Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1C=CC=N1.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1.[C:16](OCC)(=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH2:14][C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(F)cc1
Agent: c1cnoc1
Product: CCOC(=O)C(=O)CC(=O)c1ccc(F)cc1

Procedure:
In a further embodiment, an isoxazole cyclization reaction is provided in Scheme 15A. In this embodiment, 1-(4-fluorophenyl)ethanone is reacted with diethyl oxalate to provide ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate. In one embodiment, this reaction is performed in the presence of a base such as potassium tert-butoxide. In another embodiment, this reaction is performed at about room temperature for about 24 hours. The isoxazole ring is then generated by reaction of ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate with hydroxylamine hydrochloride to provide ethyl 5-(4-fluorophenyl)isoxazole-3-carboxylate. In one embodiment, this reaction is performed in at elevated temperatures. In another embodiment, this reaction is performed in ethanol for about 2 hours. Ethyl 5-(4-fluorophenyl)isoxazole-3-carboxylate is then reduced with lithium aluminum hydride to provide 5-(4-fluorophenyl)isoxazol-3-yl)methanol. In one embodiment, the reduction is performed in THF, at a temperature of about 0° C. to about room temperature overnight. 5-(4-Fluorophenyl)isoxazole-3-carbaldehyde is then formed by oxidizing (5-(4-fluorophenyl)isoxazol-3-yl)methanol. In one embodiment, the oxidation is performed using PCC. In another embodiment, the oxidation is performed in dichloromethane at about room temperature overnight. 5-(4-Fluorophenyl)isoxazole-3-carbaldehyde may then converted to a compound of Formula (I-A) using the methods described herein.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@@H:11]3[CH2:28][N:14]4[C:15](=[O:27])[CH2:16][CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[ClH:29]>CO.ClCCl.O1CCOCC1>[ClH:29].[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@@H:11]3[CH2:28][N:14]4[C:15](=[O:27])[CH2:16][CH2:17][NH:18][CH2:19][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: O=C1CCNC[C@@H]2C[C@H](Oc3cnc(C4CC4)cn3)CN12
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To tert-butyl (8S,9aS)-8-[(5-cyclopropylpyrazin-2-yl)oxy]-5-oxohexahydro-1H-pyrrolo[1,2-a][1,4]diazepine-2(3H)-carboxylate (254 mg, 0.654 mmol, Part C) in methanol/dichloromethane (1:1, 1 mL) was added 4 N HCl solution in dioxane (3 mL). The mixture was stirred at room temperature for three hours and then concentrated to give 212 mg (100% yield) of the title compound as a solid which was used without purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82 (m, 2H), 0.96 (m, 2H), 2.10 (m, 2H), 2.66 (m, 1H), 3.10 (m, 3H), 3.40 (m, 2H), 3.65 (m, 2H), 4.22 (m, 1H), 4.40 (m, 1H), 5.38 (m, 1H), 8.15 (d, J=1 Hz, 1H), 8.19 (d, J=1 Hz, 1H), 9.38 (br s, 1H), 9.50 (br s, 1H); MS (ESI) m/z 289.0 (M+H)+.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Cl:8][C:9]1[CH:16]=[C:15]([N:17]2[C:21](=[O:22])[CH2:20][C@H:19]([OH:23])[C@@H:18]2[CH3:24])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12].CI.C(O)(=O)C>C1COCC1.O>[Cl:8][C:9]1[CH:16]=[C:15]([N:17]2[C:21](=[O:22])[C@@H:20]([CH3:1])[C@H:19]([OH:23])[C@@H:18]2[CH3:24])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12]
Reactant: CC(C)NC(C)C
Reactant: C[C@H]1[C@@H](O)CC(=O)N1c1ccc(C#N)c(Cl)c1
Solvent: O
Solvent: CI
Solvent: CC(=O)O
Product: C[C@@H]1C(=O)N(c2ccc(C#N)c(Cl)c2)[C@@H](C)[C@H]1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A solution of diisopropylamine (0.150 mL) in THF (7 mL) was cooled to −78° C., and n-butyllithium-hexane solution (0.648 mL, 1.6 mol/L) was added dropwise. After the completion of the dropwise addition, the mixture was stirred at −78° C. for 1 hr. Subsequently, a solution of 2-chloro-4-[(2S,3S)-3-hydroxy-2-methyl-5-oxopyrrolidin-1-yl]benzonitrile (100 mg) in THF (2.5 mL) was added dropwise, and the mixture was further stirred at −78° C. for 30 min. Methyl iodide (0.124 mL) was added dropwise at −78° C., and the mixture was further stirred at −10° C. to −78° C. for 30 min. Acetic acid (1.0 mL) was added to the reaction mixture, and the mixture was warmed to room temperature. Water was added, and the mixture 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=10/1→1/3) to give the title compound as a colorless solid (yield: 44.4 mg, 42.0%).
Reaction SMILES: [NH:1]1[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[NH:4][CH2:3][C:2]21[CH2:13][CH2:12][CH2:11]2.Br[C:15]1[C:20]2[CH:21]=[CH:22][O:23][C:19]=2[C:18]([O:24][CH3:25])=[CH:17][CH:16]=1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[H+].[B-](F)(F)(F)F.CC([O-])(C)C.[Na+].[O-]S([O-])(=O)=O.[Mg+2]>CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O.O.C1(C)C=CC=CC=1>[CH3:25][O:24][C:18]1[C:19]2[O:23][CH:22]=[CH:21][C:20]=2[C:15]([N:4]2[C@H:5]3[C@H:10]([CH2:9][CH2:8][CH2:7][CH2:6]3)[NH:1][C:2]3([CH2:13][CH2:12][CH2:11]3)[CH2:3]2)=[CH:16][CH:17]=1
Reactant: C1CC[C@H]2NCC3(CCC3)N[C@H]2C1
Reactant: COc1ccc(Br)c2ccoc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(N2CC3(CCC3)N[C@H]3CCCC[C@H]32)c2ccoc12
Temperature: 25 °C
Yield: 32.8 %

Procedure:
A toluene (4 ml) suspension of (4a′R,8a′S)-octahydro-1′H -spiro[cyclobutane-1,2′-quinoxaline](180 mg, 0.998 mmol), 4-bromo-7-methoxybenzofuran (250 mg, 1.10 mmol), Pd(OAc)2 (11.2 mg, 0.0499 mmol), t-Bu3P.HBF4 (14.5 mg, 0.0500 mmol), and NaOt-Bu (135 mg, 1.40 mmol) was stirred for 4 hours under reflux in a nitrogen atmosphere. The reaction solution was cooled to room temperature. Then, water (0.5 mL) and AcOEt (10 mL) were added thereto, and the mixture was stirred. MgSO4 was further added thereto, and the mixture was stirred. Insoluble matter was filtered, and the residue was washed with AcOEt (5 mL×2). Then, the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (Hex-AcOEt) to obtain a colorless amorphous solid. This solid was crystallized from hexane (1 mL) to obtain (4a′R,8a′S)-4′-(7-methoxybenzofuran-4-yl)octahydro-1′H-spiro[cyclobutane-1,2′-quinoxaline](107 mg, yield: 35%) in a white powder form.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][N:17]3[C:10](=[CH:11][C:12]4[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]=43)[C:9]2=[O:22])[C:3]=1[CH:23]=[O:24].[N:25]1[N:33]2[C:28]([CH2:29][O:30][CH2:31][CH2:32]2)=[CH:27][C:26]=1[NH:34][C:35]1[C:36](=[O:51])[N:37]([CH3:50])[CH:38]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:40]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[CH3:50][N:37]1[C:36](=[O:51])[C:35]([NH:34][C:26]2[CH:27]=[C:28]3[CH2:29][O:30][CH2:31][CH2:32][N:33]3[N:25]=2)=[CH:40][C:39]([C:2]2[C:3]([CH:23]=[O:24])=[C:4]([N:8]3[CH2:19][CH2:18][N:17]4[C:10](=[CH:11][C:12]5[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]=54)[C:9]3=[O:22])[N:5]=[CH:6][CH:7]=2)=[CH:38]1
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1nccc(Cl)c1C=O)C3=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2cc3n(n2)CCOC3)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2C=O)cc(Nc2cc3n(n2)CCOC3)c1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 4-chloro-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridine-3-carbaldehyde 108a (200 mg, 0.58 mmol), 168a (433 mg, 1.16 mmol), PdCl2(dppf) (48 mg, 0.052 mmol), K3PO4 (246 mg, 1.16 mmol), sodium acetate (96 mg, 1.16 mmol), acetonitrile (10 mL), and water (0.5 mL). The system was evacuated and refilled with N2. The reaction mixture was stirred at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 168b (250 mg, 78%) as a yellow solid. MS-ESI: [M+H]+ 554.6.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[NH2:9][CH2:10][CH2:11][OH:12].CCN(C(C)C)C(C)C>C(O)CCC>[Cl:8][C:4]1[N:3]=[C:2]([NH:9][CH2:10][CH2:11][OH:12])[CH:7]=[N:6][CH:5]=1
Reactant: NCCO
Reactant: Clc1cncc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: OCCNc1cncc(Cl)n1
Temperature: 80 °C
Yield: 50 %

Procedure:
In a sealed tube, 2,6-dichloropyrazine (1 g, 6.71 mmol) was mixed with 2-aminoethanol (0.492 g, 8.05 mmol), Hunig's base (1.13 g, 8.73 mmol) in BuOH (7 mL) and the reaction mixture was heated to 80° C. over night. The mixture was concentrated in vacuo and the residue partitioned between NaHCO3 (20 mL) and EtOAc (100 mL). The organic phase was separated, washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give the title compound (0.583 g, 50%) as a light yellow foam. MS: 174.1 (M+H+).
Reaction SMILES: C(O[C:4](=[O:22])[C:5]([CH2:12][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)([CH3:11])[CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])C.[CH3:23][S:24]([NH:27][C:28]1[CH:43]=[CH:42][C:31]2[NH:32][C:33]([CH2:38][C:39](O)=[O:40])=[N:34][S:35](=[O:37])(=[O:36])[C:30]=2[CH:29]=1)(=[O:26])=[O:25].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.[H-].[Na+]>CN(C)C=O>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:13]2[CH2:12][C:5]([CH3:11])([CH2:6][CH2:7][CH:8]([CH3:9])[CH3:10])[C:4]([OH:22])=[C:38]([C:33]3[NH:32][C:31]4[CH:42]=[CH:43][C:28]([NH:27][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:29][C:30]=4[S:35](=[O:36])(=[O:37])[N:34]=3)[C:39]2=[O:40])=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)C(C)(CCC(C)C)CNCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)CCC1(C)CN(Cc2ccc(F)cc2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.6 %

Procedure:
A solution of 2-[(4-fluoro-benzylamino)-methyl]-2,5-dimethyl-hexanoic acid ethyl ester (93 mg, 0.30 mmol), (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (100 mg, 0.30 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60 mg, 0.315 mmol) in anhydrous N,N-dimethyformamide (4 mL) was treated with N-methyl morpholine (0.069 mL, 0.63 mmol). The reaction was stirred under a nitrogen environment at 25° C. for 1 h, quenched with a 1.0 M aqueous hydrochloric acid solution (50 mL), extracted with ethyl acetate (2×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting oil was dissolved in ethanol (5 mL) and treated with a 60% oil dispersion of sodium hydride (48 mg, 2.0 mmol). The reaction was heated at 60° C. under a nitrogen environment for 1.5 h. The reaction mixture was allowed to cool to 25° C., quenched with a 0.5 M aqueous hydrochloric acid solution (50 mL), extracted with ethyl acetate (2×50 mL), washed with brine (50 mL), dried with sodium sulfate, filtered, and concentrated in vacuo. The crude resin was purified by flash column chromatography (ISCO RediSep column, 0 to 100% ethyl acetate in hexanes) to afford the desired product, N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-5-methyl-5-(3-methyl-butyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}methanesulfonamide (67 mg, 38%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 0.81 (t, 6H, J=7.0 Hz), 0.87-1.04 (m, 3H), 1.14 (s, 3H), 1.23-1.56 (m, 4H), 3.06 (s, 3H), 3.15 (q, 2H, J=11.4 Hz), 4.62 (dd, 2H, J1=115.3 Hz, J2=14.7, Hz), 7.03-7.10 (m, 2H), 7.18-7.30 (m, 3H), 7.62-7.71 (m, 2H). LC-MS (ESI) calculated for C26H31FN4O6S2: 578.6, found 579.2 [M+H+].
Reaction SMILES: C(CC[O:5][P:6]([O-])([O-:8])=[O:7])#N.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C[O:23][C:24](=[O:50])[C@H:25]([CH2:48][OH:49])[NH:26][C:27](=[O:47])[CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].C1(N=C=NC2CCCCC2)CCCCC1.Cl>N1C=CC=CC=1.O>[C:27]([NH:26][C@H:25]([C:24]([OH:23])=[O:50])[CH2:48][O:49][P:6]([OH:8])([OH:7])=[O:5])(=[O:47])[CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH:34]=[CH:35][CH2:36][CH:37]=[CH:38][CH2:39][CH:40]=[CH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: N#CCCOP(=O)([O-])[O-]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)N[C@@H](CO)C(=O)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@@H](COP(=O)(O)O)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 35 %

Procedure:
A solution of pyridinium cyanoethylphosphate (2 mmol) in anhydrous pyridine (3 ml) was added to dry N-arachidonoyl-L-serine methyl ester. N,N′-Dicyclohexylcarbodiimide (413 mg, 2 mmol) was then added and the mixture was stirred at room temperature. After 20 h, the mixture was cooled to 0° C., water (0.5 ml) was added and, after stirring for 30 min at room temperature, the precipitated N,N′-dicyclohexylurea was separated by filtration. The filtrate was evaporated in vacuo and the residue obtained was fractionated by short column chromatography on silica gel. The desired phosphorylated N-arachidonoyl-L-serine methyl ester was eluted from column with chloroform-methanol (30-40:70-60, v/v). The composition of the eluates was controlled by TLC on Silica gel 60 plates (system B) using a molybdate spray for detecting the spots. The appropriate fractions were combined, evaporated to dryness in vacuo and residue was dissolved in 1 ml tetrahydrofuran. The solution obtained was added, dropwise over a period of 5 min, to a cooled (ice-bath), stirred 1.5 M NaOHaq (4 ml). After a further 25 min, the mixture was acidified with 1 N HCl to pH 2-3 and extracted with chloroform-methanol (70-60:30-40, v/v). The extract was washed with methanol-water (10:9, v/v), concentrated in vacuo and applied to a column of silica gel. The desired product was eluted from column with chloroform-methanol (30-20:70-80, v/v), the fractions containing pure substance stained on the TLC plates with molybdate spray were combined and evaporated to dryness to give 82 mg (35%) of (6): Rf 0.05-0.10 (system B); 1H-NMR (CD3SOCD3, 200 MHz) δ0.9-1.0 (t, 3H, ω-CH3); 1,3 (s, 8H, 4CH2); 2.0-2.4 (m, 6H, 2CH2CH═CH and CH2CO); 2.7-2.9 (br s, 6H, 3HC═CHCH2CH═CH); 3.9-4.0 (br s, 2H, CH2OP); 4.3-4.4 (m, 1H, NHCHCO); 5.2-5.4 (br s, 8H, 4HC═CH); 8.2-8.4 (m, 3H, NH and 2POH)
Reaction SMILES: [CH:1]1([C:7]2([CH2:15][OH:16])[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[O:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+]>ClCCl.CCOCC>[CH:1]1([C:7]2([CH:15]=[O:16])[CH2:12][O:11][C:10]([CH3:13])([CH3:14])[O:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C)OCC(CO)(C2CCCCC2)CO1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C)OCC(C=O)(C2CCCCC2)CO1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
5-Cyclohexyl-2,2-dimethyl-5-hydroxymethyl-1,3-dioxane (2.2 g.) was added to a stirred suspension of pyridinium chlorochromate (6.1 g.) and anhydrous sodium acetate (3.0 g.) in dry dichloromethane (50 ml.), at 0°, under a current of nitrogen. The mixture was stirred at room temperature for six hours. The mixture was diluted with dry ether (100 ml) and the organic solution was decanted off. The oily residue was treated with ether and the combined extracts were evaporated in vacuo. 5-Cyclohexyl-2,2-dimethyl-5-formyl-1,3-dioxane was obtained as a pale yellow oil (1.8 g.) and was used without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([CH2:13][O:14][C:15]([NH:17][C@H:18]([C:27](O)=[O:28])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Cl>O1CCCC1>[CH:7]1([CH2:13][O:14][C:15]([NH:17][C@H:18]([CH2:27][OH:28])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCC1CCCCC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: O=C(N[C@H](CO)Cc1ccc(O)cc1)OCC1CCCCC1
Yield: 33.7 %

Procedure:
In 20 ml of tetrahydrofuran, 574 mg of lithium aluminum hydride was suspended. To the suspension was added dropwise 20 ml of tetrahydrafuran solution containing 1.0 g of N-(cyclohexylmethoxycarbonyl)-tyrosine while stirring and cooling with ice. The mixture was stirred at room temperature for two hours. After addition of 5% hydrochloric acid, the mixture was concentrated in vacuo and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The residue was dissolved in chloroform and subjected to column chromatography with 10 g of silicagel to give 322 mg of N-(cyclohexylmethoxycarbonyl)-tyrosinol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[N:23]([CH:26]1[CH2:32][CH2:31][C:30]2[C:33]([F:37])=[CH:34][CH:35]=[CH:36][C:29]=2[N:28]([CH2:38][C:39]([F:42])([F:41])[F:40])[C:27]1=[O:43])=[N+:24]=[N-:25].CN(C=O)C>O.CCOC(C)=O.CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:25]=[N:24][N:23]([CH:26]3[CH2:32][CH2:31][C:30]4[C:33]([F:37])=[CH:34][CH:35]=[CH:36][C:29]=4[N:28]([CH2:38][C:39]([F:40])([F:41])[F:42])[C:27]3=[O:43])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NC1CCc2c(F)cccc2N(CC(F)(F)F)C1=O
Reactant: C#Cc1ccc(Br)cc1
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C(n2cc(-c3ccc(Br)cc3)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Yield: 75.2 %

Procedure:
1-Bromo-4-ethynylbenzene (271 mg, 1.499 mmol), cupric sulfate (65.2 mg, 0.409 mmol), sodium ascorbate (108 mg, 0.545 mmol), and 3-azido-6-fluoro-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (300 mg, 1.362 mmol) in 6.6 mL of a 1:1:1 solution of DMF:EtOH:H2O was stirred for 25 mins. The mixture was diluted with water before EtOAc was added to extract the product. The organic phase was separated and washed with water (2×) and brine (1×) before being dried with Na2SO4 and evaporated to afford an oil. This material was chromatographed on silica (0-80% EtOAc in hexanes) to yield 3-[4-(4-bromophenyl)-1H-1,2,3-triazol-1-yl]-6-fluoro-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (495.1 mg) as a solid.
Reaction SMILES: C([N:4]([C@@H:34]([CH3:39])[C:35]([F:38])([F:37])[F:36])[S:5]([C:8]1[CH:9]=[N:10][C:11]([C:14]2[N:15]([C:28]3[N:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C:16]3[C:21]([C:22]=2[C:23]#[N:24])=[CH:20][CH:19]=[C:18]([CH:25]2[CH2:27][CH2:26]2)[CH:17]=3)=[CH:12][CH:13]=1)(=[O:7])=[O:6])C=C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(Cl)Cl>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:23]([C:22]1[C:21]2[C:16](=[CH:17][C:18]([CH:25]3[CH2:26][CH2:27]3)=[CH:19][CH:20]=2)[N:15]([C:28]2[N:29]=[CH:30][CH:31]=[CH:32][N:33]=2)[C:14]=1[C:11]1[N:10]=[CH:9][C:8]([S:5]([NH:4][C@@H:34]([CH3:39])[C:35]([F:38])([F:37])[F:36])(=[O:7])=[O:6])=[CH:13][CH:12]=1)#[N:24]
Reactant: C=CCN([C@@H](C)C(F)(F)F)S(=O)(=O)c1ccc(-c2c(C#N)c3ccc(C4CC4)cc3n2-c2ncccn2)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@H](NS(=O)(=O)c1ccc(-c2c(C#N)c3ccc(C4CC4)cc3n2-c2ncccn2)nc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
To a solution of (S)-N-allyl-6-(3-cyano-6-cyclopropyl-1-(pyrimidin-2-yl)-1H-indol-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamide (70 mg, 0.13 mmol) and PdCl2(dppf) (10 mg, 0.013 mmol) in THF (1 mL) was added NaBH(AcO)3 (40 mg, 0.19 mmol). The mixture was stirred at room temperature for 16 hrs and CH2Cl2 (20 mL) was added. The mixture was washed with sat. aq. NH4C1 (20 mL), concentrated and purified on silica gel eluting with 0 to 10% ethyl acetate in CH2Cl2 to provide (S)-6-(3-cyano-6-cyclopropyl-1-(pyrimidin-2-yl)-1H-indol-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamide (54 mg, 83%). Melting point: 181-184° C.; MS m/z 513.2 M+H+; 1H NMR (500 MHz, CDCl3): δ8.28 (1H, s), 8.72 (1H, d, J=2.0 Hz), 8.60 (2H, d, J=9.0 Hz), 8.19 (1H, d, J=2.5 Hz), 8.18 (1H, d, J=2.0 Hz), 8.02 (1H, d, J=9.0 Hz), 7.76 (1H, s), 7.65 (1H, d, J=8.0 Hz), 7.21-7.20 (1H, m), 7.05 (1H, d, J=9.0 Hz), 5.50 (1H, s), 4.02-3.98 (1H, m), 2.02-1.96 (1H, m), 1.31 (3H, d, J=6.0 Hz), 0.98-0.96 (2H, m), 0.75-0.72 (2H, m).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=2[OH:25])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH2:26]([C:28]([CH3:30])=O)[CH3:27]>>[C:7]([O:11][C:12]([N:14]1[CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:30][C:28]3[CH:9]=[CH:7][CH:8]=[CH:27][CH:26]=3)=[CH:20][C:19]=2[O:25][CH2:16][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:17]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CCC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(O)cc2O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)C1

Procedure:
In a 25 ml round-bottomed flask, 1.35 g of potassium carbonate are added in small portions to a solution of 0.86 g of 3-(2,4-dihydroxyphenyl)azetidine-1-carboxylic acid tert-butyl ester (Example 1) in 9 ml of methyl ethyl ketone.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])=[N:8][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C.O>[N:15]1[CH:16]=[CH:17][C:12]([C:9]2[N:8]=[C:7]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cnc(-c2ccncc2)nc1Oc1ccccc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1Oc1nc(-c2ccncc2)ncc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of 0.70 g (2.08 mmol) 2-pyridin-4-yl-4-o-tolyloxy-pyrimidine-5-carboxylic acid ethyl ester in 20 ml ethanol a solution of 0.12 g (3.12 mmol) sodiumhydroxide in 10 ml water was added and the resulting mixture was stirred 2 h at RT. The pH of the solution was adjusted to 3 with 25% HCl. The mixture was extracted twice with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and evaporated. The resulting solid was triturated twice with 10 ml ethanol, filtered off and dried to give 0.60 g (94%) 2-pyridin-4-yl-4-o-tolyloxy-pyrimidine-5-carboxylic acid as a colorless solid, MS (EI): 307.1 (M+).