Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[CH3:17][O:18][C:19]1[CH:20]=[C:21](O)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-:27].[K+].[K+]>CN(C=O)C.O>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([O:27][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:23][CH:24]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(O)c1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 9.7 %

Procedure:
1-Chloro-5H-benzo[c][1,8]naphthyridin-6-one (30 mg, 0.13 mmol), 3-methoxyphenol (48 mg, 0.39 mmol), and potassium carbonate (90 mg, 0.65 mmol) were suspended in DMF (2 mL), and stirred overnight at 100° C. The reaction mixture was diluted with H2O, and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was purified via Biotage eluting with a gradient of 25 to 75% EtOAc in hexanes to provide 125 (4 mg, 10% yield) as a solid. LC-MS (M+H=319, obsd.=319). 1H NMR (400 MHz, d6-DMSO): δ 12.14 (s, 1H), 9.04 (d, 1H), 8.42 (dd, 1H), 8.30 (d, 1H), 7.87 (dt, 1H), 7.71 (t, 1H), 7.45 (t, 1H), 6.94 (m, 2H), 6.87 (dd, 1H), 6.58 (d, 1H), 3.79 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH:40][CH:41]([CH3:43])[CH3:42])=[O:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:32])[C:16]([CH2:19][N:20]([CH2:28][CH2:29][O:30][CH3:31])C(=O)OC(C)(C)C)=[CH:17][N:18]=3)[S:13][C:6]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH:40][CH:41]([CH3:43])[CH3:42])=[O:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:32])[C:16]([CH2:19][NH:20][CH2:28][CH2:29][O:30][CH3:31])=[CH:17][N:18]=3)[S:13][C:6]=12
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC(C)C)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCNCc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC(C)C)cc4F)c3s2)n1C
Yield: 55.9 %

Procedure:
The solution of urea 314 (150 mg, 0.245 mmol) and TFA (1 mL, 12.98 mmol) in DCM mL) was stirred 4 hr at room temperature and concentrated. The residue was partitioned between EtOAc/NaHCO3 sat. solution. The solid was collected by filtration and combined with organic layer. The mixture was concentrated and the residue was purified via Biotage (EA/MeOH 0-40%, 12 g Silicycle HR column). Collected fractions gave the desired product 315 (70 mg, 0.137 mmol, 55.8% yield) as a white solid. 1HNMR (dmso-d6) δ (ppm) 1H: 8.67 (s, 1H), 8.48 (d, 1H, J=5.5 Hz), 7.91 (s, 1H), 7.65 (dd, 1H, J1=13.7 Hz, J2=2.6 Hz), 7.32 (t, 1H, J=9.0 Hz), 7.07 (m, 2H), 6.63 (d, 1H, J=5.5 Hz), 6.13 (d, 1H, J=7.6 Hz), 4.04 (s, br, 2H), 3.08 (s, 3H), 3.72 (m, 1H), 3.47 (t, 2H, J=5.2 Hz), 3.24 (s, 3H), 2.94 (m, 2H), 1.07 (s, 3H, 1.05 (s, 3H) (presumably a mono-TFA salt). MS: 513.4 (MH)+
Reaction SMILES: [O:1]1[C@H:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C@H:2]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].Br[C@@H]([C@@H](O)C(OCC)=O)C(OCC)=O.C1CCN2C(=NCCC2)CC1>CCOCC>[O:1]1[C@@H:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C@@H:2]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)OCC
Agent: CCOC(=O)[C@@H](Br)[C@@H](O)C(=O)OCC
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)[C@@H]1O[C@H]1C(=O)OCC
Yield: 74.8 %

Procedure:
Followed general procedure for 3a using the following quantities: 2b (34.6 g, 129 mmol): Et2O (100 ml); DBU (29.4 g, 193 mmol, in Et2O [50 ml]); yielded 3b as a colorless oil (18.1 g, 74.8%). 1H NMR (CDCl3, 400 MHz): δ 4.36-4.22 (m, 4H); 3.67 (s, 2H); 1.35-1.31 (t, 6H). 13C NMR (CDCl3, 100 MHz): 166.75, 62.21, 52.01, 14.01.
Reaction SMILES: [NH2:1][C:2](=[S:12])[CH2:3][C:4]([CH3:11])([CH3:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].O.O.O.O.O.[OH-].C(=O)(O)[O-].[Mg+2].[C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32](=O)[CH2:33]Cl)(=[O:26])[CH3:25]>O1CCOCC1.C(OCC)(=O)C>[C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[N:1]=[C:2]([CH2:3][C:4]([CH3:10])([CH3:11])[CH2:5][C:6]([O:8][CH3:9])=[O:7])[S:12][CH:33]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OCCCCC(=O)CCl
Reactant: COC(=O)CC(C)(C)CC(N)=S
Agent: O=C([O-])O
Agent: [Mg+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)CC(C)(C)Cc1nc(CCCCOC(C)=O)cs1
Temperature: 60 °C
Reaction time: 10 h

Procedure:
Methyl 5-amino-3,3-dimethyl-5-thioxopentanoate (500 mg; 2.64 mmoles) was dissolved in 1,4-dioxane (10 mL) under nitrogen and magnesium carbonate hydroxide pentahydrate (640 mg; 1.32 mmoles) was added. 6-Chloro-5-oxohexyl acetate (685 mg; 3.56 mmoles; Rieke, R. D.; Brown, J. D.; Wu, X. Synth. Commun. 1995, 25(23), 3923.) was added and the mixture was magnetically stirred for 10 hours with heating to 60° C. The mixture was allowed to cool, diluted with ethyl acetate and filtered. The solvent was removed under vacuum and the residue was purified by chromatography on silica gel, eluting with hexane/ethyl acetate (3:1). Following removal of solvent the product, methyl 4-{4-[4-(acetyloxy)butyl]-1,3-thiazol-2-yl}-3,3-dimethylbutanoate, was obtained as pale yellow oil. (820 mg). The material was impure, containing some 6-Chloro-5-oxohexyl acetate. 1H NMR (400 MHz) CDCl3 δ 6.76 (1H, s), 4.04–4.11 (2H, m), 3.68 (3H, m), 3.05 (2H, s), 2.78 (2H, t, J=7.5 Hz), 2.33 (2H, s), 2.04 (3H, s), 1.61–1.82 (4H, m), 1.10 (6H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28].C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:8][N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:33]2[CH:34]=[CH:35][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:31][CH:32]=2)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[C:6](=[O:25])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN(Cc1cc(-c2ccc(S(C)(=O)=O)cc2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 14 h
Yield: 54.4 %

Procedure:
A mixture of tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), 4-(methanesulfonyl)phenylboronic acid (300 mg), tetrakis(triphenylphosphine)palladium (115 mg), sodium carbonate (320 mg), 1,2-dimethoxyethane (10 mL) and water (10 mL) was stirred under a nitrogen atmosphere at 80° C. for 14 hr. The reaction mixture was allowed to cool to room temperature, filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1→1:2) to give the title compound as an oil (yield 275 mg, 64%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=2)(=[O:16])=[O:15])[C:5]([Cl:29])=[CH:4][N:3]=1>O.CO.C(O)(=O)C.[Fe]>[NH2:23][C:19]1[CH:18]=[C:17]([S:14]([NH:13][CH2:12][C:11]2[CH:26]=[CH:27][CH:28]=[C:9]([NH:8][C:6]3[C:5]([Cl:29])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:10]=2)(=[O:15])=[O:16])[CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)NCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: Nc1cccc(S(=O)(=O)NCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Yield: 90 %

Procedure:
To a solution N-{3-[(2,5-dichloropyrimidin-4-yl)amino]benzyl}-3-nitrobenzenesulfonamide (50.0 mg, 0.11 mmol) in water (0.08 mL), methanol (0.42 mL) and acetic acid (0.17 mL) was added iron (15 mg, 0.28 mmol) powder in small quantities. When the addition was completed, the mixture was stirred in water bath for 3 h and the reaction was complete. The mixture was filtered and the cake was washed with MeOH/EtOAc. The brown filtrate was concentrated and diluted with H2O, and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the desired product as a light brown powder (42 mg, 90%). LCMS for C17H15Cl2N5O2S (M+H)+: m/z=424.0, 426.0, 428.0. 1H NMR (400 MHz, CD3OD): δ 8.22 (t, J=2.0 Hz, 1H), 8.52 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 7.48 (m, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.28 (m, 1H), 7.20 (t, J=8.0 Hz, 1H), 7.08 (ddd, J=8.4, 2.0, 1.2, 1H), 6.84 (ddd, J=8.0, 1.6, 1.2, 1H), 4.21 (s, 2H).
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21]N=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:25](N)C1C=CC=CC=1>>[CH2:18]([NH:17][C:11]1[N:10]=[C:9]([NH:8][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:25]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Agent: Cl
Product: Cc1nc(NCc2ccccc2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using benzylamine instead of (pyridin-2-ylmethyl)amine to afford the crude product. The solvent was removed by distillation, and the crude product was purified by HPLC (column: YMC-PACK ODS-AQ C18, 250 mm×20 mm, 10 μm; gradient: 20-50% acetonitrile in 0.02% trifluoroacetic acid/water over fifteen minutes; 50-100% acetonitrile in 0.02% trifluoroacetic acid/water over five minutes; flow rate: 25 mL/min; temperature: 25° C.). The titled compound was obtained as the trifluoroacetic acid salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03-1.15 (m, 1H), 1.22-1.31 (m, 4H), 1.60 (d, J=12.63 Hz, 1H), 1.68 (s, 4H), 1.86 (s, 3H), 2.21 (s, 3H), 3.86-3.90 (m, 1H), 4.52 (d, J=5.64 Hz, 2H), 7.20-7.25 (m, 1H), 7.27-7.33 (m, 4H), 7.4 (bs, 1H), 8.02 (bs, 1H); MS (ESI) m/z 311.5 (M+1)+.
Reaction SMILES: [CH2:1]([C:4]1([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH:24]([CH2:26][O:27]C(=O)CCC)[O:23][C:22]3=[O:33])=[CH:17][CH:16]=2)[O:8][C:7]2=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]2[CH2:5]1)[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl>[CH2:1]([C:4]1([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:25][CH:24]([CH2:26][OH:27])[O:23][C:22]3=[O:33])=[CH:19][CH:20]=2)[O:8][C:7]2=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]2[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(c2ccc(N3CC(COC(=O)CCC)OC3=O)cc2)Cn2cc([N+](=O)[O-])nc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C=CCC1(c2ccc(N3CC(CO)OC3=O)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.1 %

Procedure:
To a solution of Butyric acid 3-[4-(2-allyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl ester (32 mg, 0.07 mmol) in MeOH/CH2Cl2 (3:1, 2.7 mL total) was added K2CO3 (15 mg, 0.105 mmol) and stirred for 1 h 30 min at rt, quenched with 10% aq. AcOH, diluted with water and EtOAc, concentrated and extracted with EtOAc. The concentrate was applied on prep-TLC to provide 2.2 mg of product.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:18])[CH:14]=[C:15]([CH3:17])[CH3:16])=[CH:8][CH:7]=1>>[Br:5][C:6]1[CH:7]=[C:8]2[C:9](=[CH:10][CH:11]=1)[NH:12][C:13](=[O:18])[CH2:14][C:15]2([CH3:16])[CH3:17]
Reactant: CC(C)=CC(=O)Nc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC1(C)CC(=O)Nc2ccc(Br)cc21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
Aluminum chloride (5 g, 37.5 mmol) was added portionwise into N-(4-bromophenyl)-3-methylbut-2-enoic amide (Intermediate 3, 7.69 g, 30.0 mmol) in a 500 mL beaker at 130° C. over 1 h. The beaker was then cooled to 80° C. and another portion of aluminum chloride (1 g, 7.5 mmol) was added. After stirring at 80° C. for 0.5 h, the beaker was cooled with an ice-bath and ice was added slowly into the mixture. The resulting slurry was then extracted with ether (3×10 mL). The combined organic layer was washed with brine (1×10 mL), saturated NaHCO3 (1×10 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chomatography (75:25 hexane/ethyl acetate) yielded the title compound as a pale yellow solid (5.20 g, 68% yield).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:11]([CH2:18][C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=4)[N:21]([CH2:29][C:30]([OH:32])=[O:31])[C:20]=3[CH3:33])=[N:12][C:13](SC)=[N:14][CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C>[Ni].O>[C:1]1([S:7]([C:10]2[C:11]([CH2:18][C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=4)[N:21]([CH2:29][C:30]([OH:32])=[O:31])[C:20]=3[CH3:33])=[N:12][CH:13]=[N:14][CH:15]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSc1ncc(S(=O)(=O)c2ccccc2)c(Cc2c(C)n(CC(=O)O)c3ccc(F)cc23)n1
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: Cc1c(Cc2ncncc2S(=O)(=O)c2ccccc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 32 %

Procedure:
A mixture of [3-(5-benzenesulfonyl-2-methylsulfanylpyrimidin-4-ylmethyl)-5-fluoro-2-methylindol-1-yl]acetic acid (0.20 g), ethanol (12 mL) and water (12 mL) was treated with Raney Nickel 2800 (0.050 g), and the resulting reaction mixture was stirred at 60° C. for 45 minutes. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (1:19 to 49:1 by volume) to afford the title compound as an off-white solid (0.058 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)[C@H:9]([OH:12])[CH2:10]O)[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N:33]1[CH:38]=[CH:37][CH:36]=CC=1>C(OCC)(=O)C>[CH:38]1([NH:33][CH2:10][C@@H:9]([OH:12])[C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)[CH2:36][CH2:37]1
Reactant: OC[C@@H](O)[C@H](c1cccc(F)c1)n1ccc2ccccc21
Reactant: c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Product: O[C@H](CNC1CC1)[C@H](c1cccc(F)c1)n1ccc2ccccc21
Reaction time: 3 h

Procedure:
(2S,3S)-3-(3-Fluorophenyl)-3-(1H-indol-1-yl)propane-1,2-diol (example 47, step 5) (0.6 g, 2.1 mmol) was dissolved in pyridine (5 mL) and para-toluenesulfonyl chloride (0.44 g, 2.3 mmol) was added. The mixture was stirred for 3 hours then the reaction mixture was diluted with ethyl acetate and washed with water, followed by a saturated aqueous solution of copper sulfate, a 2N aqueous solution of hydrochloric acid, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was immediately dissolved in methylamine (8M solution in ethanol, 25 mL) and stirred for 16 hours. The mixture was concentrated in vacuo and purified via flash column chromatography (silica, 5% methanol saturated with ammonia in chloroform) to give (1S,2R)-3-(cyclopropylamino)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)propan-2-ol as a colorless oil. The freebase was dissolved in diethyl ether (5 mL) and treated with a 1N ethereal solution of hydrochloric acid (1 equivalent). The white precipitate was collected and dried under vacuum to give 80 mg (12%) of (1S,2R)-3-(cyclopropylamino)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)propan-2-ol hydrochloride. HRMS: calcd for C20H21FN2O+H+, 325.17107; found (ESI, [M+H]+), 325.1728.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.C([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(OC(C)(C)C)=O.N1C=CN=C1C=O>>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:36][C:35]4[NH:31][CH:32]=[CH:33][N:34]=4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCNCC3)cc2n1
Agent: O=Cc1ncc[nH]1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCN(Cc4ncc[nH]4)CC3)cc2n1

Procedure:
Via 2-chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine, prepared from 1-BOC-piperazine followed by treatment with HCL and subsequent reaction with imidazole-2-carboxaldehyde using standard reductive amination conditions. The amine, 2-chloro-6-[4-(1H-imidazol-2-ylmethyl)-piperazin-1-ylmethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was subsequently isolated.
Reaction SMILES: [CH:1]1[C:6]([C:7](O)=[O:8])=[C:5]([C:10]([OH:12])=O)[CH:4]=[N:3][CH:2]=1.C(OC(=O)C)(=O)C.C([NH2:23])(=O)C>>[C:7]1(=[O:8])[C:6]2[CH:1]=[CH:2][N:3]=[CH:4][C:5]=2[C:10](=[O:12])[NH:23]1
Reactant: CC(N)=O
Reactant: O=C(O)c1ccncc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1NC(=O)c2cnccc21
Temperature: 145 °C
Yield: 95.1 %

Procedure:
A suspension of cinchomeronic acid (30)(50 g, 300 mmol) in acetic anhydride (123.5 g, 1200 mmol) was heated to reflux (140-150° C.) until all solid material dissolved and the mixture was homogeneous. The mixture was then cooled and concentrated in vacuo. Acetamide (50 g, 846 mmol) was then added and the mixture heated to 140° C. for 3 hours whereupon it was then cooled to room temperature. The solid residue that formed upon cooling was pulverized and triturated with water (100 ml), filtered and washed with more water and dried in a desiccator to give the title compound (42.26 g, 95.1%) in suitably pure form to be used without any further purification. m/z (LC-MS, ESP): 149 [M+H]+, R/T=0.44 mins.
Reaction SMILES: I.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:16][C:17](SC)=[NH:18])[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[N:13][C:12]([CH3:15])=[N:11]1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([C:39]([F:42])([F:41])[F:40])(=[O:38])=[O:37])=[CH:32][CH:31]=1)[C:27](O)=O.CN1CCOCC1.C(N(CC)C(C)C)(C)C.[NH2:59][NH2:60]>>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:27]1[NH:60][N:59]=[C:17]([NH:16][C:6]2[CH:7]=[CH:8][C:9]([N:10]3[CH:14]=[N:13][C:12]([CH3:15])=[N:11]3)=[C:4]([O:3][CH3:2])[CH:5]=2)[N:18]=1)[C:30]1[CH:31]=[CH:32][C:33]([S:36]([C:39]([F:42])([F:40])[F:41])(=[O:37])=[O:38])=[CH:34][CH:35]=1
Reactant: O=C(O)C(CCCCCl)c1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: COc1cc(NC(=N)SC)ccc1-n1cnc(C)n1
Reactant: NN
Agent: I
Solvent: CN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(S(=O)(=O)C(F)(F)F)cc3)n2)ccc1-n1cnc(C)n1

Procedure:
Methyl 3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylcarbamimidothioate, hydroiodide (0.250 g, 0.617 mmol), from preparation F) and 6-chloro-2-(4-(trifluoromethylsulfonyl)phenyl)hexanoic acid (0.221 g, 0.617 mmol, from preparation AAM) were coupled [N-methylmorpholine (0.339 mL, 3.08 mmol) was substituted for N,N-diisopropylethylamine] and then reacted with hydrazine (0.069 mL, 2.21 mmol) using a procedure analogous to Step A of Example 13. After an aqueous workup, 5-(5-chloro-1-(4-(trifluoromethylsulfonyl)phenyl)pentyl)-N-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine was obtained as a brown residue. The crude product was used in the next step without purification. LC-MS (M+H)+ 584.0.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:19][C:20]([CH3:25])([CH3:24])[C:21](Cl)=[O:22]>C(Cl)(Cl)Cl>[C:21]([O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][NH:9][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:8])=[CH:17][CH:16]=1)(=[O:22])[C:20]([CH3:25])([CH3:24])[CH3:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(NCCc1ccc(O)cc1)c1cccnc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)Oc1ccc(CCNC(=O)c2cccnc2)cc1
Temperature: 0 °C

Procedure:
To an ice cold suspension of 4.84 g (0.02 mol) N-nicotinoyltyramine in 100 ml chloroform, 3.6 g (0.03 mol) of trimethylacetyl chloride were dropped while stirring. The mixture was refluxed overnight and the non-reacted nicotinoyltyramine was filtered off. The filtrate was washed with water until free from chloride ions, washed once with 5% solution of NaHCO3 and then with water. Chloroform was evaporated on rotavap and the residue was crystallized from ether/pet. ether. Yield 3.9 g (60%), m.p. 80°-82° C. PMR (CDCl3) δ 8.66-6.93 (m, 8H, C5H4N+C6H4), 3.56 ##STR741## 2.86 (5, 2H, J=7 Hz, CH2), 1.33 (s, 9H, C--(CH3)3).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7](/[C:15](/[CH3:22])=[CH:16]/[C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1)=[C:8]2[C:12]([OH:14])=[O:13])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl.[CH:30](=[NH:39])OCC1C=CC=CC=1>O>[CH:30]([N:18]1[CH2:19][CH2:20][CH2:21][C@H:17]1/[CH:16]=[C:15](/[C:7]1[CH2:6][C@H:5]2[N:9]([C:10](=[O:11])[C@@H:4]2[C@H:2]([OH:1])[CH3:3])[C:8]=1[C:12]([OH:14])=[O:13])\[CH3:22])=[NH:39]
Reactant: N=COCc1ccccc1
Reactant: C/C(=C\[C@@H]1CCCN1)C1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C/C(=C\[C@@H]1CCCN1C=N)C1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C1
Reaction time: 0.25 h
Yield: 32.5 %

Procedure:
A solution of (5R,6S)-6-{(1R)-1-hydroxyethyl]-7-oxo-3-[(E)-2-{(2S)-pyrrolidin-2-yl}-1-methylethenyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.48 g) in water (30 ml) was adjusted to pH 8.5 with aqueous potassium carbonate at 0° C. and benzyl formimidate hydrochloride (2.7 g) was added in portions while adjusting around pH 8.5 with addition of aqueous potassium carbonate. After stirring for 15 minutes at pH 8.5, the reaction mixture was washed with ethyl acetate and concentrated in vacuo. The residue was chromatographed on nonionic adsorption resin "Diaion Hp-20" (50 ml) eluting successively with water and 3% aqueous acetone. The fractions containing the desired compound were collected and lyophilized to give (5R,6S)-3-[(E)-2-{(2S)-1-formimidoylpyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene- 2-carboxylic acid (170 mg).
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][CH2:4][NH:3][CH2:2]1>FC(F)(F)C(O)=O.CO>[CH2:1]1[C@@H:14]2[C@@H:6]([NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)[CH2:5][CH2:4][NH:3][CH2:2]1
Reactant: c1ccc2c3c([nH]c2c1)CCNCC3
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c(c1)N[C@H]1CCNCC[C@@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
A solution of 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.93 g, 5.0 mmol) in trifluoroacetic acid (17 mL) was cooled to 0° C., and treated with a freshly prepared solution of Na(CN)BH3 (1.57 g, 25 mmol) in MeOH (4 mL). The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 h, then treated with water (75 mL), stirred for an additional 15 minutes before adjusting the pH to 14 with 45% KOH (aqueous). The resulting solution was extracted with EtOAc (3×40 mL), and the combined organic extracts were washed once with brine, dried over MgSO4, filtered, and concentrated in vacuo to give a yellow syrup. The crude product was purified by chromatography and using ethanol:ammonia:dichloromethane (15:1.5:83.5) and trituration of the resulting material gave the title compound (0.64 g) as an off-white solid: mp 102-114° C.