Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[CH3:60][C:61]1[O:62][C:63]2[CH:69]=[CH:68][C:67]([NH2:70])=[CH:66][C:64]=2[N:65]=1.Cl>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:70][C:67]4[CH:68]=[CH:69][C:63]5[O:62][C:61]([CH3:60])=[N:65][C:64]=5[CH:66]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:7])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1nc2cc(N)ccc2o1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Agent: Cl
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(Nc3ncc4ccc(-c5cccc(S(=O)(=O)NC(C)(C)C)c5)n4n3)ccc2o1
Temperature: 25 °C
Yield: 40 %

Procedure:
Prepare mixture of N-tert-Butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (75 mg, 0.22 mmol), N-Phenylbis(trifluoromethanesulphonimide) (77 mg, 0.22 mmol), N,N-Diisopropylethylamine (0.113 mL, 0.650 mmol), and N,N-Dimethylformamide (2.0 mL, 26 mmol) and stir at room temperature for half an hour. Add 2-Methyl-benzoxazol-5-ylamine; hydrochloride (52 mg, 0.28 mmol) and stir at 80° C. overnight. The reaction was concentrated, dissolved in 2 mL DMSO, filtered and placed onto the Gilson. The most pure fractions were combined basified with sat. sodium bicarbonate, extracted with DCM, dried filtered, and concentrated to give N-tert-Butyl-3-[2-(2-methyl-benzoxazol-5-ylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-benzenesulfonamide as a yellow solid (40 mg, 40%). MP=212-214° C. LCMS (E/I+) 477 (M+H). NMR 1H (DMSO-d6)-9.64 (s, 1H), 9.06 (s, 1H), 8.55 (d, 1H, J=8.20 Hz), 8.47 (s, 1H), 8.00 (s, 1H), 7.86 (d, 1H, J=8.06 Hz), 7.68-7.85 (m, 3H), 7.60 (d, 1H, J=8.86 Hz), 7.23 (d, 1H, J=4.86 Hz), 7.01 (d, 1H, J=4.86 Hz), 2.60 (s, 3H), 1.12 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]([O:15]CC)=[O:14])[C:10]2([C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CO.O>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[C:10]2([C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC12CCCc1ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CN(Cc2ccccc2)CC12CCCc1ccccc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Ethyl 1′-benzyl-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidine]-4′-carboxylate (1.1 g, 3.15 mmol) in THF/MeOH/H2O (41 ml) was added 2N sodium hydroxide (4.72 ml, 9.44 mmol). Stir overnight at 50° C. Cooled to room temperature and acidified to pH1-2 with 0.5N HCl and extracted with EtOAc. The organic layer was dried and concentrated. The crude acid was not purified.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH3:7])[CH2:3][OH:4].[CH3:8][S:9](Cl)(=[O:11])=[O:10]>>[CH3:8][S:9]([O:4][CH2:3][CH:2]([CH3:1])[CH2:5][CH2:6][CH3:7])(=[O:11])=[O:10]
Reactant: CCCC(C)CO
Reactant: CS(=O)(=O)Cl
Product: CCCC(C)COS(C)(=O)=O

Procedure:
The title compound was prepared by following the general procedure of Example 43 for mesylation as a colorless oil (856 mg, 89%) from 2-methyl-1-pentanol (497 mg, 4.90 mmol) and methanesulfonyl chloride (821 mg, 7.30 mmol). 1H NMR (CDCl3, 300 MHz) δ0.89-0.93 (m, 3H), 0.98 (d, 3H, J=6.6 Hz), 1.15-1.43 (m, 4H), 1.88-1.90 (m, 1H), 3.00 (s, 3H), 3.98-4.11 (m, 2H) ppm.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[CH3:21][O:22][C:23]1[N:28]=[C:27]([CH2:29]O)[CH:26]=[CH:25][CH:24]=1.C(P(CCCC)CCCC)CCC>C1COCC1.[Cl-].[Na+].O>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:29][C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH3:21])[N:28]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: COc1cccc(CO)n1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Agent: CCCCP(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(CN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 3.2 %

Procedure:
3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (100 mg, 0.4 mmol), (6-methoxy-pyridin-2-yl)-methanol (example 10-75a) (101 mg, 0.7 mmol), tributylphosphine (147 mg, 0.7 mmol), and 1,1″″-azobis(N,N-dimethylformamide) (125 mg, 0.7 mmol) were dissolved in THF (5 mL) and stirred at room temperature for 15 hours. The reaction was diluted with brine (100 mL) and extracted with ethyl acetate (2×, 100 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated on the rotovap. The residue was taken up in methanol (5 mL) and purified by reversed phase HPLC (5 to 95% acetonitrile in H2O:25 minute gradient). The pure fractions were combined, concentrated then re-dissolved in ethyl acetate/hexane (1:9). The solution was cooled at 5° C. for 15 hrs, where a white solid formed. The precipitate was collected to afford 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-((6-methoxypyridin-2-yl)methyl)imidazolidine-2,4-dione (5 mg, 4%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ2.11 (s, 3H), 2.37 (s, 3H), 3.74 (s, 3H), 4.17 (s, 2H), 4.54 (s, 2H), 5.17 (s, 2H), 6.69 (d, J=7.6 Hz, 1H), 6.96 (d, J=6.8 Hz, 1H), 7.67 (d, J=6.8 Hz, 1H), 7.76 (s, 1H), 8.17 (s, 1H). MS M+H calculated 397.2. found 397.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.23 μM.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20]3[C:21]4[CH:28]=[CH:27][N:26](S(C5C=CC(C)=CC=5)(=O)=O)[C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:14]2)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1.O.C([O-])([O-])=O.[K+].[K+]>CO.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20]3[C:21]4[CH:28]=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:14]2)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N[C@H]4CCCN(C(=O)CNc5cc(F)cc(Cl)c5)C4)ncnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: O=C(CNc1cc(F)cc(Cl)c1)N1CCC[C@H](Nc2ncnc3[nH]ccc23)C1
Temperature: 60 °C
Yield: 114.6 %

Procedure:
To a solution of 2-(3-chloro-5-fluorophenylamino)-1-((S)-3-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)ethanone (220 mg, 0.39 mmol) in MeOH:H2O (8:2 mL) was added K2CO3 (164 mg, 1.18 mmol) and the reaction mixture was heated to 60° C. for 1 h. The reaction mixture was concentrated in vacuo and the residue obtained was diluted with EtOAc. The EtOAc suspension was filtered through celite, the filtrate was then dried over Na2SO4, and concentrated in vacuo to give a residue that was subjected to purification by column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford the titled compound (180 mg, 83%). 1H NMR (400 MHz, CD3OD): δ 8.20 and 8.09 (2s, 1H), 7.06 (d, J=3.6 Hz, 1H), 6.61 and 6.58 (2d, J=3.6 Hz, 1H), 6.47 and 6.45 (2s, 1H), 6.35-6.27 (m, 2H), 4.97-4.79 (m, 2H), 4.25-3.95 (m, 3H), 3.11-3.05 (m, 1H), 2.95-2.86 (m, 1H), 2.14-1.85 (m, 2H), 1.80-1.55 (m, 2H). LC-MS: m/z [M+1]=403.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH2:7])=[N:4][N:3]=1.[C:8]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].OP([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:7][C:5]1[S:6][C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:20][CH2:19]2)=[N:3][N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1nnc(Br)s1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nnc(N)s2)CC1
Temperature: 100 °C
Yield: 56.6 %

Procedure:
A mixture of 5-bromo-1,3,4-thiadiazol-2-ylamine (9.27 g), Boc-piperazine (11.51 g), and K2HPO4 (13.4 g) in 30 ml of DMF is heated at 100° C. under argon for four hours, then cooled and added to 100 g of ice. The mixture is extracted with ethyl acetate, and the organic phase washed twice with water and dried (MgSO4). Following removal of the solvent under reduced pressure, the residue is flash chromatographed on silica using 4% methanol in dichloromethane to afford 8.32 g of the title compound as a solid. Recrystallization from 240 ml of 1:1 acetonitrile-toluene provides 6.65 g of solid.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].CN([CH:23]=[O:24])C>>[NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([NH:1][CH2:2][C:7]([O:24][CH3:23])=[O:9])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CN(C)C=O
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: COC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1

Procedure:
0.22 mole of Z-Leu-OH are dissolved in 500 ml of DMF. To this solution are successively added:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1[CH:12]=[C:11]2[NH:13][S:14]([C:17]3=[CH:18][CH:19]=[CH:20][C:9](=[C:10]23)[CH:8]=1)(=O)=O>CCOCC.O1CCCC1>[NH2:13][C:11]1[CH:12]=[CH:7][CH:8]=[C:9]2[C:10]=1[C:17]([SH:14])=[CH:18][CH:19]=[CH:20]2
Reactant: O=S1(=O)Nc2cccc3cccc1c23
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Nc1cccc2cccc(S)c12
Yield: 79 %

Procedure:
To a mixture of 3.0 g of lithium aluminum hydride in 150 mL of anhydrous ether was added dropwise a solution of 4.0 g of 1,8-naphthosultam in 15 mL of anhydrous tetrahydrofuran over a period of 45 minutes while maintaining a gentle reflux. After completion of the addition, the yellow mixture was refluxed for another hour. The mixture was cooled in an ice-bath and the excess of lithium aluminum hydride was destroyed by dropwise addition of 10 mL of water. The resulting mixture was acidified with 200 mL of 4N sulfuric acid and extracted with ether (3×100 mL). The ether extracts were washed with water (75 mL) and dried (magnesium sulfate). Removal of the solvent gave 2.7 g (79%) of 8-amino-1-naphthalenethiol, mp. 68°-70°. This compound is sensitive to air, and therefore was used immediately.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=1.[F:15][C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:18][CH:17]=1>>[F:15][C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C@H:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=3)[CH2:24][CH2:23]2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)N[C@H](C)c1ccc(CCl)cc1
Reactant: Fc1cccc(N2CCNCC2)n1
Product: CC(=O)N[C@H](C)c1ccc(CN2CCN(c3cccc(F)n3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using (R)-N-(1-(4-chloromethylphenyl)ethyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(6-fluoropyridin-2-yl)piperazine obtained in Example 85(2) instead of phenylpiperazine, the title compound was obtained as a pale-yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1.[C:23]1([CH2:29][CH2:30][CH2:31][CH:32]=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:55].CCOCC>ClCCCl.CO>[ClH:55].[C:23]1([CH2:29][CH2:30][CH2:31][CH2:32][N:8]2[CH2:12][CH2:11][CH:10]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:9]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=CCCCc1ccccc1
Reactant: O=S(=O)(c1ccc(O)cc1)C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=S(=O)(c1ccc(O)cc1)C1CCN(CCCCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
(RS)-4-(Pyrrolidine-3-sulfonyl)-phenol trifluoroacetic acid salt (0.22 g, 0.65 mmol), 4-phenyl-butyraldehyde (0.096 g, 0.65 mmol), triethylamine (0.090 ml., 0.65 mmol), and sodium triacetoxyborohydride (0.2 g, 0.97 mmol) were suspended in 1,2-dichloroethane (4 ml). After 3 hours stirring at room temperature, the reaction mixture was quenched with saturated NaHCO3 (10 ml). The aqueous phase was extracted with CH2Cl2 (3 times). The combined organic phases were dried over Na2SO4, filtered and the solvent was evaporated. The residue was chromatographed over silica gel (CH2Cl2—MeOH, 19:1) to provide a white solid which was suspensed in MeOH. HCl-Et2O was added to provide (RS)-4-[1-(4-phenyl-butyl)-pyrrolidine-3-sulfonyl]-phenol hydrochloride (0.180 g, 70%) as a white solid, m.p. 121-124° C. and MS: m/e=360.3 (M+H+).
Reaction SMILES: Cl.C1C2C(=CC=CC=2)C=C(C2C=CC(O)=CC=2)N=1.C1C=CC2N(O)N=NC=2C=1.[CH3:29][C:30]([O:33][C:34]([NH:36][C@H:37]([C:59]([OH:61])=[O:60])[CH2:38][CH2:39][CH2:40][N:41]=[C:42]([NH:51]C(OC(C)(C)C)=O)[NH:43]C(OC(C)(C)C)=O)=[O:35])([CH3:32])[CH3:31].CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[C:34]([NH:36][C@H:37]([C:59]([OH:61])=[O:60])[CH2:38][CH2:39][CH2:40][NH:41][C:42](=[NH:43])[NH2:51])([O:33][C:30]([CH3:31])([CH3:29])[CH3:32])=[O:35]
Reactant: CC(C)(C)OC(=O)NC(=NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1ccc(-c2cc3ccccc3cn2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 182.3 %

Procedure:
HCl (0.4 mL, 2 N) was added to 4-isoquinolin-3-yl-phenol (0.133 g, 0.6 mmol) in anhydrous DMF (5 mL). To this mixture were added HOBt (0.081 g, 0.6 mmol), Boc-Arg-(Boc)2-OH (0.285 g, 0.6 mmol), and EDCl (0.115 g, 0.6 mmol). N,N-Diisopropylethylamine (0.233 g, 1.8 mmol) was added and the mixture was stirred at rt for 24 h. Water (15 mL) was added and the white precipitate was filtered off, washed with water and dried under vacuum to give 0.3 g (74%) of the Boc-arginine derivative. The Boc derivative compound (0.3 g,) was dissolved in anhydrous dichloromethane (10 mL). HCl gas was bubbled into the solution at 0° C. for 4 h. A yellow precipitate was formed. The solvent was removed and the resulting sold was dried under vacuum. Triturating with ether gave 200 mg of 4-(isoquinolin-3-yl)phenyl 2-amino-5-guanidinopentanoate tetrahydrochloride (86%). MS (ES) m/z: 222.96 (M+1−Arg), 221.99 (M−Arg); Mp. 198-201° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]([CH:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][C:3]=1Br.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.[F-].[Cs+].CCOC(C)=O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:1][C:2]1[C:3]([C:30]2[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=2)=[CH:4][C:5]([CH:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CCOC(=O)C(CC(C)C)c1cc(Br)c(N)c(OCC(F)(F)F)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(CC(C)C)c1cc(OCC(F)(F)F)c(N)c(-c2ccc(C(F)(F)F)cc2)c1
Yield: 85.1 %

Procedure:
A mixture of ethyl 2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.70 g, 1.6 mmol), 4-trifluoromethylphenylboronic acid (0.642 g, 3.39 mmol), CsF (0.641 g, 4.2 mmol) and Pd (PPh3)4 (0.196 g, 0.16 mmol) in 40 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 35 mL of EtOAc and 35 mL of water were added. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to yellow oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (650 mg) as a colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([CH3:15])([CH3:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:6]=1.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[S:25](Cl)(=[O:27])=[O:26]>>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[S:25]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([CH3:14])([CH3:15])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:6]=1)(=[O:27])=[O:26]
Reactant: CCOC(=O)CC(C)(C)c1csc(N)n1
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: CCOC(=O)CC(C)(C)c1csc(NS(=O)(=O)c2c(C)cc(Cl)cc2Cl)n1

Procedure:
The title compound was prepared from ethyl 3-(2-amino-1,3-thiazol-4-yl)-3-methylbutanoate (METHOD I) and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic method to give a white solid (55.0 mg) with purity >90%. MS (pos) m/z 451.2, 453.2.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[S:3]([C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11](=O)[NH:12][C:8]=2[CH:7]=1)(=[O:5])=[O:4].O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:11]1[NH:10][C:9]2[CH:14]=[CH:15][C:6]([S:3]([C:2]([F:17])([F:16])[F:1])(=[O:5])=[O:4])=[CH:7][C:8]=2[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccc(S(=O)(=O)C(F)(F)F)cc2[nH]1
Product: O=S(=O)(c1ccc2[nH]c(Cl)nc2c1)C(F)(F)F

Procedure:
Reflux 5-trifluoromethylsulfonyl-1,3-dihydro-benzimidazol-2-one (380 mg) for 8 hours in POCl3 (10 mL). Evaporate the solvent in vacuo, then carefully neutralize with saturated NaHCO3, and extract with EtOAc. Dry over Na2SO4, concentrate under vacuum, and purify by flash chromatography (1:1 hexanes/EtOAc) to obtain 2-chloro-5-trifluoromethylsulfonyl-1H-benzimidazole.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:17])[CH2:13][N:14]([CH3:16])[CH3:15])[N:10]=2)[N:7]=1.[NH2:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[NH2:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[O:25][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:17])[CH2:13][N:14]([CH3:16])[CH3:15])[N:10]=2)[N:7]=1
Reactant: Nc1cccc(O)c1
Reactant: CN(C)CC(=O)Nc1cn2nc(I)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CC(=O)Nc1cn2nc(Oc3cccc(N)c3)ccc2n1
Yield: 83.8 %

Procedure:
A mixture of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)-N2,N2-dimethylglycinamide (517 mg, 1.5 mmol), 3-aminophenol (491 mg, 4.5 mmol), potassium carbonate (415 mg, 3.0 mmol) and N,N-dimethylformamide (3.0 mL) was stirred using a microwave synthesizer at 180° C. for 40 min. The reaction mixture was diluted with water, and the precipitate was collected by filtration, washed with water, and dried under reduced pressure. The obtained solid was washed with ethyl acetate to give the title compound (410 mg, 84%) as a brown powder.
Reaction SMILES: [CH3:1][C@H:2]([NH2:12])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[C:13](O)(=[O:22])[C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:15].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>CN(C)C=O.CO>[OH:15][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([NH:12][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:22]
Reactant: O=C(O)[C@@H](O)c1ccccc1
Reactant: C[C@H](N)CCCc1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Product: CC(CCCc1cccnc1)NC(=O)C(O)c1ccccc1

Procedure:
Under the conditions outlined in Example 14a, 76.2 g of the amine was reacted with 74.2 g of (S)-mandelic acid in the presence of 105.2 g of 1,3-dicyclohexylcarbodiimide and 78.4 g of 1-hydroxybenzotriazole in 1 L of dimethylformamide. A similar workup furnished 109 g of [S-(S*,S*)]-alpha-hydroxy-N-[1-methyl-4-(3-pyridinyl)butyl]benzeneacetamide, mp 143°-145° C, [α]D25 +27.8° (c, 1.0, MeOH).
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22][C:23](=O)N(C)C)=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[H-].[Na+].BrC[C:32]#[N:33]>CO.CCOC(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22][CH2:23][C:32]#[N:33])=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:4])([CH3:6])[CH3:5]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: N#CCBr
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCC#N)c2CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
Add potassium hydroxide (5.4 g, 96.2 mmol) to a solution of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.5 g, 4.7 mmol) in degassed methanol (75 mL) under a nitrogen atmosphere. Heat the mixture at 80° C. for 6 h. Cool the mixture to ambient temperature, then concentrate in vacuo to an oil. Dissolve the oil in EtOAc (50 mL) and wash with saturated aqueous ammonium chloride (30 mL). Separate the organic layer and extract the aqueous layer with EtOAc (3×50 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to an oil (1.4 g). Dissolve the oil in anhydrous DMF (25 mL), then slowly add sodium hydride (282 mg, 7.1 mmol) and bromoacetonitrile (470 7.1 mmol). Stir the mixture under nitrogen at ambient temperature for 16 h. Dilute the mixture slowly with EtOAc (100 mL) and wash with cold aqueous saturated ammonium chloride (40 mL). Separate the organic layer and extract the aqueous layer with EtOAc (3×50 mL). Combine the organic extracts and concentrate in vacuo. Purify the residue by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 7:3 gradient) to obtain 3-tert-butoxycarbonyl-7-chloro-6-(1-cyano-methylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.34 g, 81%). MS (ES+) m/z: 253.2 (M-Boc)+.
Reaction SMILES: CCOCC.[CH2:6]([Li:10])[CH2:7][CH2:8][CH3:9].BrC1C2[C:16](=[CH:17][C:18]3[O:24][CH2:23][O:22]C=3C=2)[N:15]=[CH:14][CH:13]=1.O1CCCC1>CCCCCC>[CH2:23]1[O:24][C:18]2[CH:17]=[C:16]3[C:7]([C:6]([Li:10])=[CH:13][CH:14]=[N:15]3)=[CH:8][C:9]=2[O:22]1
Reactant: [Li]CCCC
Reactant: Brc1ccnc2cc3c(cc12)OCO3
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: [Li]c1ccnc2cc3c(cc12)OCO3

Procedure:
To 250 ml. of anhydrous ether was added 19.3 ml. of a 1.45M solution of n-butyllithium in hexane. The resulting solution was cooled to -68°. Thereafter, there was added 6.55 g. of 4-bromo-6,7-methylenedioxyquinoline dissolved in 200 ml. of anhydrous tetrahydrofuran over a period of 30 minutes with stirring and under a nitrogen atmosphere to afford 6,7-methylenedioxy-4-quinolyllithium. Stirring of the mixture was continued at the same temperature for 30 minutes followed by the addition of a solution of 2.15 g. of a mixture of epimeric, racemic 4,5-erythro-5-ethylquinuclidine-2ξ-carboxaldehydes in 250 ml. of ether over a period of one hour. The reaction mixture was stirred at -70° under a nitrogen atmosphere overnight. After quenching with water, the mixture was allowed to warm to room temperature and subsequently was concentrated under reduced pressure. The residue was dissolved in ether. The ethereal solution was washed with water, dried over sodium sulfate and evaporated to dryness to give 6.54 g. of an oil. Chromatography on neutral alumina (Woelm, activity I) with ethyl acetate yielded 2.97 g. of a yellow solid. Subsequent elution with methanol yielded 3.37 g. of a brown oil. This was chromatographed on silica gel preparative plates (20 × 20 × 0.2 cm) with ethyl acetate-triethylamine (97:3) as the solvent mixture. The plates were developed three times. Elution of the lowest major band with methanolchloroform and crystallization of the eluate (510 mg.) from acetone gave racemic 6',7'-methylenedioxy-dihydrocinchonidine, m.p. 232°-233°. Elution of the next higher band with methanolchloroform and crystallization of the eluate (597 mg.) from acetone gave racemic 6',7'-methylenedioxydihydrocinchonine, m.p. 234°-235°.