Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([C@H:4]([NH:8][C:9]([C@H]1N(C([C@@H](NC(CNC([C@@H](NC([C@@H](NC([C@@H](NC(C(NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC(C)=O)CO)=O)CC2C=CC(O)=CC=2)=O)CO)=O)CCSC)=O)CCC(O)=O)=O)CC2NC=NC=2)=O)CC2C=CC=CC=2)=O)CCCNC(N)=N)=O)CC2C3C(=CC=CC=3)NC=2)=O)=O)CCCCN)=O)CCC1)=O)C(N)=O)C.O=[C:120]1[O:126][C@H:125]([C@H:127]([CH2:129][OH:130])O)[C:123](O)=[C:121]1[OH:122].[O:131]=[C:132]1[O:138][C@H:137]([C@H:139]([CH2:141][OH:142])[OH:140])[C:135]([O-:136])=[C:133]1[OH:134].[Na+:143]>>[CH3:4][NH:8][CH2:9][C@H:129]([OH:130])[C:127]1[CH:125]=[CH:123][C:121]([OH:122])=[C:120]([OH:126])[CH:132]=1.[O:131]=[C:132]1[O:138][C@H:137]([C@H:139]([CH2:141][OH:142])[OH:140])[C:135]([O-:136])=[C:133]1[OH:134].[Na+:143]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: CSCC[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(C)=O)C(=O)N[C@@H](CCC(=O)O)C(=O)NC(Cc1cnc[nH]1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(N)=O)C(C)C
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Product: CNC[C@H](O)c1ccc(O)c(O)c1

Procedure:
In a specific non-limiting embodiment of the invention Hu74 Medium is prepared as follows. Glutamine is added to Ham's F12 (GIBCO, Carlsbad, Calif.) at a concentration of 2 mM. Gentamicin is added to the culture medium to obtain a final concentration of 50 μg/ml. Fetal bovine serum (FBS, GIBCO, Carlsbad, Calif.) is added to the medium to obtain a 10% concentration (volume/volume). The medium containing FBS and gentamicin is stored at 4° C. and prepared fresh every two weeks. bFGF (PeproTech, Rocky Hill, N.J.) is dissolved in F12 medium to 2,500 ng/ml and stored in small vials at −70° C. The stored solution is added to the culture medium to obtain a final concentration of 25 ng/ml once a week. HGF (PeproTech, Rocky Hill, N.J.) is dissolved in F12 medium to 10,000 ng/ml and stored in small vials at −70° C. The stored solution is added to the culture medium to obtain a final concentration of 100 ng/ml once a week. An α-MSH solution is obtained by dissolving the α-MSH powder (Sigma, St. Louis, Mo.) to 100 μg/ml and is stored at −70° C. The stored solution of α-MSH is added to the culture medium to obtain a final concentration of 100 ng/ml once a week. (L)-Epinephrine bitartrate (Sigma, St. Louis, Mo.) is dissolved in PBS at 0.15 mg/ml with sodium ascorbate (Sigma, St. Louis, Mo.) (0.5 mg/ml) and stored at −70° C. Ephinedrine and ascorbic acid are added to the culture medium to obtain a final concentration of 1.5 μg/ml of epinephrine and 5 μg/ml sodium ascorbate once a week.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH3:20])=[C:10]([C:21]([OH:23])=O)[CH:9]=2)[CH:5]=[CH:4][N:3]=1.CC[N:26](C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.N>CN(C=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH3:20])=[C:10]([C:21]([NH2:26])=[O:23])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(Cl)cc1-c1[nH]c(-c2ccnc(N)n2)cc1C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Cl)cc1-c1[nH]c(-c2ccnc(N)n2)cc1C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A solution of 5-(2-amino-pyrimidin-4-yl)-2-(5-chloro-2-methyl-phenyl)-1H-pyrrole-3-carboxylic acid (11.62 g, 30.4 mmol) in DMF (100 mL) and DIPEA (21.2 mL, 121.6 mmol) was stirred at 0° C. EDCl (11.64 g, 60.8 mmol) and HOBT.NH3 (9.38 g, 60.8 mmol) were added and the reaction mixture was stirred for 3 h at room temperature. The mixture was diluted with water and the resultant precipitate was collected by filtration to afford the title compound (8.17 g, 82%).
Reaction SMILES: [NH2:1][CH:2]1[CH:6]([CH3:7])[CH2:5][N:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.[C:15]([O:19][C:20](O)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CO>[C:15]([O:19][C:20]([NH:1][CH:2]1[CH:6]([CH3:7])[CH2:5][N:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)O
Reactant: CC1CN(Cc2ccccc2)CC1N
Solvent: CO
Product: CC1CN(Cc2ccccc2)CC1NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of 3-amino-1-benzyl-4-methylpyrrolidine (9.5 g) in methanol (190 ml) is added anhydrous t-butoxycarboxylic acid (13.0 g) at room temperature, and the mixture is stirred for one hour. Methanol is distilled off under reduced pressure, and to the resulting residue is added water. The mixture is extracted with dichloromethane, and the extract is dried over magnesium sulfate and then dichloromethane is distilled off. The residue is purified by silica gel column chromatography (solvent, dichloromethane:methanol=19:1) to give 3-(t-butoxycarbonylamino)-1-benzyl-4-methylpyrrolidine (isomer A) (4.4 g), as colorless prisms, m.p. 131.5°-132.7° C.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11](O)=[O:12])=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([NH:35][CH2:36][CH:37]1[CH2:39][CH2:38]1)[CH2:33][CH3:34].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH:37]1([CH2:36][N:35]([CH2:32][CH2:33][CH3:34])[C:11](=[O:12])[CH2:10][C:9]2[C:8]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:7]=3[O:6][C:5]=2[C:3](=[O:4])[C:2]([CH3:1])([CH3:20])[CH3:21])[CH2:39][CH2:38]1
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Reactant: CCCNCC1CC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCN(CC1CC1)C(=O)Cc1c(C(=O)C(C)(C)C)oc2ccc(OC)cc12
Temperature: 40 °C

Procedure:
Dissolve a mixture of 17 mg [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid from the Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 12.6 μL N-propylcyclopropanemethylamine followed by 23.0 mg EDC and 35 μL DIEA. This solution was heated at 40° C. for 2 hours. It was purified directly on RP-HPLC using 60-100% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. LC-MS: 4.17 min. (m/Z=386.2, 302.1, 408.1).
Reaction SMILES: Cl.C(OC(=O)[N:8]([CH2:12][C:13]1[CH:18]=[C:17]([CH2:19][C:20](=[O:23])[NH:21][CH3:22])[CH:16]=[CH:15][C:14]=1[Cl:24])[CH:9]1[CH2:11][CH2:10]1)(C)(C)C.[OH-].[Na+]>C(Cl)Cl>[Cl:24][C:14]1[CH:15]=[CH:16][C:17]([CH2:19][C:20]([NH:21][CH3:22])=[O:23])=[CH:18][C:13]=1[CH2:12][NH:8][CH:9]1[CH2:11][CH2:10]1
Reactant: CNC(=O)Cc1ccc(Cl)c(CN(C(=O)OC(C)(C)C)C2CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CNC(=O)Cc1ccc(Cl)c(CNC2CC2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
HCl (4M in dioxane, 20 mL) was added to a sol. of (2-chloro-5-methylcarbamoylmethyl-benzyl)-cyclopropyl-carbamic acid tert-butyl ester (2.01 g, 5.97 mmol) in CH2Cl2 (20 mL) at 0° C. The mixture was stirred for 2 h at 0° C., and was carefully neutralized with aq. 1M NaOH. The layers were separated, and the aq. layer was extracted with CH2Cl2. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to yield the crude title compound (1.42 g, 99%) that was used further without purification. LC-MS: tR=0.54 min; ES+: 294.33.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[Cl:18][C:19]1[C:20]([C:27](O)=[O:28])=[N:21][CH:22]=[C:23]([C:25]#[N:26])[CH:24]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:20]3[C:19]([Cl:18])=[CH:24][C:23]([C:25]#[N:26])=[CH:22][N:21]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: N#Cc1cnc(C(=O)O)c(Cl)c1
Product: C[C@]1(c2cc(NC(=O)c3ncc(C#N)cc3Cl)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 3-chloro-5-cyano-pyridine-2-carboxylic acid (CAS 1200497-81-9) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=406.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1)=[O:10].[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:28]([C:25]2[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])=[C:3]([C:9]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[O:10])[CH:4]=1
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(C(=O)c2cc(Cl)ccc2N)cn1
Product: Cc1ccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(S(C)(=O)=O)cc2)cn1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl )-(6-methyl-pyridin-3-yl )-methanone and 4-Methanesulfonyl-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3) δ 9.77 (br s, 1H, NH), 8.44 (dm, 1H, J=2.2 Hz), 7.87 (d, 2H, J=8.8 Hz), 7.83 (d, 2H, J=8.8 Hz), 7.76 (d, 1H, J=8.8 Hz), 7.60 (dd, 1H, J=8.0 Hz, J=2.2 Hz), 7.55 (dd, 1H, J=8.8 Hz, J=2.2 Hz), 7.36 (d, 1H, J=2.2), 7.26 (d, 1H, J =8.0 Hz), 3.00 (s, 3H), 2.66 (s, 3H). MS: m/z 465 (M+1).
Reaction SMILES: CS[CH:3]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C@@H:14]([CH2:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:13][CH2:12]2)[C:4]([O:6][CH2:7][CH3:8])=[O:5]>C(O)C.[Ni]>[F:24][C:21]([F:22])([F:23])[C:20](=[O:25])[CH2:19][C@H:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:10]=2)[O:15]1
Reactant: CCOC(=O)C(SC)c1ccc2c(c1)CC[C@H](CC(=O)C(F)(F)F)O2
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)Cc1ccc2c(c1)CC[C@H](CC(=O)C(F)(F)F)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
The above crude thiomethyl compound of Example 4 was dissolved in absolute ethanol (340 mL) under argon and mixed with Raney nickel (17 teaspoons) freshly washed with water and ethanol (3 times). The resulting mixture was stirred vigorously at room temperature for 1 hours. Stirring was stopped, and the liquid layer was removed by decanting. The catalyst was then washed with ethanol (250 mL) and dichloromethane (250 mL). The liquid was removed by decanting in each case. The combined liquid layer was concentrated in vacuo. The residue was dissolved in methyl t-butyl ether (300 mL), washed with water (200 mL), and brine (200 mL) and dried over anhydrous sodium sulfate. Removal of solvent in vacuo afforded the crude product as a colorless oil (14.3 g, 83%): 1H NMR (CDCl3) δ1.26 (t, J=7.2 Hz, 3H), 1.80 (m, 1H), 2.00 (m, 1H), 2.70-2.95 (m, 2H), 3.50 (m, 3H), 3.80-3.85 (m, 1H), 4.15 (m, 4H), 6.76 (d, J=8.4 Hz, 1H), 6.98 (s,1H), 7.02 (d, J=8.7 Hz, 1H); CI-MS m/z 346 (M+H+). The crude was used for next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[N+:13]([O-])=[CH:12][CH:11]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:12]1[CH:11]=[C:10]([C:3]2[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=2[F:9])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2c(c1)c(-c1c(F)cc(F)cc1F)cc[n+]2[O-]
Product: COC(=O)c1ccc2nc(Cl)cc(-c3c(F)cc(F)cc3F)c2c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 4-(2,4,6-trifluorophenyl)quinoline-6-carboxylate 1-oxide (1.3 g) and phosphoryl chloride (10 mL) was heated under stirring in an oil bath at 100° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with water, and then extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified under silica gel column chromatography (hexane/ethyl acetate) to obtain methyl 2-chloro-4-(2,4,6-trifluorophenyl)quinoline-6-carboxylate (370 mg).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[NH:10][C:9](=O)[C@@H:8]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@H:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1>C1COCC1>[CH3:1][C:2]1[C:11]2[NH:10][CH2:9][C@@H:8]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@H:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1NC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]21
Solvent: C1CCOC1
Product: Cc1cccc2c1NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]21
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of (±)-cis tert-butyl 6-methyl-4-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]quinoline-2(9bH)-carboxylate from Example 18, Part A (2.4 g, 8 mmol) in 60 mL of THF at 0° C. was added borane THF complex (40 mL of a 1 M solution in THF, 40 mmol) dropwise. The reaction was allowed to warm to ambient temperature and was stirred for 2 h. The reaction was quenched carefully with water and extracted with ethyl acetate. The organics were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography to afford 1.55 g (67%) of the title compound. 1H NMR (CDCl3) (some signals doubled due to rotamers): δ 6.95-6.90 (m, 1H), 6.65-6.57 (m, 1H), 4.00-2.93 and 3.87-3.80 (m, 1H), 3.66-3.58 (m, 1H), 3.42-2.98 (m, 5H), 2.58-2.44 (m, 1H), 2.11 (s, 3H), 1.44 and 1.43 (s, 9H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:27])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]3=[O:26])[CH:15]=2)=[CH:8][CH:7]=1.[CH:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])O.[Na+].[BH4-].[Na+]>CO.O>[CH2:28]([NH:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:27])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]3=[O:26])[CH:15]=2)=[CH:8][CH:7]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(N3CCCCC3=O)c2)cc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: O=C(Nc1ccc([C@@H]2C[C@H]2NCc2ccccc2)cc1)c1cccc(N2CCCCC2=O)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of N-{4-[trans-2-aminocyclopropyl]phenyl}-3-(2-oxopiperidin-1-yl)benzamide hydrochloride (27.1 mg) in methanol (1 mL) were added benzaldehyde (7.14 μL) and sodium hydrogen carbonate (8.9 mg). The mixture was stirred at 70° C. for 1 hr, and ice-cooled to 0° C. and sodium borohydride (4.0 mg) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (10.9 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](O)=[O:16])[CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:6][C:5]2=1.C(Cl)CCl.O.O[N:29]1C2C=CC=CC=2N=N1.[OH-].[NH4+]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](=[O:16])[NH2:29])[CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:6][C:5]2=1
Reactant: On1nnc2ccccc21
Reactant: CCOC(=O)C1CCc2[nH]c3c(C(=O)O)cc(Br)cc3c2C1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)C1CCc2[nH]c3c(C(N)=O)cc(Br)cc3c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a light suspension of 6-bromo-3-(ethoxycarbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid (2.12 g, 5.79 mmol), EDC (1.332 g, 6.95 mmol), and 1-hydroxybenzotriazole hydrate (1.064 g, 6.95 mmol) in THF/CH2Cl2 (5/1) (100 mL) was added ammonium hydroxide (1.353 mL, 34.7 mmol) and it turned into a thick light yellow suspension and it was stirred at rt overnight. The reaction was concentrated and the residue was dissolved in water/ethyl acetate. The organic phase was separated and washed with brine, dried over Na2SO4, filtered, concentrated to afford the crude product as a light yellow solid, which was washed with a small amount of ether and air-dried. The crude ethyl 6-bromo-8-carbamoyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylate was used as such in the next reaction.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][OH:13].I[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][O:13][CH2:12][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH3:20]
Reactant: CCOC(=O)CI
Reactant: OCCc1ccc2ccccc2c1
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CCOC(=O)COCCc1ccc2ccccc2c1

Procedure:
In analogy to the procedure described in example 2.1, 2-naphthalen-2-yl-ethanol was reacted with ethyl iodoacetate in the presence of silver trifluoromethanesulfonate and 2,6-di-tert-butylpyridin to give the title compound as colorless oil. MS: m/e=259.3 [M+H+].
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([NH:7][C@H:8]([C:16]([OH:18])=[O:17])[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:6])[CH3:3].[CH2:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C1C=CN=CC=1.CN(C)C=O.ClCCl>[C:21]1([CH2:20][O:17][C:16](=[O:18])[C@H:8]([CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[NH:7][C:5]([O:4][C:2]([CH3:19])([CH3:1])[CH3:3])=[O:6])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)OCc1ccccc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 103.3 %

Procedure:
A stirred, milky solution of 25.6 g (94.5 mmole) of N-[(1,1-dimethylethoxy)carbonyl]-3-cyclohexyl-(L)-alanine, 11.2 g (104 mmole) of benzyl alcohol, and 1.15 g (9.45 mmole) of 4-dimethylaminopyridine in a mixture of 210 mL of dimethyl formamide and 150 mL of dichloromethane is cooled to 5° C., and 19.2 g of 3-N,N-dimethylaminopropylethylcarbodiimide hydrochloride is added over 5 minutes. The mixture is then warmed to ambient temperature and is stirred overnight. The reaction mixture is filtered to remove a fine precipitate, and the filtrate is concentrated in vacuo. The residue is taken up in water and extracted with ethyl acetate (3×). The combined organic solutions are washed with 0.5N aqueous citric acid and twice with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil is subjected to high vacuum to minimize volatiles to give N-[(1,1-dimethylethoxy)carbonyl]-3-cyclohexyl-(L)-alanine phenylmethyl ester (35.3 g). MS (ion spray) m/z 362 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:13]2[CH2:18][CH2:17][CH:16]3[S:19][C:20](=[O:22])[CH:21]=[C:15]3[CH2:14]2)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].ClC1C=CC(CC([O-])=O)=CC=1>>[C:23]([O:22][C:20]1[S:19][C:16]2[CH2:17][CH2:18][N:13]([C@@H:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:9]([O:11][CH3:12])=[O:10])[CH2:14][C:15]=2[CH:21]=1)(=[O:25])[CH3:24]
Reactant: COC(=O)[C@H](c1ccc(Cl)cc1)N1CCC2SC(=O)C=C2C1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])Cc1ccc(Cl)cc1
Product: COC(=O)[C@H](c1ccc(Cl)cc1)N1CCc2sc(OC(C)=O)cc2C1
Yield: 97 %

Procedure:
Following the method described in Example 4, (2S)-methyl 2-(4-chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3.2-c]pyridin-5 (2H,4H,6H)-yl)-acetate (IV-3) (100 mg) was reacted with acetic anhydride (63 μl), to prepare (S)-methyl 2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(4-chlorophenyl-acetate (I-20) (110 mg). Yield 97%. 1H-NMR (300 MHz, CDCl3) δ 2.27 (s, 3H), 2.65-2.78 (m, 4H), 3.53 (s, 2H), 3.73 (s, 3H), 4.30 (s, 1H), 6.25 (s, 1H), 7.33-7.46 (m, 4H); 13C-NMR (75 MHz, CDCl3) δ 20.7, 24.7, 48.1, 50.4, 52.2, 71.9, 111.9, 125.7, 128.9, 130.1, 134.3, 134.4, 149.6, 167.7, 171.4; ESI-MS m/z 380.1 [M+H]+; HRMS Calcd for C18H19NO4SCl [M+H]+ m/z 380.0723. found 380.0735.
Reaction SMILES: [Cl:1][C:2]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:3]=1[CH2:4][N:5]1[CH2:9][C@H:8]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[C@@H:7]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][CH:23]([O:31]C(=O)[C@H](C3C=CC=CC=3)C)[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:18][CH2:17]2)[CH2:6]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:3]=1[CH2:4][N:5]1[CH2:9][C@H:8]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[C@@H:7]([CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([CH2:22][CH:23]([OH:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:21]2)[CH2:6]1
Reactant: C[C@H](C(=O)OC(Cc1ccccc1)CC1CCN(C[C@H]2CN(Cc3ccc(Cl)cc3Cl)C[C@@H]2c2ccsc2)CC1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC(Cc1ccccc1)CC1CCN(C[C@H]2CN(Cc3ccc(Cl)cc3Cl)C[C@@H]2c2ccsc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 0.1107 g (0.16 mmol) of 1-(2,4-dichlorobenzyl)-3-(S)-(4-(3-phenyl-2-((S)-2-phenylpropionyl)oxypropyl)piperidinylmethyl)-4-(S)-(3-thienyl)pyrrolidine (isomer 1) in 2 ml of THF at 0° C. was added 0.5 mL (0.5 mmol) of a 1 M solution of LiAlH4 in THF. The solution was stirred at 0° C. for 1 h, then was quenched by addition of 0.5 mL of 5N NaOH solution. The mixture was diluted with ethyl acetate, dried over MgSO4, filtered and the filtrate concentrated. The residue was purified by chromatography (silica, hexanes:acetone, 4:1) to give the title compound. Mass Spectrum (ESI) m/e=543 (M+1 35Cl, 35Cl), 545 (M+1 35Cl, 37Cl), and 547 (M+1 37Cl, 37Cl). [α]D=+11.7 (c=1.54, CHCl3).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[CH2:13][C:14]([CH3:16])=[CH2:15]>>[CH3:15][C:14](=[CH2:13])[CH2:16][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(O)c1
Reactant: C=C(C)CCl
Product: C=C(C)COc1cccc(C(=O)OC)c1

Procedure:
Using procedures analogous to those of D. W. Robertson, et. al., J. Med. Chem., 35, 310 (1992) and V. Peesapati, and N. Lingaiah, Org. Prep. Proc. Int., 24(1), 27 (1992), the hydroxy group of methyl 3-hydroxybenzoate was alkylated with 3-chloro-2-methyl-1-propene to give methyl 3-(2-methyl-2-propenyloxy)benzoate. This material then underwent a 3,3 sigmatrophic shift to give methyl 3-hydroxy-4-(2-methyl-2-propenyl)benzoate. Formic acid catalyzed ring closure resulted in 2,2-dimethyl-6-carboxymethyl-dihydrobenzofuran.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Br:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([O:33][CH2:34][C@@H:35]1[CH2:37][O:36]1)[CH:27]=[CH:26]2>>[Br:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([O:33][CH2:34][C@@H:35]([OH:36])[CH2:37][N:1]1[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]1)[CH:27]=[CH:26]2
Reactant: Brc1ccc2cc(OC[C@@H]3CO3)ccc2c1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C[C@H](O)COc3ccc4cc(Br)ccc4c3)CC1)O2

Procedure:
Compound 216 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-{[(6-bromo-2-naphthyl)oxy]methyl}oxirane and conditions outlined in procedure Y. M.p.=183-184° C.; 400 MHz 1H NMR (CDCl3) δ: 8.06 (dd, J=7.7, 0.7 Hz, 1H), 7.92 (d, J=1.2 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.69-7.64 (m, 2H), 7.60 (d J=8.8 Hz, 1H), 7.52-7.47 (m, 2H), 7.20 (dd, J=9.2, 2.6 Hz, 1H), 7.12 (d, J=2.6 Hz, 1H), 4.25-4.18 (m, 1H), 4.12 (d, J=4.8 Hz, 2H), 3.04-2.92 (m, 1H), 2.96 (s, 2H), 2.90-2.80 (m, 2H), 2.78-2.68 (m, 2H), 2.57 (t, J=10.4 Hz, 1H), 2.25-2.12 (m, 2H), 1.98-1.84 (m, 2H); LCMS: 580 [M+H].