Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([C:7]2[C:11]([NH:12][C:13]([C:15]3[N:16]=[C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([N:26]([CH2:34][C:35]([F:38])([F:37])[F:36])C(=O)OC(C)(C)C)[CH:21]=4)[O:18][CH:19]=3)=[O:14])=[CH:10][N:9]([CH3:39])[N:8]=2)[C:4](=[O:40])[CH2:3]1.[CH2:41]=O.[BH4-].[Na+].CO>C1COCC1>[CH3:39][N:9]1[CH:10]=[C:11]([NH:12][C:13]([C:15]2[N:16]=[C:17]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:34][C:35]([F:36])([F:37])[F:38])[CH:21]=3)[O:18][CH:19]=2)=[O:14])[C:7]([N:5]2[CH2:6][C@@H:2]([NH:1][CH3:41])[CH2:3][C:4]2=[O:40])=[N:8]1
Reactant: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2C[C@@H](N)CC2=O)n1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN[C@H]1CC(=O)N(c2nn(C)cc2NC(=O)c2coc(-c3ccnc(NCC(F)(F)F)c3)n2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (4-(4-((3-((4S)-4-amino-2-oxopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)carbamoyl)-1,3-oxazol-2-yl)pyridin-2-yl)(2,2,2-trifluoroethyl)carbamate (83 mg) in THF (0.73 mL) was added 37% formalin (32 μl), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was ice-cooled, sodium borohydride (28 mg) and methanol (0.73 mL) were added thereto, and the mixture was stirred under ice-cooling for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in TFA (0.70 mL), and the solution was stirred at room temperature for 20 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate), and recrystallized from ethyl acetate/hexane to give the title compound (19 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:6]=1[S:13]([OH:16])(=[O:15])=[O:14].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36]>N1C=CC=CC=1>[NH4+:1].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:34])[NH:1][C:2]2[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:3]=2[O:4][C:5]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:6]=2[S:13]([O-:16])(=[O:15])=[O:14])=[CH:28][C:27]=1[C:35]([F:36])([F:37])[F:38]
Reactant: Nc1cc(C(F)(F)F)ccc1Oc1cc(Cl)c(Cl)cc1S(=O)(=O)O
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1cc(C(F)(F)F)ccc1Oc1cc(Cl)c(Cl)cc1S(=O)(=O)[O-]
Product: [NH4+]

Procedure:
A solution of 2-(2-amino-4-trifluoromethylphenoxy)-4,5-dichlorobenzenesulfonic acid (2 g, 4.8 mmol) and 4-chloro-3-trifluoromethylphenyl isocyanate (1.11 g, 5 mmol) in pyridine (20 mL) was stirred under argon for 72 hours (hereinafter h). The solvent was evaporated and the residue was flash chromatographed (silica gel, methylene chloride/ethanol/ammonium hydroxide) to give the title compound. 1H NMR (400 MHz, CD3OD) δ8.61 (d, 1H), 8.08 (s, 1H), 7.95 (d, 1H), 7.60 (dd, 1H), 7.43 (d, 1H), 7.30-7.36 (m, 2H), 7.10 (s, 1H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9](=[O:21])[CH:8]=1)(=O)=O.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[F:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][N:10]1[CH:11]=[CH:12][C:7]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[CH:8][C:9]1=[O:21]
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=c1cc(OS(=O)(=O)C(F)(F)F)ccn1Cc1cccc(F)c1
Product: COc1ccc(-c2ccn(Cc3cccc(F)c3)c(=O)c2)cc1
Yield: 60.7 %

Procedure:
According to Scheme 13 Method C: The title compound was prepared from 1-(3-fluorobenzyl)-1,2-dihydro-2-oxopyridin-4-yl trifluoromethanesulfonate (1 eq, 0.28 mmol, 0.10 g) and 4-methoxyphenyl boronic acid (1.5 eq, 0.43 mmol, 65 mg) according to the procedure described for Example 1 Step 3. The crude product was purified by flash chromatography on silica gel using cyclohexane/AcOEt 70/30 as eluent to afford the title compound (0.17 mmol, 52 mg, 59%) was obtained as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:18]([CH2:20][C:21]([O:23][CH:24]1[CH2:29][CH2:28][CH:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:26][CH2:25]1)=[O:22])#[N:19].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[C:14]([C:11]1[CH:10]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:12]=1[OH:13])[CH:8]=[C:20]([C:18]#[N:19])[C:21]([O:23][CH:24]1[CH2:29][CH2:28][CH:27]([C:30]([CH3:31])([CH3:32])[CH3:33])[CH2:26][CH2:25]1)=[O:22])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)C1CCC(OC(=O)CC#N)CC1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C=C(C#N)C(=O)OC2CCC(C(C)(C)C)CC2)cc(C(C)(C)C)c1O

Procedure:
5.4 g of 3,5-di-tertiary-butyl-4-hydroxybenzaldehyde were dissolved in 50 ml of toluene. 5.9 g of 4-tertiary-butylcyclohexyl cyanoacetate, 0.1 g of piperidine and 0.25 g of acetic acid were added. 0.4 g of water was removed azeotropically under reflux. The mixture was washed, dried and concentrated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].F[C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(=O)OCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 145 °C
Yield: 97.4 %

Procedure:
A mixture of 4-chloro-3-(trifluoromethyl)phenol (2 g, 10.18 mmol), 1-(4-fluorophenyl) ethanone (1.406 g) and K2CO3 (2.3 g, 16.64 mmol) in DMF (18 mL) was heated with a microwave condition at 145° C. for 4 h. The solution was diluted with EA and washed with water twice, dried over Na2SO4 and concentrated in vacuo to afford the title compound (3.12 g, 97% yield) as a brown oil. LCMS: rt=3.83 min, [M+H+]=315
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:17][N:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]2[N:10]=[C:11](SC)[N:12]=[CH:13][C:8]=2[C:7]1=[O:25])=[O:5])[CH3:2].[CH:26]1C=C(Cl)C=C(C(OO)=O)C=1.[O-:37][S:38]([O-:40])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:25])[C:8]2[CH:13]=[N:12][C:11]([S:38]([CH3:26])(=[O:40])=[O:37])=[N:10][C:9]=2[N:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1)=[O:5])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)c2nc(SC)ncc2C1=O
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cn(Cc2ccccc2)c2nc(S(C)(=O)=O)ncc2c1=O
Reaction time: 2 h

Procedure:
8-Benzyl-2-methylsulfanyl-5-oxo-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.39 g, 1.1 mmol) and m-CPBA (0.61 g (77% w/w), 2.7 mmol) were combined in DCM (20 mL). After 2 hours, a 10% solution of Na2SO3 (5 mL) was added and the mixture was partitioned between sat. NaHCO3 and DCM. The organic layer was dried (MgSO4) and concentrated. Chromatography on silica (25-100% EtOAc/hexanes gradient) provided 0.21 g of 8-benzyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.70 (s, 1H), 8.72 (s, 1H), 7.38-7.41 (m, 5H), 5.57 (s, 2H), 4.40 (q, 2H, J=7.1 Hz), 3.38 (s, 3H), 1.40 (t, 3H, J=7.1 Hz).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:19][CH2:18][C:13]3(OCC[O:14]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Cl.O>C(O)C>[F:21][C:2]([F:1])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][C:13](=[O:14])[CH2:18][CH2:19]2)=[CH:6][CH:5]=1
Reactant: FC(F)(F)Oc1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C1CCN(c2ccc(OC(F)(F)F)cc2)CC1
Yield: 80.6 %

Procedure:
A mixture of 8-(4-trifluoromethoxyphenyl)-1,4-dioxa-8-azaspiro[4.5]decane (1.23 g, 4.06 mmol) prepared in Reference Example 21, concentrated hydrochloric acid (5 ml), water (10 ml), and ethanol (30 ml) was heated under reflux for 5 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. To the residue, 10% sodium hydroxide aqueous solution was added, and the mixture was extracted with methylene chloride. The extract was washed with water and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1) to afford 1-(4-trifluoromethoxyphenyl)piperidin-4-one (848 mg, yield 81%) as a colorless oil.
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][CH2:8][CH:7]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:6]1)[CH2:2][CH:3]=[CH2:4].I[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:28][O:29][CH3:30]>>[CH3:30][O:29][CH2:28][O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:4][CH2:3][CH2:2][CH2:1][N:5]1[CH2:9][CH2:8][CH:7]([S:10]([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)(=[O:12])=[O:11])[CH2:6]1
Reactant: C=CCCN1CCC(S(=O)(=O)c2ccc(O)cc2)C1
Reactant: COCOc1ccccc1I
Product: COCOc1ccccc1CCCCN1CCC(S(=O)(=O)c2ccc(O)cc2)C1

Procedure:
The title compound, MS: m/e=420.3 (M+H+) was prepared from (RS)-4-(1-but-3-enyl-pyrrolidine-3-sulfonyl)-phenol and 1-iodo-2-methoxymethoxy-benzene. 1-Iodo-2-methoxymethoxy-benzene is a known compound and has been prepared as described in the following reference: J. R. Labrosse; C. Poncet; P. Lhoste; D. Sinou; Tetrahedron, Asymmetry; 10; 6; 1999; 1069-1078.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[NH2:13][C@H:14]([C:23](O)=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>>[NH2:13][C@H:14]([C:23]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O

Procedure:
Arg, 1.06(1); Tyr, 0.94(1); Average recovery, 90.6%
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:9](C(C)(C)C#N)=NC(C)(C)C#N.C1C=CC=CC=1.C(C1C=CC=CN=1)=C>CCCCCC>[CH:2]([C:3]1[CH:8]=[CH:7][N:9]=[CH:5][CH:4]=1)=[CH2:1].[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C=Cc1ccccn1
Solvent: C=Cc1ccccc1
Solvent: CCCCCC
Solvent: c1ccccc1
Product: C=Cc1ccncc1

Procedure:
In a 200 ml three necked flask were charged 21 g of 4-vinylpyridine, 21 g of styrene and 0.1 g of azobisisobutyronitrile and 90 ml of benzene. The mixture was polymerized at 80° C. for 6 hrs under a nitrogen atmosphere. The reaction liquid was poured into a large amount of n-hexane to thereby obtain white precipitates. After filtering and drying, a white powder was obtained. The molar fraction of vinylpyridine in the polymer was 0.57 and the yield was 20%.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][OH:27])=[CH:8][CH:7]=1)([OH:5])[CH3:4].C(Cl)Cl.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>O>[CH3:40][S:41]([O:27][CH2:26][C@H:13]1[CH2:14][N:15]([S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:20])[CH2:16][CH2:17][N:12]1[C:9]1[CH:10]=[CH:11][C:6]([C:3]([OH:5])([CH3:4])[C:2]([F:1])([F:28])[F:29])=[CH:7][CH:8]=1)(=[O:43])=[O:42]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CO)cc1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 69.7 %

Procedure:
A 1-L round-bottomed flask was charged with 1,1,1-trifluoro-2-(4-((2R)-2-(hydroxymethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (42.7 g, 95 mmol), 200 mL of CH2Cl2, and triethylamine (15.18 mL, 109 mmol). After cooling to 0° C., methanesulfonyl chloride (7.75 g, 99 mmol) was added. After 5 min, another 1 equiv of triethylamine and methanesulfonyl chloride were added. The mixture was then diluted with water and extracted with CH2Cl2. The combined organics were dried (MgSO4), filtered, and concentrated. Purification by column chromatography on silica gel (0 to 50% EtOAc in hexanes) gave ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (35.0 g) as a light-yellow brittle foam.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:29]([O:31]CC)=[O:30])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:27])[NH:15][C@@H:16]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([Br:26])[CH:20]=2)[CH2:17][OH:18])=[C:10]([F:28])[CH:9]=1.O[Li].O>CO.C1COCC1.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:29]([OH:31])=[O:30])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:27])[NH:15][C@@H:16]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([Br:26])[CH:20]=2)[CH2:17][OH:18])=[C:10]([F:28])[CH:9]=1
Reactant: CCOC(=O)c1cnc(N)c(-c2ccc(C(=O)N[C@H](CO)c3cc(F)cc(Br)c3)c(F)c2)n1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncc(C(=O)O)nc1-c1ccc(C(=O)N[C@H](CO)c2cc(F)cc(Br)c2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A mixture of (S)-ethyl 5-amino-6-(4-((1-(3-bromo-5-fluorophenyl)-2-hydroxyethyl)carbamoyl)-3-fluorophenyl)pyrazine-2-carboxylate (220 mg, 0.422 mmol) and LiOH.H2O (142 mg, 3.38 mmol) in MeOH (2 ml), THF (2 mL) and Water (2 mL) was stirred for 3 hours at RT. The mixture was concentrated, to the residue was added 2 ml of water, 3N HCl was then added under stirring until the final pH was about 4. The resultant mixture was then concentrated and further dried to afford the crude product was a light yellow solid. (208 mg, 0.422 mmol, 100% yield). LC-MS (m/z): 494.9 (MH+), 0.653 min.
Reaction SMILES: [C:1]12([CH2:10][NH2:11])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[CH2:12]([Br:15])[CH:13]=[CH2:14]>CC(C)=O>[BrH:15].[CH2:14]([NH:11][CH2:10][C:1]12[C:7]([CH3:8])([CH3:9])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2)[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: CC1(C)C2CCC1(CN)CC2
Solvent: CC(C)=O
Product: Br
Product: C=CCNCC12CCC(CC1)C2(C)C
Reaction time: 84 h

Procedure:
A solution of 10-bornanamine (obtained by basification, with sodium hydroxide, of 1.517g. 10-bornanamine hydrochloride) in acetone (20ml) containing allyl bromide (0.68ml) was kept at room temperature for 3.5 days during which time a small amount of solid crystallized. The solution was evaporated to about one third of its original volume, cooled to 0° and the crystalline material collected by filtration to give title compound m.p. above 295° with slow decomp. (Found: C,56.6; H,8.6; N,5.1. C13H24BrN requires C,56.95; H,8.8; N,5.1%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:13][C@H:12]3[C@@H:7]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:14][CH2:15][CH3:16])[CH2:6][C:5]=2[N:17]=1.[O:18]1CC[CH2:20][CH2:19]1.C(Cl)(=O)C>CN(C)C=O.CCOCC>[C:19]([NH:1][C:2]1[S:3][C:4]2[CH2:13][C@H:12]3[C@@H:7]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:14][CH2:15][CH3:16])[CH2:6][C:5]=2[N:17]=1)(=[O:18])[CH3:20]
Reactant: CCCN1CCC[C@H]2Cc3nc(N)sc3C[C@@H]21
Reactant: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Solvent: CCOCC
Product: CCCN1CCC[C@H]2Cc3nc(NC(C)=O)sc3C[C@@H]21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30.3 %

Procedure:
A solution was prepared from 0.15 g. of trans-(±)-2-amino-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinoline (from Example 1) in 3 ml. of tetrahydrofuran (THF) to which has been added two drops of dimethylformamide (DMF). Five hundredths milliliters of acetyl chloride were added and the solution stirred at room temperature for 15 minutes. In time, the reaction mixture became a solid colorless mass. The solid was suspended in ether and the ethereal suspension filtered. The solid was then recrystallized from a methanol/ether solvent mixture to give purified trans-(±)-2-acetylamino-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinoline hydrochloride; yield=30.3%; melting point above 200° C.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14])(=[O:5])=[O:4].CCCCN=[C:23]=[O:24].C1N2CCN(CC2)C1.C(Cl)(Cl)=O>>[CH3:1][N:2]([CH3:17])[S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([N:16]=[C:23]=[O:24])(=[O:15])=[O:14])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)Oc1ccccc1S(N)(=O)=O
Reactant: CCCCN=C=O
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Product: CN(C)S(=O)(=O)Oc1ccccc1S(=O)(=O)N=C=O
Temperature: 25 °C

Procedure:
To 6.0 g (0.021 mole) 2-(dimethylaminosulfonyloxy)benzenesulfonamide suspended in 75 ml dry xylenes was added 2.1 g (0.021 mole) N-butyl isocyanate and a catalytic amount of 1,4-diazobicyclo[2.2.2]octane (~0.05 g). This mixture was rapidly heated to reflux temperature (~135° C.) and 3.0 ml of phosgene was slowly added (at such a rate as to keep the reaction temperature greater than 128° C.). The phosgene addition required ~3 hours. The reaction was cooled to room temperature, filtered under N2, and the solvent evaporated under reduced pressure. The infrared spectrum of the resultant oil was consistent for 2-(dimethylaminosulfonyloxy)benzenesulfonyl isocyanate, (2240 cm-1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][C:3]=12.[CH3:18][N:19]([CH3:29])[CH2:20][CH2:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>>[ClH:1].[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]3[CH2:15][CH2:16][CH2:17][C:3]3=[C:2]([NH:26][C:25]3[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][N:19]([CH3:18])[CH3:29])=[CH:28][CH:27]=3)[CH:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CN(C)CCc1ccc(N)cc1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Product: CN(C)CCc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Product: Cl
Yield: 73.8 %

Procedure:
Following general procedure B1, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.083 g, 0.31 mmol) was reacted with 4-(2-(dimethylamino)ethyl)aniline (0.062 g, 0.37 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.098 g, 67%) as a light yellow solid. MW=464.86. 1H NMR (DMSO-d6, 500 MHz) δ 10.16 (s, 1H), 8.33 (s, 1H), 7.91-7.89 (m, 1H), 7.79-7.74 (m, 1H), 7.48-7.42 (m, 2H), 7.31-7.28 (m, 4H), 7.21 (s, 1H), 3.29-3.26 (m, 2H), 3.02-2.90 (m, 4H), 2.87-2.78 (m, 8H), 2.10 (quin, J=7.5 Hz, 2H); APCI MS m/z 392 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[C:17]#[N:18])=[CH:4][CH:3]=1.[OH:19]O.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[C:17]([NH2:18])=[O:19])=[CH:4][CH:3]=1
Reactant: N#Cc1c[nH]c2ccc(-c3ccc(Br)cc3)cc12
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1c[nH]c2ccc(-c3ccc(Br)cc3)cc12

Procedure:
A solution of 4 (1.00 g, 3.38 mmol) in ethanol was treated with hydrogen peroxide (30%) and 1N NaOH. On completion of reaction solvent was removed and the resultant solid was washed with organic solvents to give pure 5 as a beige colored solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[NH2:28][C:29]1[S:30][CH:31]=[C:32]([CH3:37])[C:33]=1[C:34]([NH2:36])=[O:35].CCN=C=NCCCN(C)C>CN(C=O)C.C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:37][C:32]1[C:33]([C:34]([NH2:36])=[O:35])=[C:29]([NH:28][C:18](=[O:20])[CH2:17][C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:16][CH:15]=2)[S:30][CH:31]=1
Reactant: O=C(O)Cc1ccc(OCCCN2CCCCC2)cc1
Reactant: Cc1csc(N)c1C(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1csc(NC(=O)Cc2ccc(OCCCN3CCCCC3)cc2)c1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring mixture of 2-(4-(3-(piperidin-1-yl)propoxy)phenyl)acetic acid (800 mg) in DMF/DCM (6 mL, 1:1) was added triethylamine (1.2 mL), DMAP (180 mg), 2-amino-4-methylthiophene-3-carboxamide (440 mg), and EDCI (1.1 g). The reaction mixture was stirred at rt overnight, quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified via preparative HPLC to give 4-methyl-2-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)acetamido)thiophene-3-carboxamide. Method[7], MS(ESI) 416.2 [M+H], Retention time=2.254 min.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH2:17][N:18]4[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:34])/[CH:26]=[CH:27]/[C:28]5[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=5)[CH2:20][CH2:19]4)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.[ClH:35]>C(O)C.[Pd].CCOCC.C(Cl)(Cl)Cl>[ClH:1].[ClH:35].[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH2:17][N:18]4[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:34])[CH2:26][CH2:27][C:28]5[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=5)[CH2:20][CH2:19]4)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: O=C(/C=C/c1cccnc1)NC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=C(CCc1cccnc1)NC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Reaction time: 18 h
Yield: 52 %

Procedure:
To a stirred solution of N-(1-[2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]-4-piperidyl)-trans-3-(3-pyridyl)propenamide (170 mg, 0.36 mmol) in ethanol (5 mL) was added 10% palladium on carbon (17 mg). This mixture was hydrogenated at 1 atmospheric pressure for 18 h. The reaction was filtered through diatomaceous earth. The filtrate was concentrated and the resulting residue was chromatographed over silica gel (eluant: 95:5 methylene chloride:methanol) to give a white foam. This material was dissolved in a cold (ice bath) solution of ether:chloroform (3:1, v/v, 15 mL) and treated with gaseous hydrochloric acid to afford the title compound as a white solid (100 mg, 52%), mp 220.0°-3.0° C.; MS(CI): 472 (M+H); NMR (300 MHz,DMSO-d6): 1.65-2.06(m, 4H), 2.46(t, 1.70H, J=7.5 Hz), 2.59(t, 0.3H, J=7.5 Hz), 2.73(m, 2H), 2.87-3.03(m, 2H), 3.17-3.66(m, 4H), 3.78(br m, 0.85H), 3.96(m, 0.15H), 4.18-4.40(m, 2H), 4.48(s, 1H), 6.95-7.10(m, 3H), 7.27-7.42(m, 3H), 7.48(s, 1H), 7.59-7.71(m, 1H), 8.02(d, 1H, J=7.5 Hz), 8.11 (d, 1H, J=7.2 Hz), 8.35(br s, ~0.15H), 8.54-8.65(m, 2H), 8.68(br s, ~0.85H), 9.70(br s, 0.15H), 9.96-10.08(br s, 0.85H).