Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:14][C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16])=[N:4][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:6]=1.O[CH:24]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[O:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C=O)C.O>[Br:1][C:2]1[C:3]([N:14]([C:15]([O:17][CH2:18][C:19]([Cl:20])([Cl:22])[Cl:21])=[O:16])[C@H:24]([C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)=[O:26])[CH2:37][CH:38]([CH3:40])[CH3:39])=[N:4][N:5]([C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])[CH:6]=1
Reactant: COc1ccc(COC(=O)C(O)CC(C)C)cc1
Reactant: CC(C)(C)OC(=O)n1cc(Br)c(NC(=O)OCC(Cl)(Cl)Cl)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c2nn(C(=O)OC(C)(C)C)cc2Br)cc1
Reaction time: 8 h

Procedure:
To tert-butyl 4-bromo-3-{[(2,2,2-trichloroethoxy)carbonyl]amino}-1H-pyrazole-1-carboxylate (2.32 g, 5.3 mmol), 4-methoxybenzyl 2-hydroxy-4-methylpentanoate (2.02 g, 8.0 mmol, prepared as described in Example 16) and triphenyl phosphine (2.1 g, 8.0 mmol) in dry DMF (50 mL) at 0° C. under dry nitrogen was added diisopropyl azodicarboxylate (1.6 mL, 8.0 mmol) dropwise and the reaction was stirred overnight. The reaction was poured into water and the product extracted with Et2O (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 2/8) to afford 4-methoxybenzyl N-[4-bromo-1-(tert-butoxycarbonyl)-1H-pyrazol-3-yl]—N-[(2,2,2-trichloroethoxy)carbonyl]leucinate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([O:20][CH3:21])[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)([CH3:24])[CH3:23].C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:31]([C:28]3[CH:29]=[CH:30][C:25]([CH:22]([CH3:24])[CH3:23])=[CH:26][CH:27]=3)(=[O:33])=[O:32])=[C:15]([O:20][CH3:21])[CH:14]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(C2CCN(Cc3ccccc3)C2)ccc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(C2CCN(Cc3ccccc3)C2)ccc1NS(=O)(=O)c1ccc(C(C)C)cc1
Temperature: 25 °C
Yield: 129.7 %

Procedure:
4-(1-Benzyl-pyrrolidin-3-yl)-2-methoxy-phenylamine (220 mg, 0.78 mmol) and 4-isopropylphenylsulfonyl chloride (170 mg, 0.78 mmol) were dissolved in tetrahydrofuran (20 ml). Triethylamine (0.32 ml, 2.34 mmol) was added and the reaction mixture stirred over night at room temperature (10% conversion) and subsequently refluxed for 4 h (70% conversion). One small portion of 4-isopropylphenylsulfonyl chloride and triethylamine were added and the reaction mixture was stirred 15 min at 150° C. in the microwave (CEM). The solvent was evaporated under reduced pressure, the residue treated with ethyl acetate (50 ml) and extracted twice with slightly acidic water. The organic layer was dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to give an oil (470 mg). The crude product was purified via silica gel chromatography with cyclohexane/ethyl acetate (gradient 0-100%). Fractions containing the product were combined, the solvent evaporated to yield an oil (143 mg, 40%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([O:17][CH2:18][CH2:19][OH:20])[CH:12]3[O:11][CH2:10]2)[C:5]([Cl:21])=[CH:4][N:3]=1.Cl.[CH3:23][N:24]1[CH:28]=[C:27]([NH2:29])[CH:26]=[N:25]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:21][C:5]1[C:6]([NH:8][CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([O:17][CH2:18][CH2:19][OH:20])[CH:12]3[O:11][CH2:10]2)=[N:7][C:2]([NH:29][C:27]2[CH:26]=[N:25][N:24]([CH3:23])[CH:28]=2)=[N:3][CH:4]=1
Reactant: OCCOC1COC2C(Nc3nc(Cl)ncc3Cl)COC12
Reactant: Cn1cc(N)cn1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Nc2ncc(Cl)c(NC3COC4C(OCCO)COC34)n2)cn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 19.6 %

Procedure:
To a suspension of 2-((6-((2,5-dichloropyrimidin-4-yl)amino)hexahydrofuro[3,2-b]furan-3-yl)oxy)ethanol (0.18 g, 0.54 mmol) in n-BuOH (5 mL) were added 1-methylpyrazol-4-amine hydrochloride (0.15 g, 1.10 mmol) and DIPEA (0.28 g, 2.18 mmol). The mixture was stirred in a sealed tube at 150° C. overnight and then concentrated in vacuo. The residue was purified by a silica chromatography (DCM/MeOH (v/v)=20/1) to give the title compound as brown sticky liquid (42 mg, 20%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:13]Cl)=[N:4][CH:5]=[CH:6][C:7]=1[N:8]([CH3:12])[CH2:9][CH2:10][OH:11].[SH:15][C:16]1[NH:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1>CC(O)C>[NH:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[S:15][CH2:13][C:3]1[C:2]([Cl:1])=[C:7]([N:8]([CH3:12])[CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][N:4]=1
Reactant: CN(CCO)c1ccnc(CCl)c1Cl
Reactant: Sc1nc2ccccc2[nH]1
Solvent: CC(C)O
Product: CN(CCO)c1ccnc(CSc2nc3ccccc3[nH]2)c1Cl
Temperature: 4 °C

Procedure:
A solution of 2-[(3-chloro-2-chloromethyl-pyridin-4-yl)-methyl-amino]-ethanol isolated in step a) (10.2 g) and 2-mercapto-benzimidazole (5.8 g, 39 mmol) in 2-propanol (250 ml) is boiled under reflux for 2 h. After cooling to 4° C. the precipitate is filtered, washed with 2-propanol and dried in vacuo. The residue is dissolved in water, adjusted to pH 8 with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic extracts are washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue is crystallized from ethyl acetate to give the title compound as an off-white solid, 7.9 g (58%). M.p. 132-5° C.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH2:29].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH:29][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1
Reactant: NCc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(F)ccc2[N+](=O)[O-])CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cc(NCc3cccc(Cl)c3)ccc2[N+](=O)[O-])CC1
Yield: 47.7 %

Procedure:
t-Butyl 4-(5-fluoro-2-nitrophenyl)piperazine-1-carboxylate (431 mg, 1.3 mmol), 3-chlorobenzylamine (187 mg, 1.3 mmol), N,N-diisopropylethylamine (342 mg, 1.3 mmol) were stirred at 80° C. in dry acetonitrile (25 mL) for 72 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 25% ethyl acetate in hexanes to afford the title compound (277 mg, 48% yield). 1H NMR (400 MHz, CD3OD): δ 7.96 (d, 1H), 7.37-7.26 (m, 4H), 6.29 (d, 1H), 6.18 (s, 1H), 4.42 (s, 2H), 3.55 (m, 4H), 2.92 (m, 4H), 1.47 (s, 9H); MS (ESI) m/z: Calculated for C22H27ClN4O4: 446.17; Observed: 469.2 (M++Na).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[C:38]([CH3:43])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[C:38]([CH3:43])[N:39]=[C:40]([CH3:42])[CH:41]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(C(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J24) (311 mg, 1.0 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (325 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow oil (356 mg, 63%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH:13]C(OCC1C=CC=CC=1)=O)[CH2:5][C:6]([F:12])([F:11])[CH2:7][CH:8]([CH3:10])[CH3:9].[ClH:25].O1CCOCC1>CO.[Pd]>[ClH:25].[CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH2:13])[CH2:5][C:6]([F:12])([F:11])[CH2:7][CH:8]([CH3:9])[CH3:10]
Reactant: COC(=O)[C@H](CC(F)(F)CC(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)CC(F)(F)CC(C)C
Reaction time: 7 h

Procedure:
A solution of (S)-2-benzyloxycarbonylamino-4,4-difluoro-6-methyl-heptanoic acid methyl ester: (333 mg, 0.97 mmol) in methanol (10 mL) and 4 M HCl in dioxane (4 mmol, 1 mL) is hydrogenated over 10% Pd/C (150 mg) at 55 psi. After 7 hr, another portion of 10% Pd/C (200 mg) is added and the hydrogenation resumed. After 5.5 hr, the reaction did not progress. Catalyst is filtered and the filtrate is concentrated in vacuum and subjected to the hydrogenation conditions. After 6.5 hr, the catalyst is removed by filtration over a pad of Celite, and the filtrate is concentrated in vacuum to afford (S)-2-amino-4,4-difluoro-6-methyl-heptanoic acid methyl ester hydrochloride as a sticky solid (240 mg, quant.).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6](=[O:23])[CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[C:17]2[C:18]([NH2:22])=[N:19][O:20][N:21]=2)=[CH:4][C:3]=1[N+:26]([O-])=O>C(O)C.O.Cl.[Fe]>[NH2:26][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:2]=1[Cl:1])[C:6](=[O:23])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:18]([NH2:22])=[N:19][O:20][N:21]=1
Reactant: Nc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(C(=O)Cn2c(-c3nonc3N)nc3ccccc32)ccc1Cl
Temperature: 80 °C

Procedure:
To a stirred solution of 4-[1-(4-chloro-3-nitrophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine (0.07 g, 0.175 mmol) in ethanol (6 ml) and water (1 ml) is added two drops of concentrated hydrochloric acid and iron powder (0.1 g, 17.5 mmol). The reaction mixture is heated at 80° C. for 8 hours. Filtration and evaporation at reduced pressure gives the crude product. Purification by extraction with ethyl acetate and chromatography on silicagel yields the title compound as colorless solid, m.p. 228-230° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH:11][CH2:14][C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(C2CCCCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)c1ccc(CNc2ccc(C3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
4-Cyclohexylaniline (8.0 g, 53 mmol) was dissolved in methanol (200 mL) and a suspension of 4-formylbenzoic acid (9.4 g, 53 mmol) in glacial acetic acid (12 mL) was added in portions and the resulting mixture was heated at reflux temperature for 1.5 hour. After cooling to room temperature a mixture of sodium cyano borohydride (5.0 g, 80 mmol) in methanol (100 mL) was added in portions, and the resulting mixture was stirred at room temperature for 16 hours. The mixture was filtered and washed thoroughly with water and dried in vacuo at 50° C. for 3 days to afford 12.8 g (78%) of 4-[(4-cyclohexylphenylamino)methyl]benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH3:12])[C:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[CH:5]2.ClS([N:23]=[C:24]=O)(=O)=O.CN(C=O)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH3:12])[C:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[C:5]2[C:24]#[N:23]
Reactant: Cn1c(-c2cccnc2)cc2cc(Cl)cc(F)c21
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1c(-c2cccnc2)c(C#N)c2cc(Cl)cc(F)c21
Reaction time: 1 h

Procedure:
To a solution of 5-chloro-7-fluoro-1-methyl-2-pyridin-3-yl-1H-indole (130 mg, 0.50 mmol) in dichloromethane (10 mL) at ambient temperature is added chlorosulfonyl isocyanate (282 mg, 2.0 mmol) and the mixture is stirred for 11 h, whereupon anhydrous DMF (1 mL) is added. After 1 h, the mixture is concentrated and the residue is purified by HPLC using an Xbridge C18 with a gradient of acetonitrile in 0.1% NH4OH to afford 5-chloro-7-fluoro-1-methyl-2-pyridin-3-yl-1H-indole-3-carbonitrile as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.89 (d, J=1.8 Hz, 3H), 7.46 (dd, J=12.4, 1.8 Hz, 1H), 7.62 (d, J=1.8 Hz, 1H), 7.71 (dd, J=7.5, 4.4 Hz, 1H), 8.16 (dt, J=8.1, 2.0, 1.8 Hz, 1H), 8.83 (dd, J=4.9, 1.6 Hz, 1H), 8.89 (d, J=1.5 Hz, 1H). HRMS (ESI) m/z 286.0558 [(M+H)+ Calcd for C15H10ClFN3: 286.0547].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[CH2:9])[CH:5]=[CH:4][C:3]=1[C@@H:11]([NH:13][S@@:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])[CH3:12].[H][H]>[Pd].CO>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[CH:5]=[CH:4][C:3]=1[C@@H:11]([NH:13][S@@:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])[CH3:12]
Reactant: C=C(C)c1ccc([C@H](C)N[S@](=O)C(C)(C)C)c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)c1ccc([C@H](C)N[S@](=O)C(C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.2 %

Procedure:
To a round bottom flask containing (R)—N—((S)-1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (204 mg, 0.72 mmol) and a stir bar was added MeOH (7.2 mL). To this solution was added palladium on carbon (77 mg, 10%, 0.07 mmol) in MeOH (1 mL). A hydrogen atmosphere was inserted and the resulting reaction mixture stirred at room temperature for 18 hours, at which time more palladium on carbon was added (300 mg) in MeOH (5 mL). A hydrogen atmosphere was inserted again and the reaction mixture allowed to stir an additional 18 hours at room temperature. The reaction mixture was filtered through a syringe filter and concentrated to afford a light brown viscous oil of (R)—N—((S)-1-(2-fluoro-4-isopropylphenyl)ethyl)-2-methylpropane-2-sulfinamide (149 mg, 0.52 mmol, 73% yield) which crystallizes upon standing. 1H NMR (400 MHz, CDCl3) δ 1.20 (s, 9H) 1.24 (d, J=5.87 Hz, 6H) 1.58 (d, J=6.70 Hz, 3H) 2.89 (dt, J=13.79, 6.90 Hz, 1H) 3.35 (d, J=5.04 Hz, 1H) 4.76-4.85 (m, 1H) 6.90 (dd, J=12.03, 1.52 Hz, 1H) 6.98 (dd, J=7.90, 1.54 Hz, 1H) 7.24 (t, J=7.97 Hz, 1H). LCMS m/z 286.3 (M+H)+, Rt 1.01 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:32]C(=O)OC(C)(C)C)[C:9](=[O:31])[NH:10][C:11]2[CH:12]=[C:13]3[C:29](=[O:30])[NH:28][N:27]=[CH:26][C:15]4=[C:16]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[NH:17][C:18]([CH:19]=2)=[C:14]34)=[CH:4][CH:3]=1.[ClH:40].C(N(CC)CC)C>O1CCOCC1>[ClH:40].[NH2:32][C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C:9]([NH:10][C:11]1[CH:12]=[C:13]2[C:29](=[O:30])[NH:28][N:27]=[CH:26][C:15]3=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[NH:17][C:18]([CH:19]=1)=[C:14]23)=[O:31]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)c1ccc(O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: N[C@@H](C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)c1ccc(O)cc1
Yield: 60 %

Procedure:
Preparation of example 175 from the title compound of Example 153 (38 mg, 0.072 mmol) and 4M HCl in dioxane (10 mL) was carried out analogously to Example 91. Isolation, also in an analogous manner, included freebasing with triethylamine and subsequent silica gel chromatography eluting with 3:1:1 hexane:ethyl acetate:ethanol. With ice bath cooling, the purified freebase in CH2Cl2 (10 mL) was treated with 4M HCl in dioxane (0.1 mL). After removal of the volatile components, the title compound (20 mg, 0.043 mmol) was obtained as an orange/yellow powder in 60% yield.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:19]=[CH:18][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])=[CH:8][CH:7]=1.N.[H][H]>[Ni].CO>[O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:19]=[CH:18][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[CH:8][CH:7]=1
Reactant: N#CCCCCCOc1ccc(C2=NCCO2)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCCCCCOc1ccc(C2=NCCO2)cc1
Yield: 100 %

Procedure:
A mixture of 3.2 parts of 6-[4-(4,5-dihydro-2-oxazolyl)phenoxy]hexanenitrile and 80 parts of methanol, saturated with ammonia, was hydrogenated at normal pressure and at room temperature with 1 part of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 3.2 parts (100%) of 6-[4-(4,5-dihydro-2-oxazolyl)phenoxy]hexanamine as a residue (int. 108).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([C:17](O)=[O:18])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)([N:28]1C=CN=C1)=O.N>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([C:17](=[O:18])[NH2:28])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCOc1noc(-c2ccccc2)c1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1noc(-c2ccccc2)c1C(N)=O
Yield: 100.3 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-carboxy-5-phenylisoxazole (0.6 g) was dissolved in tetrahydrofuran (6 ml) and carbonyldiimidazole (0.31 g) was added thereto under ice-cooling with stirring, followed by stirring of the mixture at room temperature for 30 minutes. Aqueous ammonia (1 ml) was added dropwise to the reaction mixture and the mixture was stirred at room temperature for one hour. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution and dried using anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain the title compound (0.60 g, quantitative) as a colorless powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=O.[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1>C1(C)C(C)=CC=CC=1>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:20])(=[O:21])[NH:6][C:5]=1[C:3]([NH:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1)=[O:2])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: Nc1nccs1
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Solvent: Cc1ccccc1C
Product: O=C(Nc1nccs1)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1

Procedure:
3.2 gm (0.01 mol) of 4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide and 1.5 gm (0.015 mol) of 2-amino-thiazole were heated for 16 hours in 200 ml of dry xylene analogous to Example 35. After cooling, the precipitate which had formed was suction-filtered off, and the mother liquor was evaporated in vacuo, whereby another crop of crude 4-hydroxy-N-(2-thiazolyl)-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was obtained. The two crops of crude product were combined and recrystallized three times from acetonitrile, yielding 0.85 gm (23% of theory) of the desired compound, m.p. 238° C (decomp.).
Reaction SMILES: C(C1(O[Si](C)(C)C)[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)#N.Cl.[C:21]([OH:24])(=[O:23])[CH3:22]>>[CH3:14][O:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[CH:22]([C:21]([OH:24])=[O:23])[CH2:4][CH2:5][CH2:6]2
Reactant: CC(=O)O
Reactant: COc1ccc2c(c1)CCCC2(C#N)O[Si](C)(C)C
Agent: Cl
Product: COc1ccc2c(c1)CCCC2C(=O)O
Temperature: 25 °C

Procedure:
As described with reference to Reaction Scheme I, compounds of Formula 2 can be converted to the intermediates of Formula 3 according to the procedure described by Belletire, et al. [Synthetic Commun., 12(10), 763-770 (1982)]. For example, to a 250 ml single neck round bottom reaction flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet, is added 6.0 g (21.79 mmol) of 1-cyano-1-trimethylsiloxy-6-methoxy-1,2,3,4-tetrahydronaphthalene. In one portion, 20.0 g (88.6 mmol) stannous chloride decahydrate followed by 20 ml glacial acetic acid and 20 ml concentrated hydrochloric acid is added. The reaction apparatus is immediately flushed with nitrogen and plunged into a preheated (140° C.) oil bath. With vigorous stirring the reaction mixture is heated at reflux for 65 hours, cooled to room temperature, diluted with 250 ml chloroform, the layers separated, and the aqueous layer again extracted with chloroform. The combined organic layers are extracted three times with 2N aqueous KOH, and the combined basic aqueous layers back-extracted with ether. The basic aqueous layer is acidified with ice-bath cooling, extracted three times with chloroform, the organic layers dried over magnesium sulfate, filtered, and the volatiles removed to give 6-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid, an intermediate of Formula 3, as a crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]2[C:11]3[C:12](O)=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:9]=2[C:8]([O:19]C2CCCC2)=[CH:7][CH:6]=1)=[O:4].P(Cl)(Cl)([Cl:27])=O>>[CH3:1][O:2][C:3]([C:5]1[C:10]2[C:11]3[C:12]([Cl:27])=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:9]=2[C:8]([OH:19])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(OC2CCCC2)c2oc3ccnc(O)c3c12
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc(O)c2oc3ccnc(Cl)c3c12

Procedure:
A solution of Methyl-1-hydroxy-6-cyclopentyloxybenzo[4,5]furo[3,2-c]pyridine-9-carboxylate (16.0 g) and phosphorous oxychloride (320 mL) was refluxed for 15-16 hours. Phosphorous oxychloride (300 mL) was removed under vacuo. Water (20.0 ml) was added at 60-70° C. Then after water (200 mL) was added, the solid obtained was filtered, washed with water (2×100 mL) and dried to get 8.8 g of product as yellow solid.
Reaction SMILES: C([Li])CCC.CCCCCC.C([N-]C(C)C)(C)C.[Li+].[Cl:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[CH2:27][CH3:28].[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[C:37](=[O:44])[CH2:38][N:39]1[CH:43]=[N:42][CH:41]=[N:40]1>C1COCC1>[Cl:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[CH:27]([CH3:28])[C:37]([C:31]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=1[F:29])([OH:44])[CH2:38][N:39]1[CH:43]=[N:42][CH:41]=[N:40]1
Reactant: CCc1ccncc1Cl
Reactant: O=C(Cn1cncn1)c1ccc(F)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(c1ccncc1Cl)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: -20 °C

Procedure:
To a solution of diiscpropylamine (1.01 g, 10 mmol) in dry THF (60 ml) at -60° C. and under a nitrogen atmosphere was added dropwise a 1.6M solution of n-butyllithium in hexane (6.25 ml, 10 mmol). The mixture was allowed to warm to -20° C. then recooled to -70° C. and to the resulting solution of lithium diisopropylamide (LDA) (10 mmol) at -70° C. was added dropwise 3-chloro-4-ethylpyridine (see D. L. Comins et al, Heterocycles, 22, 339 (1984)) (1.41 g, 10 mmol). The resulting mixture was stirred at this temperature for 15 minutes after which time a solution of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (2.23 g, 10 mmol) in THF (15 ml) was added. This mixture was allowed to warm to room temperature over a 30 minute period and the reaction was quenched by the addition of water (30 ml) and extracted with ethyl acetate (3×60 ml). The combined organic extracts were dried over magnesium sulphate, filtered, concentrated under reduced pressure and the title compound isolated by "flash" chromatography on silica eluting with ethyl acetate. The product was recrystallised from ethyl acetate (yield=0.46 g), m.p. 182°-184° C. Found: C,55.76; H,4.15; N,15.23; C17 H15ClF2N4O requires: C,55.98; H,4.14; N,15.36%.