Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[NH:4][N:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[N:19]=[CH:18][C:17]([CH2:20][C:21]#N)=[CH:16][CH:15]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:36])[C:33](O)=[O:34])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([C@H:32]([OH:36])[C:33]([N:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[CH3:1])[CH2:21][CH2:20][C:17]2[CH:18]=[N:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=2)=[O:34])=[CH:30][CH:31]=1
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Reactant: O=C(O)C(=O)c1ccc(F)cc1
Reactant: Cc1n[nH]c2ccc(N)cc12
Product: Cc1n[nH]c2ccc(N(CCc3ccc(C(F)(F)F)nc3)C(=O)[C@@H](O)c3ccc(F)cc3)cc12

Procedure:
In analogy to example 47, 3-Methyl-1H-indazol-5-ylamine, (6-Trifluoromethyl-pyridin-3-yl)-acetonitrile & (4-fluoro-phenyl)-oxo-acetic acid were successively coupled then reduced to give after silica gel and chiral chromatography the target compound. MS(m/e): 473.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7](Cl)=[O:8].[CH3:13][NH2:14]>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([NH:14][CH3:13])=[O:8]
Reactant: O=C(Cl)/C=C/c1cccc(Br)c1
Reactant: CN
Solvent: c1ccccc1
Product: CNC(=O)/C=C/c1cccc(Br)c1

Procedure:
A solution of trans 3-bromocinnamoyl chloride (5 g) in dry benzene (100 ml) was added with stirring to an ethereal (200 ml) solution of methylamine (3 g). After the addition was complete, a slow stream of methylamine gas was bubbled through the reaction mixture at room temperature for one hour. Solvent and excess amine were removed under reduced pressure. The crude product was triturated with water, filtered, and recrystallized from ethanol-water to give trans 3-bromo-N-methylcinnamamide, m.p. 147°-147.5° C. NMR, IR, and elemental analysis were consistent with this structure.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[C:33](O)=[O:34])[CH:26]=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:33]([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:32]=2[N:23]=[CH:24][CH:25]=[CH:26]3)=[O:34])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1cccc2cccnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (4.50 mg, 1.44 mmol) in acetonitrile (30 ml) were added 8-quinolinecarboxylic acid (249 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (413 mg, 2.15 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml), and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1). Recrystallization from ethyl acetate-hexane gave the title compound (162 mg, 24%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]2[N:12]([C:13]([CH:18]3[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]3)=[N:14][N:15]=2)[C:11]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]1([CH3:38])[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Mg]Cl>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]2[N:12]([C:13]([CH:18]3[CH2:19][CH2:20][C:21]([OH:24])([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[CH3:38])[CH2:22][CH2:23]3)=[N:14][N:15]=2)[C:11]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccccc1[Mg]Cl
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2C2CCC(=O)CC2)C1
Solvent: C1CCOC1
Product: Cc1ccccc1C1(O)CCC(c2nnc3n2-c2ccc(Cl)cc2CN(C(=O)OC(C)(C)C)C3)CC1
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of 8-chloro-1-(4-oxo-cyclohexyl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester (0.2 g, 0.5 mmol) in dry tetrahydrofuran (5 ml) was added a 1M o-tolylmagnesium chloride solution in tetrahydrofuran (0.5 ml, 0.5 mmol) at room temperature. After stirring for 2 h the reaction mixture was quenched with aqueous saturated ammonium chloride solution and extracted with two portions of ethyl acetate. The combined organic layers were washed with one portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.17 g, 70%) as white solid. MS m/e: 509 ([[M+H]]+)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])#[N:2].Cl.[CH3:16][NH:17][OH:18].C(=O)([O-])[O-].[Na+].[Na+].[C:25]([C:32]([O:34][CH2:35][CH3:36])=[O:33])#[C:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(O)C.O.C(O)C>[CH2:35]([O:34][C:32]([C:25]1([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[O:18][N:17]([CH3:16])[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[S:9](=[O:11])(=[O:10])[N:12]([CH3:14])[CH3:13])=[N:2]1)=[O:33])[CH3:36]
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: CN(C)S(=O)(=O)c1ccccc1C#N
Reactant: CNO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC1(C(=O)OCC)N=C(c2ccccc2S(=O)(=O)N(C)C)N(C)O1
Temperature: 90 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
To a solution of 2-cyano-N,N-dimethyl-benzenesulfonamide (4.68 g, 22.3 mmol) in ethanol/water (1:1, 150 mL) was added N-methylhydroxylamine hydrochloride (3.72 g, 44.6 mmol) followed by sodium carbonate (2.36 g, 22.3 mmol). The resulting mixture was stirred at 90° C. for 8 h then concentrated. The residue was triturated with MeOH/CHCl3 (10%) and filtered. The solution was concentrated leaving an orange residue that was dissolved in ethanol (50 mL). Added to this solution was diethyl acetylene-dicarboxylate (3.6 mL, 22.3 mmol) and the resulting mixture stirred at room temp for 30 min. The mixture was concentrated and purified by flash chromatography (25% to 50% EtOAc/Hexanes) to give the title product as a yellow oil (5.57 g, 58% over two steps). 1HNMR (300 MHz, CDCl3) δ: 7.93–7.87 (1H, m), 7.66–7.60 (2H, m), 7.57–7.51 (1H, m), 4.39–4.22 (2H,m), 4.16 (q, 2H, J=7.20 Hz), 3.40 (1H, d, J=16.47 Hz), 3.15 (1H, d, J=16.47 Hz), 3.00 (3H, s), 2.82 (6H, s), 1.24 (6H, td, J=6.95, 1.46 Hz). LCMS calcd for C18H26N3O7S (M+H): 428.14; found: 428.10.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].CCOC(C)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:4][C:3]=1[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(O)ccc1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(OS(C)(=O)=O)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-fluoro-3-methylphenol (35.0 g, 277 mmol) in 100 mL of methylene chloride at 0° C. was added triethylamine (77 mL mL, 554 mmol), followed by methanesulfonyl chloride (32.2 mL, 416 mmol). The reaction was allowed it to warm to room temperature and stirred at room temperature for 1 hr. The solution was poured into EtOAc, washed with H2O and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting yellow solid product was used without further purification.
Reaction SMILES: [CH:1]([N:4](C(C)C)CC)(C)C.ClC(OCC)=O.[C:16]([S:19][CH:20]([CH:25]([C:30]([NH:32][C@H:33]([C:43]([NH:45][CH3:46])=[O:44])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)=[O:31])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:21][C:22]([OH:24])=O)(=[O:18])[CH3:17].CN>C1COCC1>[C:16]([S:19][CH:20]([CH2:21][C:22]([NH:4][CH3:1])=[O:24])[CH:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:30]([NH:32][C@H:33]([C:43]([NH:45][CH3:46])=[O:44])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)=[O:31])(=[O:18])[CH3:17]
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)O)SC(C)=O
Reactant: CCN(C(C)C)C(C)C
Agent: CCOC(=O)Cl
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)CC(SC(C)=O)C(CC(C)C)C(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)NC
Reaction time: 3 h

Procedure:
Diisopropylethylamine (0.13 ml, 0.7 mmol) and ethyl chloroformate (0.07 ml, 0.7 mmol) were added to a solution of 3-acetylmercapto-6-methyl-4-[[[1-(S)-[(methylamino)carbonyl]-2-(4-methoxyphenyl)ethyl]amino]carbonyl]heptanoic acid (E5, Isomer A; 300 mg, 0.66 mmol) in dry THF (10 ml), at -20° C. After 15 min a solution of methylamine (20 mg) in THF (0.8 ml) was added dropwise and the mixture was stirred in an ice bath for 3 h. The solvent was evaporated in vacuo, and a solution of the residue in dichloromethane was washed successively with water, 1 M hydrochloric acid, water, saturated sodium hydrogen carbonate and brine. The solution was dried (MgSO4) and evaporated in vacuo. Column chromatography on silica (10 g), eluting with 5% methanol/ethyl acetate gave the title compound, mp 195°-199° C.
Reaction SMILES: [ClH:1].[OH:2][C@H:3]([CH2:18][O:19][CH2:20][CH2:21][CH:22](CC)[CH2:23][CH2:24][CH3:25])[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[ClH:28].OC(COC1C=CC([Cl:53])=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.OC(COC1C=CC(C(C)(C)C)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.O[C@H](COC1C=CC=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:53].[OH:2][CH:3]([CH2:18][O:19][C:20]1[C:21]([Cl:1])=[CH:22][CH:23]=[CH:24][C:25]=1[Cl:28])[CH2:4][NH:5][C:6]([CH3:16])([CH3:17])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: CCCC(CC)CCOC[C@@H](O)CNC(C)(C)Cc1ccc(OC)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: COc1ccc(CC(C)(C)NC[C@H](O)COc2ccccc2)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2c(Cl)cccc2Cl)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 382 (M-15,1), 279 (11), 279 (9), 277 (64), 275 (100), 163 (11), 163 (5), 161 (6), 121 (33), 114 (12).
Reaction SMILES: [CH:1]1([C:4]2[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]3[C:6](=[CH:7][N:8]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.[Br:23]N1C(=O)CCC1=O>CN(C=O)C>[Br:23][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=2)[N:9]=[C:10]2[C:6]=1[CH:5]=[C:4]([CH:1]1[CH2:3][CH2:2]1)[C:12]([N+:13]([O-:15])=[O:14])=[CH:11]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-n2cc3cc(C4CC4)c([N+](=O)[O-])cc3n2)nc1
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc3cc([N+](=O)[O-])c(C4CC4)cc3c2Br)nc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of (ii) (1.08 g, 3.67 mmol) in DMF (15 mL) was added N-bromosuccinimide (780 mg, 4.40 mmol) and the resulting mixture stirred at 80° C. for 1.5 h. The reaction mixture was then cooled to RT and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with aq. saturated sodium bicarbonate (20 mL) and brine (20 mL). The organic phase was dried (MgSO4) and the volatiles removed in vacuo to give (iii) (1.37 g, >99%). ESI-MS: calculated [M+H]+ 373.0/375.0, observed [M+H]+ 373.1/375.1.
Reaction SMILES: [CH3:1][CH:2]([N:10]1[C:14]([NH2:15])=[C:13](C(O)=O)[CH:12]=[N:11]1)[CH:3](OCC)OCC.Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:3][C:2]1[N:10]2[N:11]=[CH:12][CH:13]=[C:14]2[NH:15][CH:1]=1
Reactant: CCOC(OCC)C(C)n1ncc(C(=O)O)c1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c[nH]c2ccnn12
Temperature: 25 °C
Yield: 64.6 %

Procedure:
1-(1-Methyl-2,2-diethoxyethyl)-4-carboxy-5-aminopyrazole (9.9 g) was dissolved in tetrahydrofuran (200 ml) and thereto was added 3N-hydrochloric acid (52 ml). The mixture was refluxed for 3 hours. The reaction mixture was cooled at room temperature, adjusted to pH 6 with aqueous 30% potassium carbonate and extracted with ethyl acetate (100 ml). Further the separated aqueous layer was extracted with ethyl acetate {50 ml). The organic layer was combined and dried over magnesium sulfate. The solvent was distilled off in vacuo. The residue was pulverized with isopropyl ether and the powder was collected by filtration to give 3-methyl-1H-imidazo[1,2-b]pyrazole (3.01 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[I-].[Na+].[OH-].[Na+].Cl[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]>O>[C:3]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]
Reactant: OCCCCCCCCCl
Reactant: Oc1ccccc1-c1ccccc1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCCCCCCCOc1ccccc1-c1ccccc1

Procedure:
The compound was prepared using essentially the procedure of Preparatory Example 1 with 2-hydroxy biphenyl (40 g.), water (250 g.), sodium iodide (3.5 g.) and sodium hydroxide (37.6 g. of 50% in water). This mixture was heated to 100° C. with agitation and 8-chloro-1-octanol (77.4 g.) was added. The product was recovered essentially as in Preparatory Example 1.
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[NH4+:5].[CH3:6][C:7]1[N:8]([CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)[C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11](OC3C=CC=CC=3)[C:10]=2[N:24]=1.[ClH:35]>C(O)(C)C.C(OCC)C>[ClH:35].[NH2:5][C:11]1[C:10]2[N:24]=[C:7]([CH3:6])[N:8]([CH2:25][CH2:26][NH:27][C:1](=[O:4])[CH3:2])[C:9]=2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=1
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCNC(=O)OC(C)(C)C)c2c1C
Reactant: [NH4+]
Reactant: CC(=O)[O-]
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: CC(=O)NCCn1c(C)nc2c(N)nc(C)c(C)c21
Temperature: 160 °C

Procedure:
A mixture of ammonium acetate (95 g) and tert-butyl 2-(2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)ethylcarbamate (9.5 g) was heated at 160° C. in a sealed tube for 24 hours. The reaction mixture was allowed to cool to ambient temperature and then it was partitioned between water and chloroform. The aqueous layer was made basic (pH 13) with 50% sodium hydroxide and then extracted with chloroform (10×400 mL). The combined organics were dried over magnesium sulfate and then concentrated under reduced pressure to provide a brown solid. The solid was dissolved in warm isopropanol (80 mL) and then combined with 1M hydrochloric acid in diethyl ether (23.7 mL). The resulting precipitate was isolated by filtration, washed with cold isopropanol and diethyl ether, and then dried in a vacuum oven at 80° C. overnight to provide 5.0 g of N-[2-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)ethyl]acetamide hydrochloride as a white solid, m.p.>250° C. Analysis: Calculated for: C13H19N5O.1.00 HCl: % C, 52.43; % H, 6.77; % N, 23.52; Found: % C, 52.25; % H, 6.81; % N, 23.41.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:9]=[C:8]([CH3:20])[C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][O:28][C:29]2[CH:42]=[CH:41][C:32]3[C@H:33]([CH2:36][C:37]([O:39]C)=[O:38])[CH2:34][O:35][C:31]=3[CH:30]=2)[CH:22]=1)(=O)C.CO.[OH-].[Na+].Cl>O.O1CCCC1>[OH:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:9]=[C:8]([CH3:20])[C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][O:28][C:29]2[CH:42]=[CH:41][C:32]3[C@H:33]([CH2:36][C:37]([OH:39])=[O:38])[CH2:34][O:35][C:31]=3[CH:30]=2)[CH:22]=1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OCCCS(C)(=O)=O)cc4COC(C)=O)c3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCCCS(C)(=O)=O)cc(CO)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
To a solution of methyl [(3S)-6-({2′-(acetoxymethyl)-6′-methyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetate (1.11 g, 1.86 mmol) in a mixed solvent of methanol (4 mL) and tetrahydrofuran (8 mL) was added 2 M aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was diluted with water, acidified with 1 M hydrochloric acid, and 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 (ethyl acetate:hexane=50:50-100:0) and preparative HPLC, and the obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (0.508 g, yield 51%) as colorless crystals.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].[O:10]=[CH:11][C:12]([Cl:15])([Cl:14])[Cl:13]>C(CC(C)(C)C)(C)C.CC1C=C(OC)C=C(C)C=1.C(CC(C)(C)C)(C)C.Cl[Ti](Cl)(Cl)Cl>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][O:5][CH:11]([OH:10])[C:12]([Cl:15])([Cl:14])[Cl:13])[CH3:2]
Reactant: CCCCC(CC)CO
Reactant: O=CC(Cl)(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: COc1cc(C)cc(C)c1
Solvent: CC(C)CC(C)(C)C
Product: CCCCC(CC)COC(O)C(Cl)(Cl)Cl
Temperature: -15 °C
Reaction time: 4.5 h

Procedure:
In a separate reaction vessel, the chloral 2-ethylhexyl hemiacetal was prepared from 1.05 g 2-ethyl-1-hexanol and 1.19 g (0.00807 mole) chloral substantially as described in Example 3. This material was dispersed in 1 ml of iso-octane and was added dropwise over twenty minutes to the 3,5-dimethylanisole/iso-octane/TiCl4 mixture. A sticky material precipitated, but the reaction solution was stirred at -15° C. for 4.5 hours before being with quenched with water, treated with NaOH, and worked-up substantially as described in Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][C:33]=1[N+:40]([O-:42])=[O:41].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([CH2:36][C:35]2[CH:38]=[CH:39][C:32]([Cl:31])=[C:33]([N+:40]([O-:42])=[O:41])[CH:34]=2)[CH2:19]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)c([N+](=O)[O-])c2)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (0.150 mmol), 4-chloro-3-nitrobenzaldehyde (0.45 mmol), methanol (4.5 mL), and acetic acid (0.048 mL) was added NaBH3CN (0.75 mmol) in methanol (1.50 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH. Product was eluted off using 2 N NH in CH3OH and concentrated to afford (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4-chloro-3-nitrobenzyl)pyrrolidine.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11])(=[O:3])[CH3:2].[N:12](OC(C)(C)C)=O.C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:4]1([C:1](=[O:3])[CH3:2])[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:10]2[CH:11]=[N:12]1
Reactant: CC(C)(C)ON=O
Reactant: CC(=O)Nc1cnccc1C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)n1ncc2ccncc21
Temperature: 25 °C
Yield: 6.3 %

Procedure:
To a suspension of 3-acetylamino-4-methylpyridine (301.5 mg, 2.0 mmol, 1 equiv) in toluene (3 mL) was added tert-butyl nitrite (t-BuONO) (420 μL, 3.2 mmol, 1.6 equiv), acetic anhydride (560 μL, 6.0 mmol, 3 equiv) and potassium acetate (235.2 mg, 2.4 mmol, 1.2 equiv). The resultant mixture was heated at 80° C. for 2 hours, cooled to room temperature, and diluted with ethyl acetate (200 mL). The mixture was washed with saturated sodium bicarbonate solution (50 mL), water (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide a crude residue. The residue was purified by flash chromatography (silica, 15% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give 1-pyrazolo[3,4-c]pyridin-1-yl-ethanone (20.2 mg) which was used without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19]([NH:21][C@H:22]1[CH2:26][CH2:25][N:24]([C@H:27]2[CH2:32][CH2:31][C@@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29][C@H:28]2[CH2:41][OH:42])[C:23]1=[O:43])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C:19]([NH:21][C@H:22]1[CH2:26][CH2:25][N:24]([C@H:27]2[CH2:32][CH2:31][C@@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:39])[CH3:37])[CH2:29][CH:28]2[CH:41]=[O:42])[C:23]1=[O:43])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)C(C=O)C1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 100.8 %

Procedure:
A solution of oxalyl chloride (2.0 M in dichloromethane, 370 μL, 735 μmol) in dichloromethane (1.6 mL) was stirred at −78° C. Dimethyl sulfoxide (108 μL, 1.51 mmol) was added dropwise over about 2 min, and the mixture was stirred for 35 min. A solution of tert-butyl (1R,3R,4S)-4-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-3-(hydroxymethyl)cyclohexylcarbamate (219 mg, 475 μmol, See Example 4a, Step 1) in dichloromethane (1.5 mL) was added and the solution was stirred at −78° C. for 65 min. Triethylamine (215 μL, 1.54 mmol) was added, and after 10 min the mixture was warmed to 0° C. and stirred for 2 h. The mixture was diluted with dichloromethane, washed with saturated aqueous ammonium chloride, then with water, and was dried over sodium sulfate and concentrated under vacuum to provide tert-butyl (1R,4S)-4-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-3-formylcyclohexylcarbamate as a tan glassy foam (220 mg). MS found: (M+Na)+=482.37.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[C:31]4[CH2:36][CH2:35][CH2:34][CH2:33][N:32]4[CH:37]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:38]=[N+:39]=[N-:40].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:40][N:39]=[N:38][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[C:31]4[CH2:36][CH2:35][CH2:34][CH2:33][N:32]4[CH:37]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1nc2c(C)cc(-c3cn4c(n3)CCCC4)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(-c3cn4c(n3)CCCC4)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.