mmol), and dioxane (3 ml) were combined and stirred for 18 hours at 75° C. The reaction mixture was concentrated in vacuo to give approximately 650 mg of crude 3-fluoro-5-iodo-N,N-dimethyl-2-[(pyridin-4-ylmethyl)-amino]-benzamide, which was used directly in the next step. MS: m/z 400.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:5][CH:4]([CH:6]([NH:20][C:21]2[CH:22]=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([F:31])=[CH:26][CH:25]=3)[C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13]C(C)(C)C)=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:32])[CH2:3][CH:4]([CH:6]([NH:20][C:21]2[CH:22]=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([F:31])=[CH:26][CH:25]=3)[C:7]2[CH:19]=[CH:18][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH2:5]1
Reactant: CC1(C)CC(C(Nc2cnc3ccc(F)cc3c2)c2ccc(C(=O)OC(C)(C)C)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC(C(Nc2cnc3ccc(F)cc3c2)c2ccc(C(=O)O)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a flask containing tert-butyl 4-((3,3-dimethylcyclobutyl)(6-fluoroquinolin-3-ylamino)methyl)benzoate (13.0 mg, 0.0300 mmol) was added anhydrous methylene chloride (0.150 mL) and trifluoroacetic acid (0.150 mL, 0.0300 mmol). The reaction was stirred at room temperature for 1 h. The mixture was concentrated and azeotrophed with toluene to provide crude 4-((3,3-dimethylcyclobutyl)(6-fluoroquinolin-3-ylamino)methyl)benzoic acid (11 mg, 96% yield) as an oil. (M+1): 379.2.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:13]=[N:14][C:15]([O:19][CH3:20])=[CH:16][C:17]=3[CH3:18])[N:7]([CH2:21][CH2:22][CH2:23][CH2:24]O)[C:6]=2[C:5]([CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:12]4[CH:13]=[N:14][C:15]([O:19][CH3:20])=[CH:16][C:17]=4[CH3:18])[CH2:24][CH2:23][CH2:22][CH2:21][N:7]3[C:6]=2[C:5]([CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3cnc(OC)cc3C)n(CCCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: c1ccncc1
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1cnc(OC)cc1C
Temperature: 25 °C
Reaction time: 40 h
Yield: 47.4 %

Procedure:
To a solution of 4-{4-chloro-7-(1-ethylpropyl)-2-[(6-methoxy-4-methylpyridin-3-yl)amino]-1H-benzimidazol-1-yl}butan-1-ol (100 mg, 0.23 mmol) in pyridine (2 mL) was added methanesulfonyl chloride (0.090 mL, 1.16 mmol) dropwise at 0° C. The mixture was warmed to room temperature and stirred for 40 hr. Aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The resulting crude mesylate was dissolved in N,N-dimethylformamide (4 mL) and potassium carbonate (160 mg, 1.16 mmol) was added. The mixture was stirred at 80° C. for 3 hr. Water was added and the mixture was extracted with ethyl acetate. Organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 20-40% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound (45 mg, 0.109 mmol, 47%) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O>C(O)C.[C].[Pd]>[CH3:16][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:8]([NH2:13])=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)CCCNc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCCNc1ccccc1N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100.1 %

Procedure:
10% of palladium-carbon (0.18 g) was added to a solution containing N1,N1-dimethyl-N3-(2-nitrophenyl)-1,3-propanediamine (0.90 g) in ethanol (9 ml) and stirred for 2.5 hours under a hydrogen gas atmosphere at room temperature. After the catalyst was removed out by filtration, the filtrate was concentrated, thereby yielding the entitled compound (0.78 g) as reddish brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C.O>CN(C=O)C.C(OCC)(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:6]2[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([F:1])[CH:7]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(F)c2)CC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 32.3 %

Procedure:
A mixture of 2,4-difluoro-nitro-benzene (2.2 mL, 20 mmol), piperazine-1-carboxylic acid tert-butyl ester (3.7 g, 20 mmol), and triethylamine (10 mL) in anhydrous DMF (20 mL) was stirred at 90° C. for 16 hr. After the reaction, the reaction mixture was mixed with water and ethyl acetate, and two layers were separated. The aqueous layer was extracted with ethyl acetate twice. Organic layers were collected, combined, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was applied on a silica gel flash column with ethyl acetate and hexanes as eluenting solvents to give 4-(3-fluoro-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (2.1 gm, 32%) as a brown solid. LCMS calcd for C15H20FN3O4 (m/e) 325, obsd 326 (M+H).
Reaction SMILES: [F:1][CH2:2][C:3](=[CH2:17])[CH2:4][N:5]([CH2:11][CH:12](OC)[O:13]C)[C:6](=[O:10])[O:7][CH2:8][CH3:9].C(O)=O.[Cl-].[Na+]>O>[F:1][CH2:2][C:3](=[CH2:17])[CH2:4][N:5]([CH2:11][CH:12]=[O:13])[C:6](=[O:10])[O:7][CH2:8][CH3:9]
Reactant: C=C(CF)CN(CC(OC)OC)C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: C=C(CF)CN(CC=O)C(=O)OCC

Procedure:
25 g (0.1 mol) of ethyl N-(2-fluoromethylallyl) -N-(2,2-dimethoxyethyl)carbamate are heated under reflux for two hours with 5 g of formic acid in 100 ml of water. The mixture is saturated with sodium chloride and extracted with methylene chloride, and the organic phases are washed with sodium hydrogen carbonate solution until neutral. They are dried over magnesium sulphate and concentrated, and the residue is distilled.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH2:23][OH:24])[N:22]=3)[CH2:14][C@H:13]2[O:30][CH3:31])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH:23]=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:30][CH3:31])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 94.6 %

Procedure:
Ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-(hydroxymethyl)-1,3-thiazole-5-carboxylate obtained by the method described in Example (27b) (0.17 g, 0.36 mmol) was dissolved in dichloromethane (8 mL). The Dess-Martin reagent (0.2 g, 0.48 mmol) was added, and the mixture was stirred at room temperature for 45 minutes. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated aqueous sodium thiosulfate solution, saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=5/1, 1/1, 1/3) to obtain 0.16 g of the title compound as a pale yellow solid (92%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)([CH3:6])[C:4]#[N:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[F:1][C:2]([F:17])([F:18])[C:3]([CH3:6])([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH2:4][NH2:5]
Reactant: COc1ccc(CNC(C)(C#N)C(F)(F)F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CNC(C)(CN)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0° C.) solution of 3,3,3-trifluoro-2-(4-methoxybenzylamino)-2-methyl propanenitrile (1.5 g, 5.81 mmol) in dry diether ether (50 ml) was added LiAlH4 (11.62 ml of a 2M solution in THF) and the resulting mixture was stirred at RT overnight. The reaction mixture was hydrolyzed by successive addition of water 15% KOH, and water. The resulting precipitate was filtered on Celite® (filter material) and the organic portion was washed with water, dried over MgSO4 and concentrated under reduced pressure to afford the title product; 1H NMR (400 MHz, Methanol-d4) δ 7.97 (1H, s), 7.85 (1H, s), 7.60 (1H, s), 3.97 (3H, s), 3.77 (1H, m), 3.56 (1H, m), 1.37 (3H, s)
Reaction SMILES: C(O[C:9]([NH:11][C@@H:12]1[CH2:19][N:18]2[C:20]3[C:31]([CH3:32])=[C:30]([C:33]([O:35]C)=[O:34])[S:29][C:21]=3[C:22]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[C:17]2[C:16]2[CH:37]=[CH:38][CH:39]=[CH:40][C:15]=2[O:14][CH2:13]1)=O)C1C=CC=CC=1.[CH3:41]COC(C)=O.CO.C=O.[BH3-]C#N.[Na+]>C(Cl)Cl.O.CC(O)=O>[CH:23]1([C:22]2[C:21]3[S:29][C:30]([C:33]([OH:35])=[O:34])=[C:31]([CH3:32])[C:20]=3[N:18]3[C:17]=2[C:16]2[CH:37]=[CH:38][CH:39]=[CH:40][C:15]=2[O:14][CH2:13][C@H:12]([N:11]([CH3:41])[CH3:9])[CH2:19]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CCOC(C)=O
Reactant: COC(=O)c1sc2c(C3CCCCC3)c3n(c2c1C)C[C@@H](NC(=O)OCc1ccccc1)COc1ccccc1-3
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(C(=O)O)sc2c(C3CCCCC3)c3n(c12)C[C@@H](N(C)C)COc1ccccc1-3
Temperature: 40 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
Methyl (7R)-7-{[(benzyloxy)carbonyl]amino}-13-cyclohexyl-10-methyl-7,8-dihydro-6H-thieno[2′,3′:4,5]pyrrolo[1,2-e][1,5]benzoxazocine-11-carboxylate was dissolved EtOAc/MeOH and the solution (0.014M) was degassed. Pd/C was added and hydrogen atmosphere was applied. The mixture was left stirring under hydrogen atmosphere for 4 h. The mixture was filtered and evaporated i. vac. The residual material was lyophilised from MeCN/water to give a colourless powder. This material was dissolved in DCM (0.05M) and the pH was adjusted with AcOH to 4. A solution of formaldehyde (16 eq.) in water was added and the mixture was left stirring for 10 min at RT. Then NaCNBH3 (12 eq.) was added and stirring was continued for 6 h. The mixture was diluted with DCM and extracted with sat. aq. NaHCO3-solution. The organic phase was dried over Na2SO4 and evaporated i. vac. This material was dissolved in MeOH and THF was added (0.02M). To the solution 1M aq. KOH solution (excess) was added and the resulting mixture was warmed to 40° C. overnight. The product was isolated by prep. RP-HPLC. After lyophilisation, the product was obtained as a colourless powder (68%). 1H-NMR (TFA-salt, 400 MHz, DMSO-d6, 300K, δ): 12.77 (bs, 1H); 10.40 (bs, 1H), 7.46-7.42 (m, 1H), 7.23-7.09 (m, 3H), 5.03-5.00 (m, 1H), 4.44-4.41 (m, 1H), 4.10-4.03 (m, 1H), 3.82-3.58 (m, 2H), 2.97 (bs, 6H) 2.83 (s, 3H), 2.67-2.52 (m, 1H), 1.99-1.55 (m, 7H), 1.38-1.12 (m, 3H); MS (ES+) m/z 439 (M+H)+.
Reaction SMILES: [CH3:1][C@@:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH:19]4[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20]4)[CH:14]=3)[CH:9]=2)[CH2:6][O:5]C(=O)[NH:3]1.C(O)C.O.[OH-].[Li+]>O>[NH2:3][C@@:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH:19]3[CH2:20][CH2:21][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:24]3)[CH:14]=2)[CH:9]=1)([CH3:1])[CH2:6][OH:5]
Reactant: CCCC1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCC1CCC(Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1
Temperature: 80 °C
Yield: 94 %

Procedure:
(R)-4-methyl-4-(6-(4-propylcyclohexyloxy)naphthalen-2-yl)oxazolidin-2-one (0.4786 g, 0.001302 mol) was dissolved in ethanol (5.00 mL, 0.0856 mol) in a capped 40 mL vial equipped with a magnetic stir bar. 4.2 M Lithium hydroxide, monohydrate in water (2.8 mL) was added and the mixture was heated overnight at 80° C. TLC analysis showed that the reaction was complete. The reaction mixture was concentrated under vacuum. The product was dissolved in methylene chloride (5 mL) and washed with water (2×5 mL). The layers were separated (phase separator cartridge) and the organic layer was concentrated under vacuum and purified by HPLC to give 0.418 g of the title compound (9% yield). MS: m/z=325.35 [M−NH2]+. 1H NMR (400 MHz, MeOD) 0.95 (t, J=7.28 Hz, 3H), 1.10-1.23 (m, 1H), 1.25-1.33 (m, 2H), 1.35-1.51 (m, 5H), 1.57-1.74 (m, 3H), 1.80 (s, 3H), 1.87-1.95 (m, 1H), 2.04-2.13 (m, 2H), 2.21-2.28 (m, 1H), 3.80-3.86 (m, 1H), 3.91-3.97 (m, 1H), 4.36-4.46 (m, 0.3H), 4.73-4.78 (m, 0.7H), 7.19 (dd, J=8.91, 2.38 Hz, 0.3 H), 7.24 (dd, J=8.91, 2.38 Hz, 0.7H), 7.28 (d, J=2.26 Hz, 1H), 7.53 (dd, J=8.78, 2.01 Hz, 1H), 7.80-7.90 (m, 3H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10]Br)=[N:7][C:6]=2[CH:12]=1.[F:13][C:14]1[C:22]([OH:23])=[CH:21][CH:20]=[C:19]([F:24])[C:15]=1[C:16]([NH2:18])=[O:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:23][C:22]3[C:14]([F:13])=[C:15]([C:19]([F:24])=[CH:20][CH:21]=3)[C:16]([NH2:18])=[O:17])=[N:7][C:6]=2[CH:12]=1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Reactant: BrCc1nc2cc(Br)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1c(F)ccc(OCc2nc3cc(Br)ccc3s2)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 769.7 %

Procedure:
To a solution of 5-bromo-2-bromomethyl-benzothiazole (1.1 g, 0.358 mmol) in 5 ml of anhydrous DMF was added 2,6-difluoro-3-hydroxybenzamide (0.620 g, 0.22 mol) and potassium carbonate (1.73 g, 1.25 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. Water was added to the reaction mixture the compound was precipitated out, filtered and washed with diethylether to give the title compound as yellow solid (1.1 g, 76%). 1H NMR (DMSO-d6, 400 MHz): δ 5.71 (s, 2H), 7.11 (dt, 1H J=8.8 Hz (o-coupling), 7.38-7.39 (m, 1H), 7.65 (d, 1H, J=8.8 Hz (o-coupling), 7.90 (broad s, 1H), 8.13 (d, 1H, J=8.8 Hz (o-coupling), 8.18 (s, 1H), 8.26 (broad s, 1H). MS ES+ (400.9), HPLC (method 5) Rt=16.57 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([CH:22]([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:18][C:17]=2[O:31][CH3:32])[C@@H:9]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=O)(C)(C)C.Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[C:33]1([C@H:9]2[C@@H:10]([NH:14][CH2:15][C:16]3[CH:21]=[C:20]([CH:22]([C:27]([F:28])([F:29])[F:30])[C:23]([F:24])([F:25])[F:26])[CH:19]=[CH:18][C:17]=3[O:31][CH3:32])[CH2:11][CH2:12][CH2:13][NH:8]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COc1ccc(C(C(F)(F)F)C(F)(F)F)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(C(C(F)(F)F)C(F)(F)F)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 115.2 %

Procedure:
To a solution of Compound 13 (170 mg) in AcOEt (6 ml) was added conc. HCl (1 ml). The mixture was stirred at room temperature for 45 minutes. The mixture was poured into NaHCO3 aq., and extracted with CH2Cl2. The combined extracts were dried (Na2SO4), and concentrated in vacuo to give Compound 14 (160 mg) as a yellow oil.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[O:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][C:12](=[O:21])[C:10]3=2)[N:5]=[C:4]([C:22]([O:24][CH3:25])=[O:23])[CH:3]=1.S(Cl)([Cl:28])=O>ClC(Cl)C.CN(C)C=O>[Cl:28][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[O:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][C:12](=[O:21])[C:10]3=2)[N:5]=[C:4]([C:22]([O:24][CH3:25])=[O:23])[CH:3]=1
Reactant: CCOC(=O)c1cc(=O)c2c(ccc3nc(C(=O)OC)cc(O)c32)o1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc(=O)c2c(ccc3nc(C(=O)OC)cc(Cl)c32)o1

Procedure:
The product of step (a) (1.35 g; 3.9 mmole) suspended in dichloroethane was treated with thionyl chloride (0.9 g; 7.5 mmole) and dimethylformamide (4 drops). The mixture was heated under reflux for 6 hrs adding more thionyl chloride (0.2 ml) after 3 hrs. The mixture was evaporated to dryness and triturated with ether to give a buff solid (1.35 g; 96%), mp 193° shown to be the title compound by its NMR and mass spectrum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:18][CH2:17][CH2:16][CH:15]=[C:14]2[C:13](=[O:19])[NH:12][C:11](=[O:20])[CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH2:23](Br)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C)C=O>[CH2:23]([N:12]1[C:11](=[O:20])[CH2:10][C:9]2([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:14](=[CH:15][CH2:16][CH2:17][CH2:18]2)[C:13]1=[O:19])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: COc1cccc(C23CCCC=C2C(=O)NC(=O)C3)c1
Reactant: CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCN1C(=O)CC2(c3cccc(OC)c3)CCCC=C2C1=O
Yield: 67.5 %

Procedure:
The procedure in Example 9, Part A, was followed in which 4a-(m-methoxyphenyl)-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline (12 g, 0.05 moles) in 150 ml of anhydrous dimethylformamide was added to a 55% suspension of sodium hydride in mineral oil (2.4 g) in 100 ml of dimethylformamide at 70°; n-hexyl bromide (9.1 g) was added, the reaction heated at 70° for 18 hrs. The crude material obtained from this procedure was chromatographed to yield 12 g of product.