Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:35])[C@@H:9]([N:14]1[CH2:18][C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C@H:27]3[CH2:31][O:30]C(C)(C)[O:28]3)=[CH:22][CH:21]=2)=[CH:16][C:15]1=[O:34])[CH2:10][CH:11]([CH3:13])[CH3:12].Cl>O1CCCC1>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:35])[C@@H:9]([N:14]1[CH2:18][C:17]([O:19][C:20]2[CH:21]=[CH:22][C:23]([CH2:26][C@H:27]([OH:28])[CH2:31][OH:30])=[CH:24][CH:25]=2)=[CH:16][C:15]1=[O:34])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)C[C@@H](C(=O)Nc1cnccn1)N1CC(Oc2ccc(C[C@H]3COC(C)(C)O3)cc2)=CC1=O
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)Nc1cnccn1)N1CC(Oc2ccc(C[C@H](O)CO)cc2)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
A solution of (S)-2-{4-[4-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid pyrazin-2-ylamide (0.025, 0.05 mmol) in tetrahydrofuran (5 mL) was treated with 1 M hydrochloric acid (1 mL) and stirred at room temperature overnight. The resulting mixture was partitioned between ethyl acetate and water. The layers were separated and the aqueous phase made basic (pH=8) by the addition of a 1N aqueous sodium hydroxide and extracted with ethyl acetate. The combined organic layers were concentrated in vacuo and the residue purified by flash column chromatography (silica gel 0% to 20% tetrahydrofuran/ethyl acetate) to afford (S)-2-{4-[4-((S)-2,3-dihydroxy-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid pyrazin-2-ylamide (15 mg, 65%) as a white solid: HR-ES-MS m/z calculated for C23H28N4O5 [M+H]+ 441.2133, observed 441.2132; 1H NMR (300 MHz, CDCl3) δ ppm 1.05 (d, J=6.4 Hz, 3H), 1.10 (d, J=6.4 Hz, 3H), 1.43-1.82 (m, 2H), 1.85-2.00 (m, 1H), 2.62 (dd, J=13.0, 11.2 Hz, 1H), 2.85 (d, J=13.9 Hz, 1H), 3.35 (br. s., 2H), 3.61-3.84 (m, 2H), 3.94-4.16 (m, 2H), 4.31 (d, J=18.1 Hz, 1H), 4.78-4.87 (m, 1H), 4.87 (br. s., 1H), 7.01 (d, J=8.2 Hz, 2H), 7.24-7.27 (m, 2H), 8.26 (s, 1H), 8.38 (s, 1H), 9.62 (s, 1H), 10.27 (br. s., 1H).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([C:16]2[C:24]([Cl:25])=[C:23]([Cl:26])[C:22]([Cl:27])=[C:21]([Cl:28])[C:17]=2[C:18]([OH:20])=O)=[O:15])=[C:6]1[CH3:29])[CH2:2][CH2:3][CH3:4].[CH3:30][N:31]([CH3:41])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]([CH3:40])[CH3:39])[CH:33]=1.C(OC(=O)C)(=O)C.[OH-].[Na+]>>[CH3:39][N:38]([CH3:40])[C:34]1[CH:33]=[C:32]([N:31]([CH3:41])[CH3:30])[CH:37]=[CH:36][C:35]=1[C:14]1([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]=2[CH3:29])[C:16]2[C:17](=[C:21]([Cl:28])[C:22]([Cl:27])=[C:23]([Cl:26])[C:24]=2[Cl:25])[C:18](=[O:20])[O:15]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: CCCCn1c(C)c(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: CCCCn1c(C)c(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c2ccccc21
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of 5.20 g (0.01 mole) of 2-[(1-n-butyl-2-methyl-3-indolyl)carbonyl]-3,4,5,6-tetrachlorobenzoic acid, prepared in part A above, 2.0 g (0.012 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine and five ml of acetic anhydride was warmed over a period of approximately forty minutes at 110° C. The reaction mixture was then cooled to ambient temperature, set aside overnight, rendered alkaline with 10 percent aqueous sodium hydroxide solution and extracted with benzene. Petroleum ether was slowly added to the separated benzene extract and the solid which slowly separated was collected by filtration and dried to obtain 3-[2,4-bis(dimethylamino)phenyl]-3-(1-n-butyl-2-methyl-3-indolyl)-4,5,6,7-tetrachlorophthalide (Formula III: R0 =R1 =R2 =R3 =Cl; R=R5 =CH3 ; R4 =N(CH3)2 ; R6 =(CH2)3CH3 ; Y1 =H), as white crystals having a melting point of 173°-175° C. The nuclear magnetic resonance spectrum was consistent with the structure; a maximum of 1770 cm-1 (C=O; s) appeared in the infrared spectrum; the spectrum showed a m/e peak at 617 (M+, 4 Cl).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:12]([CH3:13])[NH:11][C:10]1=[O:14])=[O:7])([CH3:4])(C)C.FC(F)(F)C(O)=O.[C:22]1(OC)[CH:27]=[CH:26]C=[CH:24][CH:23]=1>ClCCl>[CH2:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:12]([CH3:13])[NH:11][C:10]1=[O:14])=[O:7])[C:4]1[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1
Reactant: C[C@@H]1NC(=O)[C@H]1NC(=O)OC(C)(C)C
Reactant: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1
Reaction time: 1.5 h

Procedure:
A solution of 3.3 g of (3S-trans)-3-t-butoxycarbonylamino-4-methylazetidinone in 10 ml each of dichloromethane and anisole is cooled to 0° C. and 112 ml of trifluoroacetic acid is added. The solution is stirred for 90 minutes and evaporated in vacuo (benzene added and evaporated three times). The residue is dissolved in 70 ml of acetone and the solution is adjusted to pH 7 with 5% sodium bicarbonate solution. A total of 5.33 g of benzyl chloroformate is added over 1 hour at pH 6.5-7.5. The mixture is stirred for 30 minutes at pH 7, diluted with 100 ml of saturated salt, and extracted with ethyl acetate (three 400 ml portions). The residue obtained by evaporation is chromatographed on a 1 liter silica gel column. Elution with chloroform-ethyl acetate (4:1) gives 2.19 g of compound. Crystallization from ether-hexane yields 1.125 g of the title compound.
Reaction SMILES: [CH2:1]([C@@H:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][O:10][C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([C@@H:8]1[NH:13][C@H:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:11][O:10][C:9]1=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OCC(c2ccccc2)=N[C@H]1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C1OC[C@@H](c2ccccc2)N[C@H]1Cc1ccccc1
Reaction time: 5 h
Yield: 32.7 %

Procedure:
To a solution of (3S)-3-Benzyl-5-phenyl-3,6-dihydro-2H-1,4-oxazin-2-one (1.56 g, 5.88 mmol, 1.0 equiv.) in anhydrous methanol (40 mL) under an atmosphere of nitrogen was added palladium on activated carbon (156 mg, 0.1 equiv. by mass). The mixture was consecutively degassed and purged three times with hydrogen and then stirred for 5 hours under an atmosphere of hydrogen. Filtration through a short pad of CELITE® diatomaceous earth and removal of solvent from the filtrate in vacuo yielded the crude product which was purified by flash column chromatography on silica eluting with petrol and diethyl ether (4:1) to furnish the title product as a white solid (514 mg, 33%); m.p. 75.0-76.0° C. (lit. 76.0-78.0° C.); v(max)(KBr) 3321 (N—H), 2949 (C—H), 1731 (C═O), cm−1; δH (250 MHz, CDCl3) 7.36-7.21 (10H, m, Ph), 4.34-4.15 (3H, m, PhCHCH2), 3.97 (1H, dd, J 3.2, T 10.0 Hz, NHCH), 3.56, (1H, dd, J 3.2, J 13.6 Hz, CHPh×1), 3.00, (1H, dd, /10.0, T 13.6 Hz, CH2Ph×1), 1.84 (1H, br, NH); δH, (62.5 MHz, CDCl3) 169.6, 138.0, 137.8, 129.8, 129.3, 129.2, 129.1, 127.5, 127.4, 75.3, 60.6, 57.9, 39.4; m/z (CL, NH3), 268 (MH+, 40%), 267 (80%, M+), 223 (100%), and 209 (57%); HRMS for C17H17NO2 requires 267.1259 found 267.1263. [α]D20 −156.4 (c 1.02 CHCl3) (lit. [α]D20 −157.9 (c 2.00 CHCl3)).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C(CS[C:12](=[S:18])[S:13][CH2:14][C:15]([OH:17])=O)(O)=O.[C:19]([NH:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)(=[O:21])[CH3:20]>O>[C:19]([NH:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:15](=[O:17])[CH2:14][S:13][C:12]2=[S:18])=[CH:26][CH:25]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)NNc1ccc(N)cc1
Reactant: O=C(O)CSC(=S)SCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)NNc1ccc(N2C(=O)CSC2=S)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium carbonate (1.06g. 0.010 mole) was dissolved in water (100 ml). Bis(carboxymethyl)trithiocarbonate (4.52g, 0.02 mole) was added portionwise with vigorous stirring. When solution was complete, the reaction mixture was warmed to 80°-85° C and 1-acetyl-2-(4-aminophenyl)hydrazine (3.30 g, 0.020 moles) was added in one portion. The reaction mixture was heated with stirring for 11/2 hours, cooled to about 50°-60° C, then reheated at 80°-85° C. The product began to precipitate during reheating. After another 2 hours of heating the mixture was cooled to room temperature, chilled and filtered. The solid which was collected was washed with water and dried. Yield 2.95g (53%), mp 210°-213° C (dec).
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([S:7]([CH:10]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Cl:24])[CH:15]=2)[NH:11][CH:12]=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.O=P(Cl)(Cl)Cl.C(N(CC)CC)C>C(COC)OC>[Cl:24][C:16]1[CH:15]=[C:14]([CH:10]([N+:11]#[C-:12])[S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:25])=[CH:6][CH:5]=2)(=[O:9])=[O:8])[CH:19]=[C:18]([O:20][CH3:21])[C:17]=1[O:22][CH3:23]
Reactant: COc1cc(C(NC=O)S(=O)(=O)c2ccc(C)cc2)cc(Cl)c1OC
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Solvent: COCCOC
Product: [C-]#[N+]C(c1cc(Cl)c(OC)c(OC)c1)S(=O)(=O)c1ccc(C)cc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Compound 3a (4.57 g, 11.92 mmol) was suspended in dry dimethoxyethane (100 mL) and cooled to −10° C. POCl3 (3.4 mL, 36.1 mmol) was added and a mixture of triethylamine (8.3 mL, 59.5 mmol) in dimethoxyethane (10 mL) was dropped slowly to the reaction mixture. After stirring for 2 h at −5° C., the reaction mixture was poured into ice water. The aqueous phase was extracted with ethyl acetate, the organic phase was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuum. Upon refrigeration (4° C.) over night a yellow solid crystallized, which was collected and dried in vacuum.
Reaction SMILES: C([O:4][C@@H:5]([CH3:52])[C:6]([N:8]([CH2:35][C@H:36]1[C@@H:40]([F:41])[CH2:39][N:38](C(OCC2C=CC=CC=2)=O)[CH2:37]1)[C@@H:9]([C:14]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[N:17]=[C:16]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[F:34])[N:15]=1)[C:10]([CH3:13])([CH3:12])[CH3:11])=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.CO.[Pd]>[F:34][C:28]1[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=1[C:16]1[N:15]=[C:14]([C@H:9]([N:8]([CH2:35][C@H:36]2[C@@H:40]([F:41])[CH2:39][NH:38][CH2:37]2)[C:6](=[O:7])[C@@H:5]([OH:4])[CH3:52])[C:10]([CH3:11])([CH3:12])[CH3:13])[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[N:17]=1
Reactant: CC(=O)O[C@@H](C)C(=O)N(C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)[C@@H](c1nc(-c2cc(F)ccc2F)nn1Cc1cccc(F)c1)C(C)(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@H](O)C(=O)N(C[C@@H]1CNC[C@@H]1F)[C@@H](c1nc(-c2cc(F)ccc2F)nn1Cc1cccc(F)c1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of (3R,4R)-benzyl 3-(((S)-2-acetoxy-N-((R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)propanamido)methyl)-4-fluoropyrrolidine-1-carboxylate (2.24 g, 3.09 mmol) in degassed EtOAc (25 mL, 0.1 M solution) was added Pd/C (224 mg, 10 wt %) under anhydrous N2 atmosphere. After flushed with hydrogen gas, the reaction mixture equipped with a hydrogen gas balloon was stirred at room temperature for overnight. The reaction mixture was filtered through Celite® pad that was washed with EtOAc. The volatile organic filtrate was removed in vacuo to give the crude amine. Then, the crude product was dissolved in MeOH (200 mL, 0.015 M solution) followed by addition of anhydrous potassium carbonate (4.2 g, 30.9 mmol). The reaction was then stirred for 15 min at room temperature. After white precipitate was removed by filtration, the organic filtrate was concentrated in vacuo. The crude product was purified by preparative reverse phase HPLC. The combined fractions of the product were neutralized with saturated NaHCO3 solution, which was then extracted with EtOAc (200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The dried product was then dissolved in acetonitrile and water (1:1 ratio) and lyophilized for 48 h. The white powdery (S)—N—((R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-N-(((3S,4R)-4-fluoropyrrolidin-3-yl)methyl)-2-hydroxypropanamide was obtained in 57% yield (962 mg, over 3 steps) as a free amine 1H NMR (CD3OD, 400 MHz): 7.81 (1H, m), 7.40-7.16 (5H, m), 7.06 (1H, m), 6.12 (1H, s), 5.44 (2H, m), 4.77 (2H, m), 3.87 (1H, m), 2.82 (2H, m), 2.28 (1H, m), 2.17 (1H, m), 1.95 (1H, m), 1.43 (3H, m), 1.22 (1H, m), 0.91 (9H, s). LC/MS (uplc): MH+ 548.3, 0.94 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH2:13][N:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH2:13][N:14]1[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N3CCCC3)cc2Cl)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cc(N2CCCC2)ccc1CN1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
A 50 mL round-bottom flask was charged with tert-butyl 4-[[2-chloro-4-(pyrrolidin-1-yl)phenyl]methyl]piperazine-1-carboxylate (0.270 g, 0.710 mmol, 1.00 equiv), dichloromethane (10 mL). Trifluoroacetic acid (3.00 g, 26.3 mmol, 37.00 equiv) was added at 0° C. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to yield 0.160 g (crude) of 1-[[2-chloro-4-(pyrrolidin-1-yl)phenyl]methyl]piperazine as yellow oil. LCMS (ESI, m/z): 280 [M+H]+.
Reaction SMILES: Br[CH:2]([CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])[C:3]([CH3:11])([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Na]>O1CCCC1>[Cl:14][C:13]([Cl:15])([Cl:16])[CH:12]=[CH:2][C:3]([CH3:10])([CH3:11])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)(C)C(Br)CC(Cl)(Cl)Cl
Agent: [Na]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(C)C=CC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
Two milliliters of a solution of anhydrous tetrahydrofuran containing 709 mg (2 mmoles) of ethyl 4-bromo-6,6,6-trichloro-3,3-dimethylhexanoate was added dropwise to a suspension of 163 mg (2.4 mmoles) of sodium ethoxiae in 20 ml of anhydrous tetrahydrofuran. The mixture was stirred at room temperature for about 16 hours, poured into ice water and extracted with diethyl ether. The extract was dried over magnesium sulfate and then distilled to give 448 mg (82% yield) of ethyl 6,6,6-trichloro-3,3-dimethyl-4-hexenoate, b.p. 83°-85°/0.1 mm.
Reaction SMILES: [C:1]([CH:5]([OH:28])[C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[C:14]([C:15]([N:17]=[CH:18][N:19]=3)=[NH:16])=[N:13][C:12]2=[SiH2:21])[C@H:8]([OH:22])[C@@H:7]1[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:4])([CH3:3])[CH3:2].[CH3:29]OS(OC)(=O)=O.[H-].[Na+]>CN1CCCC1=O.CN(C=O)C.C1(C)C=CC=CC=1>[C:1]([CH:5]([OH:28])[C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[C:14]([C:15]([N:17]=[CH:18][N:19]=3)=[NH:16])=[N:13][C:12]2=[SiH2:21])[C@H:8]([O:22][CH3:29])[C@@H:7]1[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)O[C@H]1[C@@H](O)[C@H](n2c(=[SiH2])nc3c2=NC=NC3=N)O[C@@H]1C(O)C(C)(C)C
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: CO[C@@H]1[C@H](OC(C)(C)C)[C@@H](C(O)C(C)(C)C)O[C@H]1n1c(=[SiH2])nc2c1=NC=NC2=N
Temperature: -35 °C
Yield: 60 %

Procedure:
Compound (72) (35.9 g, 88.1 mmol) was dissolved in mixture of 1-methyl-2-pyrrolidinone (60 ml) and DMF (240 ml) at 80° C. The resulting solution was cooled to −35° C. and dimethylsulfate (20.9 ml, 220.4 mmol) was added. Sodium hydride (5.99 g as 60% suspension in mineral oil, 149.8 mmol) was washed with ca. 75 ml of toluene and then suspended in toluene (approximately 15 ml). The resulting suspension was added to the reaction mixture dropwise via syringe while stirring. The reaction was allowed to proceed at −35° C. until nearly all starting material was consumed (about 4 h). The reaction was quenched by careful addition of methanol (200 ml) followed by water (100 ml). The resulting suspension was stirred 30 min at −20-−30° C. The precipitate of (73) was filtered out and washed with methanol twice on filter bed and then dried in vacuo to give 28.1 g of crude (73) having about 85% of purity. Yield 60-65%.
Reaction SMILES: CO[C:3]1[C:9](=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:11][C:12]([NH2:14])=[S:13].C[O-].[Na+].C(O)(=O)C>CO>[SH:13][C:12]1[N:11]=[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=[C:9]2[N:14]=1
Reactant: NC(N)=S
Reactant: COc1cccccc1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Sc1nc2cccccc-2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
According to the method disclosed in Journal of the American Chemical Society, vol. 76, pages 3352 and 3353 (1954), 150 g of 2-methoxytropone and 84 g of thiourea were added to 255 g of a solution of 28% sodium methoxide in methanol, and stirred at room temperature for 30 minutes. Further, 600 ml of methanol was added thereto and acetic acid was added until the pH of the solution becomes around 5. Deposited crystals were filtered and washed with methanol. The obtained crystals were added to 1 l of methanol, and refluxed with heating for 30 minutes. After being allowed to cool to room temperature, the crystals were filtered and dried.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]([O:25]CC)=[O:24])[CH:21]=4)[CH:15]=3)[N:10]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>CO.O1CCCC1>[F:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]([OH:25])=[O:24])[CH:21]=4)[CH:15]=3)[N:10]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Reaction time: 2 h
Yield: 88.2 %

Procedure:
A mixture of 100 mg (0.22 mmol) of ethyl 2-(4-(3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1H-pyrazol-1-yl)acetate and 1 ml of 1 M aqueous solution of lithium hydroxide in 6 ml of methanol and 2 ml of tetrahydrofuran was stirred for 2 hours. The mixture was concentrated in vacuum and neutralized to pH 5 by careful addition of 1 N aqueous HCl. The product was collected by filtration, washed with water and dried in high vacuum to afford 82 mg (85%) of 2-(4-(3-(6-Fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1H-pyrazol-1-yl)acetic acid. ESI MS m/z 423.0 (M+1).
Reaction SMILES: [CH:1]([S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O)([CH3:3])[CH3:2].Cl.[Sn]>CO>[CH:1]([S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12])([CH3:3])[CH3:2]
Reactant: CC(C)SCc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [Sn]
Solvent: CO
Product: CC(C)SCc1ccccc1N
Yield: 45.6 %

Procedure:
11.8 g (55.6 mmol) 1-[1-(isopropylthio)methyl]-2-nitrobenzene (VII-2) in 150 ml methanol are placed in a 500 ml three-necked flask equipped with a stirrer and thermometer, mixed with 150 ml concentrated hydrochloric acid with stirring, and 17.6 g powdered tin (148.5 mmol) are added in portions at 20-40° C. Stirring of the mixture wird is continued at 40° C. for about an hour. The reaction is cooled, filtered and mixed with 1300 ml of an ice-cooled 10% sodium hydroxide solution. Then it is extracted twice with dichloromethane, dried over sodium sulfate, and the solvent is evaporated under vacuum. The crude product is purified on silica gel with 3:1 hexane/methyl t-butyl ether. 4.6 g (94.6% purity by HPLC, 43.2% theoretical yield) of 2-[1-(isopropylthio)methyl]aniline are obtained as a yellow oil [logP (pH 2.3)=1.94].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]#[N:17])[CH2:12][CH2:11]1.[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH3:30])[C:27](O)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[C:18]([O:22][C:23](=[O:24])[NH:25][C@H:26]([C:27](=[O:28])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]#[N:17])[CH2:14][CH2:15]1)[CH3:30])([CH3:19])([CH3:20])[CH3:21]
Reactant: N#C[C@H]1CC[C@H](Nc2cc(F)ccc2N)CC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1N[C@H]1CC[C@H](C#N)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of trans-4-(2-amino-5-fluorophenylamino)cyclohexanecarbonitrile (195 mg, 0.83 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (174 mg, 0.92 mmol), HOAt (125 mg, 0.92 mmol), 4-methylmorpholine (0.20 mL, 1.83 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (192 mg, 1.0 mmol) in THF (3 mL) was stirred at RT for 18 h under a nitrogen atmosphere. The reaction mixture was partitioned between EtOAc and water. The organic fraction was washed with brine, dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane) to afford the title compound as a white foam (199 mg, 60%). LCMS (Method B): RT 3.37 [M+H]+ 405.2
Reaction SMILES: B#B.[C:3]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)(=[O:8])[CH2:4][CH2:5][CH2:6][CH3:7].O1C=CN=B1.Cl>C1COCC1.CCOCC.CO>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C@@H:3]([OH:8])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCC(=O)c1ccco1
Agent: B#B
Agent: Cl
Agent: b1ncco1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: CCCC[C@H](O)c1ccco1
Temperature: 10 °C
Yield: 70 %

Procedure:
10.4 mmol (10.4 mL) of diborane (1 M solution in THF) was added dropwise in a period of 10 m at room temperature to a solution of 2-valeryl furan (2.62 g, 17.2 mmol) and 1.68 mmol (4.2 mL) of (3aR)-1,3,3-triphenyl pyrrolidino [1,2-c] [1,3,2] oxazaborole (see E. J. Corey et al. J. Am. Chem. Soc. 1987, 109, 7925-26, 0.4M solution in THF) in 25 mL THF. The reaction mixture was stirred for 20 m and was cooled to 10° C. 6 mL methanol was cautiously added and followed by adding 62 mg HCl (by weight) in ether. Stirred for 0.5 h, white solid was precipitated out. The cloudy mixture was poured into 100 mL ether and 100 mL water. The organic layer was separated, washed with saturated sodium bicarbonate, water, brine, dried and filtered. The filtrate was evaporated to an yellowish oil which was chromatographed eluting with 10 % ethyl acetate in hexane to obtain 70% of the product. [α]25D =-13°, 60% ee by Mosher' ester analysis.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:20]([C:34]([F:37])([F:36])[F:35])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:39]>C(O)C>[ClH:39].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:20]([C:34]([F:35])([F:36])[F:37])[CH:19]=1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3ccccc3)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2ccccc2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
Compound 8-1 (740 mg) was dissolved in ethanol (20 ml), concentrated hydrochloric acid (3 ml) was added, and the mixture was stirred at 80° C. for 2.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (540 mg) as a white powder.