Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)/[CH:3]=[CH:4]/[C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[N:22]1([C:2](=[O:1])/[CH:3]=[CH:4]/[C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[CH2:11][NH:10][CH2:9][CH2:8]3)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(/C=C/C(=O)N3CCCC3)ccc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(/C=C/c1ccc2c(c1)CCNC2)N1CCCC1
Reaction time: 16 h
Yield: 91.6 %

Procedure:
A solution of 125c (400 mg, 1.12 mmol) in CH2Cl2 (4 ml) was treated with TFA (1.28 g, 11.21 mmol)) at 20-35° C. for 16 h. The progress of the reaction was monitored by TLC. After 16 h of stirring, the clear solution was concentrated under vacuum and the resultant solid was washed with diethyl ether to get the desired compound as a gummy liquid (380 mg, 91%). 1H NMR (400 MHz, DMSO-d6) δ 9.05 (bs, 2H), 7.58 (d, J=8.3 Hz, 2H), 7.43 (d, J=15.6 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 6.99 (d, J=15.6 Hz, 1H), 4.32-4.24 (m, 2H), 3.63 (t, J=6.9 Hz, 2H), 3.39 (t, J=6.9 Hz, 4H), 3.01 (t, J=6.1 Hz, 2H), 1.98-1.89 (m, 2H), 1.88-1.76 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C@H:10]1[CH2:13][C@H:12]([NH:14]C(=O)OC(C)(C)C)[CH2:11]1.Cl.O1CCOCC1>C(OCC)C>[ClH:1].[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C@H:10]1[CH2:11][C@H:12]([NH2:14])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](Oc2cccc(Cl)c2Cl)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: N[C@H]1C[C@H](Oc2cccc(Cl)c2Cl)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 184 %

Procedure:
To 1,1-dimethylethyl {trans-3-[(2,3-dichlorophenyl)oxy]cyclobutyl}carbamate (10.78 g, 17.85 mmol) was added 4M hydrochloric acid in dioxane (150 mL, 600 mmol) and the reaction mixture stirred in a sealed vessel at room temperature for 18 hours. The mixture was then diluted with diethyl ether (300 mL), stirred for 10 min and then filtered and the solid dried in vacuo to give the title compound (4.4096 g).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].[BH4-].[Na+].O>CO>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([OH:14])[CH3:13])=[CH:10][CH:11]=1)[CH:2]=[C:3]([CH3:5])[CH3:4]
Reactant: CC(=O)c1ccc(CC=C(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)=CCc1ccc(C(C)O)cc1
Yield: 91.5 %

Procedure:
To a solution of 20.0 g of p-prenylacetophenone in 200 ml of methanol, 1.5 g of sodium borohydride was added at 20° C. with stirring. After stirring for 4 hours, 300 ml of water was added, the resulting solution was extracted with ethyl ether. The extract was washed with water, dried, concentrated and distilled to give 18.5 g of 1-(p-prenylphenyl)-ethanol, b.p. 107-108 °C/0.30 mmHg.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[N:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=2)[CH:32]=1)=[O:30])(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[N:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=2)[CH:32]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)ccc1N
Product: COc1ccc(-c2cccc(C(=O)CC(=O)Nc3ccc(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert-butyl ester (Example J13) (240 mg, 0.78 mmol) and 3-[3-(6-methoxy-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K10) (293 mg, 0.89 mmol) according to the general procedure M. Obtained as a red foam (288 mg, 66%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)[CH2:11][C:12]#[CH:13].C(N(CC)CC)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:20]1([N:17]2[CH2:16][CH2:15][N:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]3[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=3)[CH2:19][CH2:18]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: C#CCCN1CCN(c2ccccc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=Cc1ccc(C#CCCN2CCN(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.3 %

Procedure:
A mixture of 4-bromobenzaldehyde (4.05 g), 1-but-3-ynyl-4-phenylpiperazine (Step A) (4.69 g), triethylamine (9.2 mL), bis (triphenylphosphine)palladium dichloride (0.31 g) and copper (I) iodide (0.08 g) in acetonitrile (100 mL) is degassed with nitrogen and stirred at room temperature for 16 hours. The solvent is evaporated and the residue is dissolved in dichloromethane (200 mL), washed with 2N sodium carbonate (150 mL), dried over MgSO4, filtered and evaporated to leave a brown oil. This oil is purified by MPLC on silica gel eluting with 15% then 30% ethyl acetate (EtOAc)/hexanes to give 4.2 g of the title compound as a yellow waxy solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=1)=[O:11].Cl[C:26]1[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)nn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6′-methyl-[2,3′-bipyridin]-2′-yl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. MS (ESI) 471 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[O:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][OH:21].[OH-].[K+]>>[O:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][O:21][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(Cl)n1
Reactant: OCC1CCCO1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1ccc(C(F)(F)F)c(OCC2CCCO2)n1

Procedure:
In analogy to the procedure described in Example 4 a), 6-chloro-5-(trifluoromethyl)picolinic acid (CAN 855915-21-8) was reacted with (tetrahydrofuran-2-yl)methanol (CAN 97-99-4) in the presence of potassium hydroxide to yield the title compound as yellow solid; MS (EI): m/e=290.0 [MH+].
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.Cl.C(N(CC)CC)C.Cl[S:14]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[NH:26][CH3:27])[C:20]([OH:22])=[O:21])(=[O:16])=[O:15]>C(OCC)(=O)C>[N:1]1([S:14]([C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=2[NH:26][CH3:27])[C:20]([OH:22])=[O:21])(=[O:16])=[O:15])[CH2:4][CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: CNc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CNc1ccc(C(=O)O)cc1S(=O)(=O)N1CCC1
Reaction time: 4 h
Yield: 60 %

Procedure:
Azetidine Ae (HCl salt) (0.2 g, 2 mmol) was dissolved in ethyl acetate (8 mL). Triethylamine (0.3 mL, 2 mmol) and 3-(chlorosulfonyl)-4-(methylamino)benzoic acid (1.2, 0.1 g, 0.5 mmol) were added. The reaction was left to stir for 4 hours, then extracted with 0.5 M HCl, washed with water and brine, and dried over magnesium sulfate. The ethyl acetate was evaporated and 3-(azetidin-1-ylsulfonyl)-4-(methylamino)-benzoic acid (1.3.Ae) was obtained (0.08 g, 60% yield). MS analysis (m−1)=269.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:23]=[C:22]3[C:14]([N:15]4[C:20](=[CH:21]3)[C:19](=[O:24])[NH:18][CH2:17][CH2:16]4)=[N:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].FC(F)(F)S(O[CH2:31][C:32]([F:35])([F:34])[F:33])(=O)=O.[H-].[Na+]>>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([O:10][C:11]2[CH:23]=[C:22]3[C:14]([N:15]4[C:20](=[CH:21]3)[C:19](=[O:24])[N:18]([CH2:31][C:32]([F:35])([F:34])[F:33])[CH2:17][CH2:16]4)=[N:13][CH:12]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)N1CCC(Oc2cnc3c(c2)cc2n3CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2cnc3c(c2)cc2n3CCN(CC(F)(F)F)C2=O)CC1
Yield: 42 %

Procedure:
The title compound was synthesized in analogy to example 17, from 7-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one (example 84), 2,2,2-trifluoroethyl trifluoromethanesulfonate and sodium hydride, to give the desired product as a colorless solid (42%).
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].[C:16]([O-:19])(=[O:18])[CH3:17].[Na+]>C(O)C>[C:16]([O:19][CH:2]([CH3:15])[C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4])(=[O:18])[CH3:17]
Reactant: CC(=O)[O-]
Reactant: CC(Br)C(=O)c1cccc2ccccc12
Agent: [Na+]
Solvent: CCO
Product: CC(=O)OC(C)C(=O)c1cccc2ccccc12

Procedure:
2-bromo-1-(napth-1-yl)-1-propanone (2 g) and sodium acetate (0.63 g) were boiled under reflux in anhydrous ethanol (10 ml) for 16 hours. The mixture was cooled and evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried with sodium sulphate, filtered and evaporated in vacuo. The title compound was obtained as an oil (0.75 g) following silica gel column chromatography of the residue in 50% dichloromethane in petroleum ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].Cl>CC(=O)CC>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: Oc1cccc(F)c1
Reactant: CCOC(=O)CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(O)CCCOc1cccc(F)c1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A 1 L 3-neck round bottom flask equipped with a magnetic stirrer bar and a reflux condenser was charged with 17.17 g (150 mmol) of 3-fluorophenol, 33.82 g (165 mmol) of ethyl 4-bromobutyrate, 24.88 g, 180 mmol potassium carbonate and 600 mL of 2-butanone. The slurry heated to reflux. After stirring for 21 hr at reflux, the reaction mixture was cooled to 25° C., filtered and concentrated. The residue was taken up in of water and treated with 150 mL of 2N aqueous sodium hydroxide (300 mmol). The reaction mixture was heated to reflux for 30 min and cooled to 25° C. The brown solution was acidified with aqueous 150 ml of 2N hydrochloric acid. The resulting pink solid was isolated by filtration washing with hexanes to yield 25.04 g, mp 53-54° C. Combustion analysis: Found: C, 60.53; H, 5.79%; F, 9.84%; C10H11FO3 requires C, 60.60; H, 5.59%; F, 9.59%; 1H NMR (d6-DMSO): δ 12.1, bs, 1H (COOH); δ 7.20, dd, 1H, (H para to OR); δ 6.7, m, 3H (aryl H's); δ 3.90, t 2H, (CH2 α to O); δ 2.30, t, 2H (CH2 α to COOR); δ 1.87, p, 2H (CH2 β to ArO and COOH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:19]([NH2:20])=[N:18][C:12]2[N:13]=[C:14]([NH2:17])[N:15]=[CH:16][C:11]=2[CH:10]=1.[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[NH2:17][C:14]1[N:15]=[CH:16][C:11]2[CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[C:19]([NH:20][C:26]([NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])=[N:18][C:12]=2[N:13]=1
Reactant: COc1ccccc1-c1cc2cnc(N)nc2nc1N
Reactant: CC(C)(C)N=C=O
Product: COc1ccccc1-c1cc2cnc(N)nc2nc1NC(=O)NC(C)(C)C

Procedure:
The title compound was prepared from 0.203 g of 6-(2-methoxy-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 100 and 0.093 mL of tert-butyl isocyanate according to Example 2. The product was purified by medium pressure liquid chromatography eluting with 1:1CHCl3 :EtOAc; mp 300°-301° C.; CIMS (1% ammonia in methane): m/z (relative intensity) 367 (MH+ +1, 67), 368 (MH+ +2, 14), 236 (100).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B.Cl.[OH-].[Na+]>C1COCC1>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][NH2:13])=[CH:14][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)c1ccc(-c2ccccc2)cc1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: NCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
Under a nitrogen atmosphere, 4-phenylbenzamide (2.01 g, 10.2 mmol) was dissolved in THF (50 mL) and heated to reflux. To the mixture was added dropwise 1 M borane in THF (80.0 mL, 80.0 mmol). After refluxing for 18 h, the reaction mixture was cooled to room temperature and treated with 1 N HCl (40 mL). The solution was made basic via addition of 3 N NaOH (60 mL) and extracted with ethyl acetate (3×370 mL). The extract was washed with brine and dried over sodium sulfate. Concentration yielded 4-phenylbenzyl amine as a white solid (1.73 g, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.Cl[CH2:13][C:14](=O)[CH3:15].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:13]=[C:14]([CH3:15])[N:11]=2)=[N:6][CH:7]=1
Reactant: NC(=S)Nc1ccc(Br)cn1
Reactant: CC(=O)CCl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc(Nc2ccc(Br)cn2)n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
1.2 (5-Bromo-pyridine-2-yl)-thiourea (1 mmol) is dissolved in DMF (2 ml) and 1-Chloro-propane-2-one (1 eq.) in DMF (2 ml) is added and stirred 2 h at 70° C. After cooling to RT the reaction solution is poured into water and the resulting precipitate is filtered, washed with water and dried 16 h in vacuo at 40° C. (5-Bromo-pyridine-2-yl)-(4-methyl-thiazole-2-yl)-amine is obtained as a colourless powder in a yield of 86%; mp. 241.5-242.6° C.; HPLC (method C): 1.55 min, 269.95 (M+H+); LC-MS (method A): 1.432 min; 1H-NMR (DMSO-d6, 400 MHz): δ [ppm] 11.314 (s, 1H), 8.363 (d, 1H, J=2.9 Hz), 7.865 (dd, 1H, J=2.9 Hz, J=8.9 Hz), 7.037 (d, 1H, J=8.9 Hz), 6.578 (s, 1H), 2.242 (s, 3H).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:15]=1[C:16](O)=[O:17]>>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[C:15]=1[C:16]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:17]
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: COc1cccc(C(F)(F)F)c1C(=O)O
Product: COc1cccc(C(F)(F)F)c1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, off-white solid, MS: m/e=357.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-methoxy-6-trifluoromethylbenzoic acid.
Reaction SMILES: C[O:2][C:3](=[O:14])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.[OH-].[Li+]>O>[Br:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][NH:5][CH2:4][C:3]([OH:14])=[O:2])=[CH:12][CH:11]=1
Reactant: COC(=O)CNCc1ccc(Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CNCc1ccc(Br)cc1

Procedure:
To (4-bromo-benzylamino)-acetic acid methyl ester (100 mg, 0.342 mmol) in water (3 mL) was added lithium hydroxide (57 mg, 0.684 mmol). After 4 hours the solution was partially quenched with 1 M HCl (1.5 mL) to give a solution pH of ca 8.5. The pH of the solution was carefully adjusted to pH 5 by the addition of 3-4 drops of 1 M HCl. Stirring overnight yielded a white precipitate. This was isolated via filtration, rinsing with a small amount of cold water, to give the desired zwitterion.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>>[OH:13][CH2:12][CH2:14][NH:15][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCO
Product: Cc1ccc(S(=O)(=O)NCCO)cc1
Yield: 94.8 %

Procedure:
The preparation is carried out as in Example 1(a) but this time 381.3 g of p-toluenesulphonyl chloride (2 mol) and 128.3 g of ethanolamine (2.1 mol) are used for the reaction. The amount obtained is 400.8 g, i.e. a yield of 94.8%.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([S:7][CH3:8])[S:5][CH:6]=1.[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)=[O:12]>>[CH3:9][O:10][C:11](=[O:12])[C:13]1[CH:18]=[CH:17][C:16]([C:2]2[N:3]=[C:4]([S:7][CH3:8])[S:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: CSc1nc(Br)cs1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Product: COC(=O)c1ccc(-c2csc(SC)n2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure M starting from 4-Bromo-2-methylsulfanyl-thiazole (CAS 204513-62-2) and 4-methoxycarbonylphenylboronic acid. MS (ES+) 266.2.
Reaction SMILES: [ClH:1].[CH2:2]([C@@H:4]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17]CC2C=CC=CC=2)[CH:12]=1)[C@@H:5]([CH3:10])[CH2:6][N:7]([CH3:9])[CH3:8])[CH3:3]>O>[ClH:1].[CH3:9][N:7]([CH3:8])[CH2:6][C@H:5]([CH3:10])[C@H:4]([C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)[CH2:2][CH3:3]
Reactant: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)CN(C)C
Agent: Cl
Solvent: O
Product: CC[C@@H](c1cccc(O)c1)[C@@H](C)CN(C)C
Yield: 90 %

Procedure:
20 mL of water and 20 mL of concentrated hydrochloric acid were added to the product of Example 38 (2.5 g, 8 mmol), then it was reacted at 80° C. for 17 hours, after that, the reaction solution was concentrated and recrystallized with isopropanol and isopropyl ether to give the target 1.9 g, yield: 90%. The HNMR spectrum data is the same as that in Example 7.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(O)C>N1C=CC=CC=1>[I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][S:17]([C:14]1[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:16][CH:15]=1)(=[O:19])=[O:18]
Reactant: Nc1ccccc1I
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCO
Product: COc1ccc(S(=O)(=O)Nc2ccccc2I)cc1
Temperature: 80 °C
Yield: 72.1 %

Procedure:
To a stirred solution of 2-iodoaniline (24.82 g, 113.3 mmol) in anhydrous pyridine (36 mL) was added 4-methoxybenzenesulfonyl chloride (23.42 g, 113.3 mmol). The dark solution was heated at 80° C. for one hour. The reaction mixture was evaporated in vacuo and the residue was poured onto an ice/water mixture. The aqueous phase was decanted and the oily residue was triturated several times with 150 mL portions of water. The resulting solid was collected by filtration and washed with water and hexane. The crude material was dried under a stream of air for three hours. Recrystallization from ethanol afforded tan crystals of the title compound (39.0 g, 81.71 mmol, 72% ). An analytically pure sample was prepared by recrystallization from acetone.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:8]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:7][CH:6]=[CH:5][C:4]=2[CH2:3]1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+].Cl>>[C:17]1([S:23]([NH:1][CH:2]2[CH2:11][CH2:10][C:9]3[C:8]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:7][CH:6]=[CH:5][C:4]=3[CH2:3]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC1CCc2c(cccc2OCC(=O)O)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)COc1cccc2c1CCC(NS(=O)(=O)c1ccccc1)C2

Procedure:
10 mmol of 6-amino-5,6,7,8-tetrahydro-naphth-1-yl-oxyacetic acid and 20 mmol of benzenesulphonyl chloride are warmed at 80° C. in 40 ml of 10% strength NaOH for 2 hours. The mixture is then acidified with concentrated HCl and the milky suspension is extracted by shaking twice with ethyl acetate. The combined ethyl acetate phases are rapidly extracted by shaking with 10% strength NaOH (product precipitates out of the ethyl acetate), the NaOH phase is acidified with concentrated HCl and extracted by shaking twice with ethyl acetate and the extract is dried over Na2SO4 and evaporated. The residue is boiled up in ethyl acetate and the mixture is filtered. The product crystallizes out after 2-3 hours in a refrigerator.
Reaction SMILES: [CH2:1]1[N:12]2[C:13]3[C:9]([C@@H:10]4[CH2:17][NH:16][CH2:15][CH2:14][C@@H:11]42)=[CH:8][C:7]([C:18]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:19]=2[CH:20]=[O:21])=[CH:6][C:5]=3[CH2:4][S:3][CH2:2]1.[CH3:28][Mg]Br>O1CCCC1>[CH2:1]1[N:12]2[C:13]3[C:9]([C@@H:10]4[CH2:17][NH:16][CH2:15][CH2:14][C@@H:11]42)=[CH:8][C:7]([C:18]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:19]=2[CH:20]([OH:21])[CH3:28])=[CH:6][C:5]=3[CH2:4][S:3][CH2:2]1
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c(C=O)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c(C(C)O)c1

Procedure:
To a solution of 2-[(7bR,11aS)-1,2,7b,8,9,10,11,11a-octahydro-4H-pyrido[4,3-b)[1,4]thiazepino[6,5,4-hi]indol-6-yl]-5-methoxybenzaldehyde, the free base of EXAMPLE 16 (0.03 g, 0.08 mmol), in 5 mL of tetrahydrofuran at 0° C. was added methyl magnesium bromide (0.52 mL of a 3M solution in THF, 1.58 mmol). Stirred with warning to ambient temperature for several hours and then quenched with sat'd ammonium chloride. Extracted with ethyl acetate, washed organics with brine, dried (MgSO4) and concentrated. The residue was purified by prep HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA). Fractions containing desired compound were then immediately free based with 1 N sodium hydroxide, extracted with ethyl acetate, dried (MgSO4) and concentrated to afford the title compound of EXAMPLE 21. LRMS (ES+): 397.1 (M+H)+.
Reaction SMILES: O=C1CCC(=O)N1[CH2:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH:17]([C:22]1[S:23][CH:24]=[CH:25][C:26]=1[CH3:27])[N:18]([CH:20]=[O:21])[CH3:19].[BH4-].[Na+]>CS(C)=O>[CH:20]([N:18]([CH3:19])[CH:17]([C:22]1[S:23][CH:24]=[CH:25][C:26]=1[CH3:27])[CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][CH3:8])=[O:21]
Reactant: Cc1ccsc1C(Cc1ccccc1NCN1C(=O)CCC1=O)N(C)C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CNc1ccccc1CC(c1sccc1C)N(C)C=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 6.39 g of 2-[(2,5-dioxo-1-pyrrolidinyl)methyl]amino-N-formyl-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine, 20 ml of anhydrous dimethyl sulfoxide and 0.72 g of sodium borohydride was stirred at ambient temperature for 15 minutes and then heated on a steam bath for 15 minutes with occasional agitation. After standing for 2 hours at ambient temperature, the reaction mixture was decanted into 150 ml of water and extracted with diethyl ether (2×100 ml). The organic phase was washed with water (2×100 ml), dried over anhydrous sodium sulfate, and concentrated to an oil. Thin layer chromatography of the resultant oil indicated a multi-component mixture. Purification of the mixture was accomplished by HPLC (Waters Associates Prep LC/System 500, silica gel, elution with methanol]. Concentration of the appropriate fractions afforded N-formyl-N-methyl-2-methylamino-α-(3-methyl-2-thienyl)benzeneethanamine) as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2].[C:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)([CH3:24])=[CH2:23]>>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[C:22]([CH3:24])=[CH2:23])[CH2:32][CH2:33]2)=[O:21])[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: C=C(C)c1ccccc1N1CCNCC1
Product: C=C(C)c1ccccc1N1CCN(C(=O)Nc2cc(CC)c(C)nc2OC)CC1
Yield: 51 %

Procedure:
Phenyl N-(5-ethyl-6-methyl-2-methoxypyridin-3-yl)carbamate and 1-(2-isopropenylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.