Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.CC(C)([O-])C.[K+].O>CS(C)=O.CCOC(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:11][CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Fluoro-nitrobenzene (0.728 mL, 6.96 mmol) was added to a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (A110) (1.40 g, 6.96 mmol) and potassium tert-butoxide (1.09 g, 9.74 mmol) in anhydrous DMSO (7.5 mL) and the resulting mixture was stirred for 2 hours at room temperature. Water and EtOAc were added to the mixture and the phases were separated. The aqueous phase was extracted with EtOAc, then the combined organic extracts were washed with water, brine and dried over Na2SO4. The volatiles were evaporated under reduced pressure and the residue was adsorbed onto silica gel and purified by column chromatography (SiO2 cartridge, 0-15% EtOAc in cyclohexane) to give the title compound A111 as an oil (2.20 g, 98%); 1H NMR (300 MHz, CDCl3); δ 8.09 (d, J=9.4 Hz, 2H), 6.91 (d, J=9.3 Hz, 2H), 4.58 (m, 1H), 3.65 (m, 2H), 3.33 (m, 2H), 1.92 (m, 2H), 1.72 (m, 2H), 1.41 (s, 9H). LCMS-B: rt 8.22 min; m/z 323.3 [M+H]+.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH2:16][CH2:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C1C=C2N=NN(O)C2=CC=1.O.[C:32]([O:36][C:37](=[O:51])[CH2:38][CH:39]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:40](O)=[O:41])([CH3:35])([CH3:34])[CH3:33].Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CCOCC>[C:32]([O:36][C:37](=[O:51])[CH2:38][CH:39]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:40]([N:17]1[C:18]2[C:14](=[CH:13][C:12]([O:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:6][CH2:7]3)=[CH:20][CH:19]=2)[CH2:15][CH2:16]1)=[O:41])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)C1CCC(Oc2ccc3c(c2)CCN3)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC(NC(=O)OC(C)(C)C)C(=O)N1CCc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc21
Temperature: 50 °C

Procedure:
To a solution of 5-(4-tert-butyl-cyclohexyloxy)-2,3-dihydro-1H-indole (110 mg, 0.4 mmol) in dimethylformamide (2 mL) was added HOBT monohydrate (10 mg, 0.1 mmol), 2-tert-butoxycarbonylamino-succinic acid 4-tert-butyl ester (230 mg, 0.8 mmol) and finally N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (92 mg, 0.48 mmol). The reaction was heated at 50° C. overnight. The solution was diluted with ether and washed twice with water. The organic phase was dried over MgSO4, filtered and concentrated to give crude product (220 mg, yield: 100%). The crude was used directly in Example 53. ESI-MS: 545.4 (M+H)+.
Reaction SMILES: CNC([OH:5])C.[CH2:6]([O:13][C:14](Cl)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:17]([N:19]([CH2:22]C)CC)[CH3:18]>C(Cl)Cl>[CH2:6]([O:13][C:14](=[O:15])[N:19]([CH2:17][CH2:18][OH:5])[CH3:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNC(C)O
Solvent: ClCCl
Product: CN(CCO)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of N-methylaminoethanol (1.20 ml, 15.0 mmol) in methylene chloride (36 ml) were added chloroformic acid benzyl ester (2.56 ml, 18.0.mmol) and triethylamine (2.52 ml, 18.0 mmol) in an ice bath. The mixture was stirred at room temperature for 3 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford N-(2-hydroxyethyl)-N-methyl-carbamic acid benzyl ester (2.8 g, yield 90%) as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH2:19]([CH:21]1[O:23][CH2:22]1)Cl>C1COCC1.CN(C=O)C>[O:23]1[CH2:22][CH:21]1[CH2:19][O:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: Oc1ccc2c(c1)ncn2-c1ccccc1
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: c1ccc(-n2cnc3cc(OCC4CO4)ccc32)cc1
Reaction time: 0.08 h

Procedure:
A solution of 5-hydroxy-1-phenylbenzimidazole (Example 14) (0.24 g, 1.14 mmol) 1:1 THF/DMF (5 mL) was added under nitrogen to a stirred suspension of sodium hydride (41 mg of a 60% dispersion in oil, 1.71 mmol). After 5 minutes, epichlorohydrin (98 μL, 1.26 mmol) was added, and the solution was refluxed for 4 hours. The cooled solution was partitioned between diethyl ether and water, and the extract was washed with 2N NaOH and worked up to give an oil which was chromatographed on silica gel. EtOAc/petroleum ether (1:1) eluted foreruns, while EtOAc eluted the epoxide Example 34 (0.14 g, 46%): mp (EtOAc/petroleum ether) 96-97.5° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[Cl:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[C:11]2[CH2:18][N:19]1[C:27]([C:28]2[N:32]([CH3:33])[CH:31]=[C:30]([C:34]#[N:35])[CH:29]=2)=[C:26]2[C:21]([N:22]([CH2:39][CH:40]3[CH2:42][CH2:41]3)[C:23](=[O:38])[N:24]([CH3:37])[C:25]2=[O:36])=[N:20]1>CN(C)C=O>[Cl:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[C:11]2[CH2:18][N:19]1[C:27]([C:28]2[N:32]([CH3:33])[CH:31]=[C:30]([C:34]3[NH:35][N:3]=[N:2][N:1]=3)[CH:29]=2)=[C:26]2[C:21]([N:22]([CH2:39][CH:40]3[CH2:42][CH2:41]3)[C:23](=[O:38])[N:24]([CH3:37])[C:25]2=[O:36])=[N:20]1
Reactant: Cn1cc(C#N)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2nnn[nH]2)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Temperature: 120 °C
Yield: 64.3 %

Procedure:
Sodium azide (0.054 g) and ammonium chloride (0.044 g) were added to a solution of 5-[2-[(6-chloro-4-quinolinyl)methyl]-7-(cyclopropylmethyl)-4,5,6,7-tetrahydro-5-methyl-4,6-dioxo-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carbonitrile (0.083 g) in dimethylformamide (5 ml) at 0° C. The mixture was heated at 120° C. for 31 hour. The crude reaction was purified on preparative HPLC to give the title compound (0.058 g). Mass: 543.08 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C@@H:17]3[O:26][C@@H:20]4[O:21]C(C)(C)[O:23][C@@H:19]4[C@@H:18]3[CH2:27][CH2:28][N:29]3[C:37](=[O:38])[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]3=[O:39])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].Cl(O)(=O)(=O)=O>C(#N)C.O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C@H:17]3[C@@H:18]([CH2:27][CH2:28][N:29]4[C:30](=[O:39])[C:31]5[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:37]4=[O:38])[C@@H:19]([OH:23])[C@@H:20]([OH:21])[O:26]3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2ccc(CC[C@@H]3O[C@@H]4OC(C)(C)O[C@@H]4[C@@H]3CCN3C(=O)c4ccccc4C3=O)cc2)cc1F
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(-c2ccc(CC[C@@H]3O[C@H](O)[C@H](O)[C@@H]3CCN3C(=O)c4ccccc4C3=O)cc2)cc1F
Temperature: 55 °C

Procedure:
To a solution of the compound obtained from step m above (0.28 g) in acetonitrile (20 mL) and water (2 mL), 30% perchloric acid (0.4 mL) was added at room temperature. The reaction mixture was heated to 55° C. for 30 minutes. The reaction mixture was then quenched using a sodium bicarbonate solution. The solvents were evaporated at reduced pressure. The residue thus obtained was taken in ethyl acetate and water. The organic layer was separated, washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was concentrated under reduced pressure to yield the title compound (0.418 g) as crude mass which was used further without any purification and characterization.
Reaction SMILES: C[Si]([N-:5][Si](C)(C)C)(C)C.[K+].[CH2:11]([O:13][C:14]1[C:19]([C:20]2[NH:21][C:22](=[O:38])[C:23]3[C:24](=[C:26]([CH2:36][CH3:37])[N:27]([CH2:29][C:30]4[N:31]=[N:32][CH:33]=[CH:34][CH:35]=4)[N:28]=3)[N:25]=2)=[CH:18][C:17]([S:39]([N:42]2[CH2:47][CH2:46][N:45]([CH2:48][CH3:49])[CH2:44][CH2:43]2)(=[O:41])=[O:40])=[CH:16][N:15]=1)[CH3:12].[CH2:50](O)[CH2:51]CC>>[NH3:5].[CH2:11]([O:13][C:14]1[C:19]([C:20]2[NH:21][C:22](=[O:38])[C:23]3[C:24](=[C:26]([CH2:36][CH3:37])[N:27]([CH2:29][C:30]4[N:31]=[N:32][CH:33]=[CH:34][CH:35]=4)[N:28]=3)[N:25]=2)=[CH:18][C:17]([S:39]([N:42]2[CH2:47][CH2:46][N:45]([CH2:48][CH3:49])[CH2:44][CH2:43]2)(=[O:41])=[O:40])=[CH:16][N:15]=1)[CH2:12][CH2:50][CH3:51]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(Cc3cccnn3)nc2c(=O)[nH]1
Reactant: CCCCO
Agent: [K+]
Product: CCCCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(Cc3cccnn3)nc2c(=O)[nH]1
Product: N
Temperature: 110 °C
Yield: 59 %

Procedure:
Potassium bis(trimethylsilyl)amide (35 mg, 0.176 mmol) was added to a solution of the title compound of Example 146 (80 mg, 0.145 mmol) in n-butanol (2 ml), and the reaction stirred at 110° C. for 6½ hours. The cooled mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate (20 ml) and sodium bicarbonate solution (10 ml). The phases were separated, the organic layer washed with additional sodium bicarbonate solution (10 ml), brine (10 ml), dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 99.6:0.4:0.5) to afford the title compound (50 mg, 59%) as a white foam.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH:10]([OH:19])[C:11]([NH:13][O:14][CH2:15][C:16]([OH:18])=O)=[O:12])=O)(C)(C)C.Cl.[CH2:28]([O:30][C:31](=[O:35])[C@H:32]([CH3:34])[NH2:33])[CH3:29].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[NH2:8][C@H:9]([CH2:20][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[CH:10]([OH:19])[C:11]([NH:13][O:14][CH2:15][C:16]([NH:33][C@@H:32]([CH3:34])[C:31]([O:30][CH2:28][CH3:29])=[O:35])=[O:18])=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(O)C(=O)NOCC(=O)O
Reactant: CCOC(=O)[C@H](C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)NC(=O)CONC(=O)C(O)[C@H](N)CC1CCCCC1
Reaction time: 1 h

Procedure:
A solution of Example 118A (0.17 g, 0.45 mmol), L-alanine ethyl ester hydrochloride (0.098 g, 0.64 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.098 g, 0.51 mmol), 1-hydroxybenzotriazole (0.091 g, 0.67 mmol), and N-methylmorpholine (0.11 mL, 1.0 mmol) in dichloromethane (5 mL) at room temperature was stirred for 16 hours, diluted with dichloromethane, washed sequentially with 1 M HCl, aqueous NaHCO3, dried (MgSO4), filtered, and concentrated. The concentrate was dissolved in saturated HCl/dioxane (4 mL), stirred for 1 hour, concentrated, then purified by HPLC to provide the desired product.
Reaction SMILES: [H-].[Na+].CN(C)[CH:5]=[CH:6][C:7]([C:9]1[NH:13][C:12]([CH3:14])=[N:11][CH:10]=1)=O.[Cl:16][C:17]1[CH:18]=[C:19]([NH:23][C:24]([NH2:26])=[NH:25])[CH:20]=[CH:21][CH:22]=1>C(O)CCC>[Cl:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[NH:23][C:24]1[N:26]=[C:7]([C:9]2[NH:13][C:12]([CH3:14])=[N:11][CH:10]=2)[CH:6]=[CH:5][N:25]=1
Reactant: N=C(N)Nc1cccc(Cl)c1
Reactant: Cc1ncc(C(=O)C=CN(C)C)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCO
Product: Cc1ncc(-c2ccnc(Nc3cccc(Cl)c3)n2)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20.6 %

Procedure:
Sodium hydride (45 mg of a 60% suspension in mineral oil, 1.12 mmol) was added to a stirred suspension of 5-(3-dimethylaminoprop-2-en-1-oyl)-2-methylimidazole (100 mg, 0.56 mmol) and 3-chlorophenylguanidine (95 mg, 0.56 mmol) in dry 1-butanol (4.0 ml) under nitrogen. The mixture was stirred at ambient temperature for 15 minutes then heated at 126° C. for 26 hours. The reaction mixture was allowed to cool and the volatiles were removed by evaporation. The residue was suspended in water (20 ml) and acetic acid (67 μl) was added and the solution extracted with DCM (3×20 ml). The extracts were combined, dried (NaSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with DCM/MeOH (100:0 increasing in polarity to 92:8) to give the title compound 33 mg, (21%) as a solid. NMR: 2.35 (s, 3H), 6.95 (d, 1H), 7.23 (d, 1M, 7.30 (t, 1H), 7.67 (s, 1H), 7.72 (s, 1H), 8.05 (s, 1H), 8.43 (d, 1H), 9.62 (s, 1H), 12.15 (s, 1H); m/z: 286.
Reaction SMILES: [O-]CC.[Na+].[Cl:5][C:6]1[C:7](=[N:12][NH2:13])[NH:8][CH:9]=[CH:10][CH:11]=1.[C:14](OCC)(=[O:22])/[CH:15]=[CH:16]\[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(O)(=O)C>O.C(O)C>[Cl:5][C:6]1[C:7]([N:12]2[CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][C:14](=[O:22])[NH:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: NN=c1[nH]cccc1Cl
Reactant: CCOC(=O)/C=C\C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1CC(=O)NN1c1ncccc1Cl
Temperature: 83 °C
Reaction time: 2 h

Procedure:
A 2-L four-necked flask equipped with a mechanical stirrer, thermometer, addition funnel, reflux condenser, and nitrogen inlet was charged with absolute ethanol (250 mL) and an ethanolic solution of sodium ethoxide (21%, 190 mL, 0.504 mol). The mixture was heated to reflux at about 83° C. It was then treated with 3-chloro-2(1H)-pyridinone hydrazone (68.0 g, 0.474 mol). The mixture was re-heated to reflux over a period of 5 minutes. The yellow slurry was then treated dropwise with diethyl maleate (88.0 mL, 0.544 mol) over a period of 5 minutes. The reflux rate increased markedly during the addition. By the end of the addition all of the starting material had dissolved. The resulting orange-red solution was held at reflux for 10 minutes. After being cooled to 65° C., the reaction mixture was treated with glacial acetic acid (50.0 mL, 0.873 mol). A precipitate formed. The mixture was diluted with water (650 mL), causing the precipitate to dissolve. The orange solution was cooled in an ice bath. Product began to precipitate at 28° C. The slurry was held at about 2° C. for 2 hours. The product was isolated via filtration, washed with aqueous ethanol (40%, 3×50 mL), and then air-dried on the filter for about 1 hour. The title product compound was obtained as a highly crystalline, light orange powder (70.3 g, 55% yield). No significant impurities were observed by 1H NMR.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([O:20]C)=[O:19])[CH2:14][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@H]1CC[C@H](CN[C@@H]2C[C@H]2c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@H]1CC[C@H](CN[C@@H]2C[C@H]2c2ccccc2)CC1

Procedure:
The trans-methyl 4-(((trans-2-phenylcyclopropyl)amino)methyl)cyclohexanecarboxylate (80 mg, 0.278 mmol) was stirred in a mixture of methanol (3 mL) and sodium hydroxide (3 ml, 3.00 mmol) for 1 hour at room temperature. The solution was then concentrated and purified by preperatory HPLC (5 to 50% AcCN:H2O with 0.1% formic acid modifier). The fractions were combined, 0.5 mL of 6 M HCl was added into each fraction and the product was evaporated. trans-4-(((trans-2-Phenylcyclopropyl)amino)methyl)cyclohexanecarboxylic acid (30 mg, 0.082 mmol, 29.6% yield) was isolated as white solid. 1H NMR (400 MHz, METHANOL-d4) δ 7.29-7.38 (m, 2H), 7.22-7.28 (m, 1H), 7.08-7.22 (m, 2H), 3.09 (d, J=7.07 Hz, 2H), 3.00 (dt, J=4.07, 7.77 Hz, 1H), 2.53 (ddd, J=3.79, 6.57, 10.36 Hz, 1H), 2.29 (tt, J=3.54, 12.25 Hz, 1H), 2.08 (dd, J=3.28, 13.39 Hz, 2H), 1.94 (dd, J=3.03, 13.14 Hz, 2H), 1.76 (ddd, J=4.29, 7.71, 11.24 Hz, 1H), 1.55 (ddd, J=4.55, 6.57, 10.61 Hz, 1H), 1.43-1.52 (m, 2H), 1.35-1.42 (m, 1H), 1.15 (qd, J=3.54, 12.72 Hz, 2H); LC-MS Rt=0.62 min; MS (ESI): 274.2 [M+H]+.
Reaction SMILES: [N:1]1C=CC=CC=1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>C(Cl)Cl>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH2:1])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: c1ccncc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(Br)cc1
Reaction time: 8 h

Procedure:
The resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) followed by 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.O=[C:19]([CH2:26][CH2:27][CH3:28])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([CH2:26][CH2:27][CH3:28])[NH:12][C:13]2=[N:14][NH:15][CH:16]=[C:17]12
Reactant: CCCC(=O)CC(=O)OCC
Reactant: Nc1cc[nH]n1
Reactant: COc1ccc(Cl)c(C=O)c1
Product: CCCC1=C(C(=O)OCC)C(c2cc(OC)ccc2Cl)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2-chloro-5-methoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: N#N.[CH:3]1[C:15]2[C:14]3[S:13][C:12]4[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=4[C:10]=3[CH:9]=[C:8]([CH:20]=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[NH2:22][C:23]([CH3:28])([CH2:26][OH:27])[CH2:24][OH:25].O.C1(C)C=C[C:33]([S:36](O)(=[O:38])=[O:37])=CC=1.[BH4-].[Na+]>O.C1(C)C=CC=CC=1>[CH3:33][S:36]([O:25][CH2:24][C:23]([NH:22][CH2:20][C:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:15]=2[C:14]2[S:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[C:10]=2[CH:9]=1)([CH3:28])[CH2:26][OH:27])(=[O:38])=[O:37]
Reactant: CC(N)(CO)CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=Cc1cc2c3ccccc3sc2c2ccccc12
Agent: N#N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(CO)(COS(C)(=O)=O)NCc1cc2c3ccccc3sc2c2ccccc12
Temperature: 25 °C

Procedure:
To a RB flask equipped with magnetic stirring bar, condenser, thermometer, Dean-Stark trap, and N2 inlet and bubbIer was added benzo[b]naphtho[2,1-d-]-thiophene-5-carbaldehyde (SISA Pharmaceutical Laboratories, Inc., 763 Concord Ave., Cambridge, Mass., 02138, 4.94 g, 18.83 mmol), 2-amino-2-methyl-1,3-propanediol (Aldrich, 1.98 g, 18.83 mmol), p-toluenesulfonic acid monohydrate (Aldrich, 0.1 g) and PhCH3 (200 mL). The mixture was stirred at reflux with removal of H2O for 2.5 h (or until no H2O is collected). Most of the PhCH3 was then removed by distillation. The mixture was then cooled in an ice bath and diluted with abs. EtOH (200 mL) and further cooled. Solid NaBH4 (MCB Manufacturing Chemists, Inc., 2909 Highland Ave., Cincinnati, Ohio, 45212, 0.712 g, 18.83 mmol) was added in one portion to the reaction mixture. The ice bath was then removed, the reaction mixture allowed to warm to RT and stirred overnight. The reaction was then acidified with 10% HCl and the solvents removed by rotary evaporation. The crude solid was shaken with 1N HCl (300 mL) filtered, washed with 1N HCl (300 mL), sucked semidry, and washed with Et2O (300 mL). The material was dissolved in CH3OH (200 mL), filtered and basified with 1N NaOH solution (1 L). A white solid formed which was extracted with EtOAc (3×500 mL). The EtOAc washings were combined, filtered, washed with saturated NaCl (3×500 mL), dried with K2CO3 (Mallinckrodt, 25 g) filtered, and concentrated by rotary evaporation to give a white solid. This was dissolved in a mixture of abs. EtOH (200 mL) and CH3SO3H (99.5%, Morton Thiokol, Inc. - Alfa Products, P.O. Box 299, 152 Andover St., Danvers, Mass., 01923, 3 mL), filtered and diluted to 4 L with a mixture of Et2O/hexane (1:1). This material was recrystallized three times from EtOH/hexane (1:3) to give 2-[(benzo-[b]naphtho[2,1-d]thiophen-5-ylmethyl)amino]-2-methyl-1,3-propanediol methanesulfonate, mp 221°-222° (C,H,N.,S).
Reaction SMILES: C([NH:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:10](O)[CH3:11])=[S:7])(C)(C)C.Cl>O>[CH2:13]([C@H:9]1[C@H:10]([CH3:11])[S:7][C:6]([NH2:5])=[N:8]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(O)[C@H](Cc1ccccc1)NC(=S)NC(C)(C)C
Agent: Cl
Solvent: O
Product: C[C@@H]1SC(N)=N[C@H]1Cc1ccccc1
Temperature: 100 °C

Procedure:
The process is performed as in Example 3, starting with 3.9 g of diastereoisomer A of the N-(tert-butyl)-N′-((1S)-1-benzyl-2-hydroxypropyl)thiourea in 46 cm3 of aqueous 6N hydrochloric acid. After heating for 5 hours at a temperature in the region of 100° C., the reaction mass is concentrated under reduced pressure (5 kPa) at a temperature in the region of 50° C. The oil obtained is dissolved in 50 cm3 of water; the solution is washed with twice 50 cm3 of dichloromethane. The aqueous phase is made alkaline by addition of 3 cm3 of 30% caustic soda and then extracted with 3 times 50 cm3 of dichloromethane. The organic extracts are combined and dried over sodium sulfate. After filtration and concentration under reduced pressure (5 kPa) at a temperature in the region of 40° C., 2.5 g of (−)-(4S,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine are obtained in the form of a white solid melting at 89° C. (trans isomer). (αD20=−87.3±1.3 at a concentration of 0.5% in methanol).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:23])=[C:10]([C:15]3[N:16]=[C:17]([CH2:20][NH:21][CH3:22])[S:18][CH:19]=3)[C:11]=2[O:13]C)[C:6](=[O:24])[C:5]([C:25]([OH:27])=[O:26])=[CH:4]1)[CH3:2].Br>C(O)(=O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:23])=[C:10]([C:15]3[N:16]=[C:17]([CH2:20][NH:21][CH3:22])[S:18][CH:19]=3)[C:11]=2[OH:13])[C:6](=[O:24])[C:5]([C:25]([OH:27])=[O:26])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-c3csc(CNC)n3)c(OC)c21
Agent: Br
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-c3csc(CNC)n3)c(O)c21
Temperature: 70 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To 700 mg (1.79 mmol) of the 1-ethyl-6-fluoro-1,4-dihydro-8-methoxy-7-[2-[(methylamino)methyl]-4-thiazolyl]-4-oxo-3-quinolinecarboxylic acid was added 8 ml of hydrobromic acid in acetic acid and the mixture was heated to 70° C. After four hours 8 ml more hydrobromic acid was added and the mixture stirred overnight. The solids were collected, dissolved in aqueous ammonia and concentrated to one fourth volume. Filtration gave 580 mg of 1-ethyl-6-fluoro-1,4-dihydro-8-hydroxy-7-[2-[(methylamino)methyl]-4-thiazolyl]-4-oxo-3-quinolinecarboxylic acid, mp 242°-246° C.