Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]([NH:13][CH2:14][C:15]([O:17]CC)=O)=[O:12].[H-].[Na+].I[CH:23]([CH3:25])[CH3:24]>CN(C)C=O>[CH3:24][CH:23]([N:13]1[CH2:14][C:15](=[O:17])[N:10]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[C:11]1=[O:12])[CH3:25]
Reactant: CC(C)I
Reactant: CCOC(=O)CNC(=O)Nc1ccc(OC)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N2C(=O)CN(C(C)C)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 17.02 g (0.0630 mole) of N-(2-fluoro-4-methoxyphenyl-N'-ethoxycarbonylmethylurea in 50 mL of N,N-dimethylformamide was added dropwise to a suspension of 2.65 g (0.0662 mole) of sodium hydride in 30 mL of N,N-dimethylformamide during a 20 minute period. Gas evolution and a slight rise in temperature occurred during the addition. This mixture was stirred at room temperature for 45 minutes, by which time it had become a homogeneous solution. To this solution was added dropwise, over a period of 15 minutes, a solution of 21.42 g (0.126 mole) of 2-iodopropane in 10 mL of N,N-dimethylformamide. The temperature rose to 38° C. during the addition period. This reaction mixture was stirred for approximately 65 hours, then poured over ice and extracted with diethyl ether. The extract was washed twice with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure, leaving an orange oil as a residue. This oil was placed on a silica gel column and eluted sequentially with 97.5/2.5 and 95/5 mixtures of methylene chloride and ethyl acetate. After the product-containing fractions were combined and the solvents evaporated under reduced pressure, 5.85 g of 1-(1-methylethyl-3-(2-fluoro-4-methoxyphenyl)imidazolidin-2,4-dione was isolated as an orange solid, m.p. 88°-90° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([N+:28]([O-])=O)[C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=3[F:27])=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1.[Zn]>[NH2:28][C:13]1[C:14]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:12]=12
Reactant: Cc1c(Nc2ccc(I)cc2F)c([N+](=O)[O-])c2n(c1=O)CCN2Cc1ccccc1
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCN2Cc1ccccc1
Yield: 51 %

Procedure:
Following the procedure set forth in Example 1 for the preparation of I-1g, 1-benzyl-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-8-nitro-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one (280 mg, 0.001 mol) in THF (30 mL) was reacted with zinc (211 mg, 0.003 mol) and HCl (1 mL) to afford 250 mg of the crude product which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[C:23]1(B(O)O)[CH2:27][CH2:26][CH2:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>O1CCOCC1.O.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]1([C:2]2[CH:7]=[C:6]([C:8]3[N:9]=[C:10]4[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][NH:14][C:11]4=[N:12][CH:13]=3)[CH:5]=[CH:4][N:3]=2)[CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: OB(O)C1=CCCC1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3ccnc(Cl)c3)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3ccnc(C4=CCCC4)c3)nc12
Yield: 24.3 %

Procedure:
A mixture of 1-[2-(2-chloro-pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (0.060 g, 0.19 mmol), cyclopenten-1-yl boronic acid (0.032 g, 0.29 mmol), potassium carbonate (0.101 g, 0.73 mmol), and Pd(dppf)Cl2.CH2Cl2 (0.012 g, 0.015 mmol) in 3 mL of 1,4-dioxane and 0.75 mL of water was stirred at 160° C. in a microwave for 30 min. The resulting black suspension was partitioned between 30 mL of ethyl acetate and 30 mL of water, and the aqueous layer was extracted with 30 mL of ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated to a residue. Column chromatography (0->60% EtOAc/hexanes) afforded 0.016 g (25%) of 1-[2-(2-cyclopent-1-enyl-pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a pale yellow solid.
Reaction SMILES: C(C1C2N=CNC(=O)C=2NN=1)CC.[OH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([S:23]([C:26]2[CH:27]=[CH:28][C:29]([O:46][CH2:47][CH2:48]C)=[C:30]([C:32]3[NH:33][C:34](=[O:45])[C:35]4[N:40]([CH3:41])[N:39]=[C:38]([CH2:42][CH2:43][CH3:44])[C:36]=4[N:37]=3)[CH:31]=2)(=[O:25])=[O:24])[CH2:19][CH2:18]1>>[CH2:47]([O:46][C:29]1[CH:28]=[CH:27][C:26]([S:23]([N:20]2[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][OH:14])[CH2:22][CH2:21]2)(=[O:24])=[O:25])=[CH:31][C:30]=1[C:32]1[NH:33][C:34](=[O:45])[C:35]2[N:40]([CH3:41])[N:39]=[C:38]([CH2:42][CH2:43][CH3:44])[C:36]=2[N:37]=1)[CH3:48]
Reactant: CCCOc1ccc(S(=O)(=O)N2CCN(CCO)CC2)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Agent: CCCc1n[nH]c2c(=O)[nH]cnc12
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(CCO)CC4)ccc3OCC)nc12

Procedure:
1-methyl-5-[5-piperazinylsulphonyl)-2-n-propoxyphenyl]-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; and 5-{5-[4-(2-hydroxyethyl)piperazinylsulphonyl]-2-n-propoxyphenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one.
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[C:15]2[N:14]=[C:13]([NH:16][C:17]3[C:18]([CH3:26])=[N:19][C:20]([N:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=3)[N:12]([CH2:27][CH2:28][CH2:29]O)[C:11]=2[C:10]([C:31]([O:33][CH3:34])=[O:32])=[CH:9][CH:8]=1.S([O-])(=O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CN(C)C=O.C(=O)([O-])O.[Na+].C(N(CC)CC)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:31]([O:33][CH3:34])=[O:32])=[C:11]2[C:15]=1[N:14]=[C:13]1[N:16]([C:17]3[C:18]([CH3:26])=[N:19][C:20]([N:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=3)[CH2:29][CH2:28][CH2:27][N:12]21
Reactant: COC(=O)c1ccc(Cl)c2nc(Nc3ccc(N(C)C)nc3C)n(CCCO)c12
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(N(C)C)nc1C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 69.9 %

Procedure:
Methanesulfonyl chloride (0.29 mL, 3.66 mmol) was added to a stirred solution of methyl 4-chloro-2-{[6-(dimethylamino)-2-methylpyridin-3-yl]amino}-1-(3-hydroxypropyl)-1H-benzimidazole-7-carboxylate (Reference example 121, 510 mg, 1.22 mmol) and triethylamine (0.68 mL) in tetrahydrofuran (12 mL) at 0° C. The mixture was stirred at 0° C. for 90 min, and concentrated in vacuo. A mixture of the resulting mesylate, potassium carbonate (506 mg, 3.66 mmol) in N,N-dimethylformamide (12 mL) was stirred at 80° C. for 17 hr. The mixture was diluted with aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-40% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a colorless solid (341 mg, 0.853 mmol, 70% in 2 steps).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Cl.[CH:29]1[CH:34]=[C:33]2[CH:35]([OH:39])[O:36][C:37](=O)[C:32]2=[CH:31][CH:30]=1.C[O-].[Na+]>CO>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[CH:37][C:32]1[CH:31]=[CH:30][CH:29]=[CH:34][C:33]=1[C:35]([OH:39])=[O:36]
Reactant: ClCc1ccccc1Cl
Reactant: O=C1OC(O)c2ccccc21
Agent: C[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: O=C(O)c1ccccc1C=Cc1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
To 78 g (297 mmol) of triphenylphosphine in 150 ml of methanol were added dropwise with stirring 48.3 g (300 mmol) of 2-chlorobenzyl chloride, and the reaction mixture was heated under reflux for 2 hours. After the reaction mixture had been cooled down to 0° C., 46.4 g (309 mmol) of o-phthalaldehydic acid were added with stirring in the course of about 1 min. Thereafter 135 g (750 mmol) of a 30% strength solution of sodium methylate in methanol were added at 0°-10° C. with stirring in the course of 45 min and stirred in at 0°-10° C. for 3 hours, and the reaction mixture was worked up in a conventional manner to give 72 g (94%) of (E/Z)-2-[2-(2-chlorophenyl)ethenylbenzoic acid in a ratio of ~11:89 in the form of colorless crystals having a melting point of 144°-148° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([OH:18])=O)[C:9]2=[O:12])=[CH:4][CH:3]=1.CN(C(ON1N=[N:38][C:33]2[CH:34]=[CH:35][CH:36]=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CCC1.O>CN(C=O)C>[CH:33]1([NH:38][C:16](=[O:18])[C:15]2[CH:19]=[CH:20][C:21]([CH3:22])=[C:13]([N:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=4)[C:9]3=[O:12])[CH:14]=2)[CH2:34][CH2:35][CH2:36]1
Reactant: Cc1ccc(C(=O)O)cc1-n1ccc2ccc(O)cc2c1=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)NC2CCC2)cc1-n1ccc2ccc(O)cc2c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.1 %

Procedure:
3-(7-Hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzoic acid (295 mg), HATU (406 mg) and cyclobutylamine (0.43 ml) were dissolved in DMF (25 ml) and stirred at room temperature for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (magnesium sulfate) and concentrated. The residue was purified by column chromatography with ethyl acetate to give N-cyclobutyl-3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzamide as a white solid (150 mg); NMR Spectrum: (DMSOd6) 1.35 (m, 2H), 2.03 (m, 2H), 2.10 (s, 3H), 2.20 (m, 2H), 4.40 (m, 1H), 6.65 (d, 1H), 7.12 (d, 1H), 7.22 (m, 1H), 7.46 (d, 1H), 7.60 (m, 2H), 7.76 (s, 1H), 7.85 (d, 1H) 8.60 (d, 1H), 10.00 (s, 1H); Mass Spectrum: M+H+ 349.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1.[CH:19](=O)[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25].C([BH3-])#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[NH2:1][CH:2]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=[CH2:19])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]([CH3:15])([CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:17][CH:18]=1
Reactant: C=CCCCCC=O
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN)cc1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCCCCC(N)Cc1ccc(OC(C)(C)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 11.3 %

Procedure:
1.2 g of ethyl 2-[4-(2-aminoethyl)phenoxy]-2-methylpropionate [WO 92/10468, example 2, intermediate (c)] was dissolved in THF (20 mL). Hept6-enal (0.43 g) and 4A sieves (0.6 g ) were added. After 10 minutes, 0.25 g of sodium cyanoborohydride was added and the mixture stirred at room temperature for 50 minutes. The reaction mixture was poured into 5% aq. sodium carbonate and extracted with ethyl acetate. The organic extract was washed with brine, dried over MgSO4 and concentrated. Purification by flash chromatography (5-10% MeOH/CH2Cl2) gave 0.15 g of ethyl 2-[4-(2-amino-[6-heptenyl]ethyl) phenoxy]-2-methylpropionate as a light brown viscous oil. This material was dissolved in CH2Cl2 (5 mL) and 4-fluorophenylisocyanate (0.05 mL) was added. The solution was stirred at rt for 3 hours and then concentrated. Purification by flash chromatography gave 0.08 g of ethyl 2-(4-[2-(3-[4-fluorophenyl]-1-[6-heptenyl]ureido) ethyl]phenoxy)-2-methylpropionate as a yellow solid. This material was dissolved in EtOH (3 mL) and 1M aq. NaOH (1.5 mL), and the solution was heated at reflux for 30 min. The solution was concentrated, poured into 1N HCl and extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated to a yellow solid. Recrystallization fron ether/hexane gave 0.05 g of 2-(4-[2-(3-[4-fluorophenyl]-1-[6-heptenyl]ureido)ethyl]phenoxy)-2- methylpropionic acid as a white powder; m.p. 143-5 degC.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]#[N:19])=[CH:13][CH:12]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH:25]=O>>[CH3:20][O:21][C:22]1[CH:23]=[C:24](/[CH:25]=[C:17](/[C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:16][CH:15]=2)\[C:18]#[N:19])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: N#CCc1ccc(OCCCCCCCCO)cc1
Reactant: COc1ccc(C=O)cc1OC
Product: COc1ccc(/C=C(\C#N)c2ccc(OCCCCCCCCO)cc2)cc1OC
Yield: 65 %

Procedure:
(2Z)-3-(3,4-dimethoxyphenyl)-2-{4-[(8-hydroxyoctyl)oxy]phenyl}prop-2-enenitrile is prepared starting from {4-[(8-hydroxyoctyl)oxy]phenyl}acetonitrile and commercial 3,4-dimethoxybenzaldehyde according the same procedure following for example 1 in 65% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.C([Li])CCC.[Br:25]C(Cl)(Cl)C(Br)(Cl)Cl.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Br:25][C:10]1[N:5]2[N:4]=[C:3]([S:2][CH3:1])[C:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[C:6]2[CH:7]=[CH:8][CH:9]=1
Reactant: CSc1nn2ccccc2c1NC(=O)OC(C)(C)C
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1nn2c(Br)cccc2c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After dissolving tert-butyl N-[2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate (220 mg) in tetrahydrofuran (3 mL), a solution of n-butyllithium in hexane (1.6 M; 1.51 mL) was added dropwise at −78° C. under a nitrogen stream, and the mixture was stirred for 30 minutes. A solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (384 mg) in tetrahydrofuran (2 mL) was added to the reaction mixture, and stirring was continued for 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, the temperature was raised to room temperature, extraction was performed with ethyl acetate and the extract was washed with water and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and tert-butyl N-[7-bromo-2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate was obtained from the n-hexane:ethyl acetate (10:1) fraction as yellow crystals. After dissolving this in 1,2-dimethoxyethane (6 mL) and water (1 mL), 2,4-dichlorophenylboric acid (191 mg), tetrakis(triphenylphosphine)palladium (0) complex (116 mg) and barium hydroxide octahydrate (315 mg) were added and the mixture was heated and stirred at 80° C. for 4 hours under a nitrogen stream. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (160 mg) was obtained from the n-hexane:ethyl acetate (20:1) fraction as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][NH:17][C:16](=[O:20])[N:15]=3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][N:17]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:16](=[O:20])[N:15]=3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1nc(N2CC=C(c3ccc(F)cc3)CC2)nc[nH]1
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(Cn2cnc(N3CC=C(c4ccc(F)cc4)CC3)nc2=O)cc1
Yield: 81.6 %

Procedure:
4-[4-(4-Fluorophenyl)-5,6-dihydropyridin-1(2H)-yl]-1,3,5-triazin-2(1H)-one (294 mg, 1.08 mmol) synthesized in Reference Synthesis Example 342 and 1-(chloromethyl)-4-methoxybenzene (162 μL, 1.19 mmol) were used to obtain the title compound (346 mg, yield 82%) by synthesis in a similar manner to Reference Synthesis Example 16.
Reaction SMILES: [H-].[Na+].I[CH3:4].[F:5][CH:6]([F:30])[CH2:7][N:8]1[C:12]([N:13]2[CH2:19][CH2:18][CH2:17][C@@H:16]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH2:15][CH2:14]2)=[C:11]([N+:27]([O-:29])=[O:28])[CH:10]=[N:9]1.O>C1COCC1>[F:30][CH:6]([F:5])[CH2:7][N:8]1[C:12]([N:13]2[CH2:19][CH2:18][CH2:17][C@@H:16]([N:20]([CH3:4])[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH2:15][CH2:14]2)=[C:11]([N+:27]([O-:29])=[O:28])[CH:10]=[N:9]1
Reactant: CI
Reactant: O=C(N[C@@H]1CCCN(c2c([N+](=O)[O-])cnn2CC(F)F)CC1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)C(F)(F)F)[C@@H]1CCCN(c2c([N+](=O)[O-])cnn2CC(F)F)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-chloro-1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole (438 mg, 2.07 mmol), (R)—N-(azepan-4-yl)-2,2,2-trifluoroacetamide (438 mg, 2.07 mmol) and DIPEA (1 mL) in EtOH (4 mL) was heated at 155° C. in the microwave for 5 hr. The solvent was removed under reduced pressure and the residue purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give (R)—N-(1-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide as a pale orange gum (518 mg). A portion of this gum (39 mg, 0.10 mmol) in dry THF (2 mL) was treated with sodium hydride (60% in mineral oil, 5 mg, 0.12 mmol). After stirring at room temperature for 10 min, iodomethane (0.01 mL, 0.20 mmol) was added and the reaction mixture was stirred at room temperature for 2 hr. The reaction was repeated on the remaining (R)—N-(1-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide. Water (50 mL) was added carefully and the mixture was extracted with EtOAc (2×100 mL). The organic layers were combined, dried over MgSO4 and the solvent was removed under reduced pressure to give (R)—N-(1-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoro-N-methylacetamide as a pale yellow gum (518 mg). This gum (514 mg, 1.29 mmol) was dissolved in MeOH (20 mL) and treated with ammonium formate (325 mg, 6.15 mmol) and 10% palladium on carbon (50 mg). The mixture was heated at 85° C. for 2 hr. After cooling to room temperature the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was partitioned between DCM (50 mL) and water (30 mL) and the aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were passed through a phase separation cartridge and the solvent was removed under reduced pressure to afford (R)—N-(1-(4-amino-1-(2,2-difluoroethyl)-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoro-N-methylacetamide as a pale yellow gum (348 mg, 46% over three steps). 1H NMR (400 MHz, CDCl3) δ 7.13 (s, 1H), 6.19 (tq, J=55.4, 4.4 Hz, 1H), 4.65-4.15 (m, 3H), 3.40-3.10 (m, 4H), 3.10 and 2.97 (2s, 3H), 2.80 (br s, 2H), 2.10-1.70 (m, 6H).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(C)([O-])C.[K+].[F:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24]Br>C1COCC1.CN(C=O)C>[C:4]([O:3][C:1]([NH:8][CH:9]([CH2:10][O:11][CH2:24][C:23]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:22]=1[F:21])[C:12]([OH:14])=[O:13])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(COCc1ccc(F)cc1F)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a solution of N-Boc-(D)-serine (452 g, 2.2026 mol) in a mixture of THF (7 L) and DMF (3 L) at about 0° C. was added potassium tert-butoxide solution (515.8 g, 4.5963 mol). The reaction mixture was stirred at about 0° C. for about 30 min., then 2.4-difluorobenzyl bromide (456.5 g, 2.2051 mol) was added. After warming to room temperature, the reaction mixture was concentrated in vacuo to remove the THF. The reaction mixture was partitioned between 4.5 L H2O and 4.5 L IPE. The layers were saparated and the pH of the aqueous layer was adjusted with 1 N HCl to about 3. The aqueous layer was extracted twice with 4 L each of IPE. The organic solution was dried over Na2SO4, and concentrated in vacuo to yield a yellow waxy solid (518.0 g, yield: 70.9%). 1H-NMR (CDCl3) δ 1.44 (s, 9H), 0.73 (m, 1H), 3.94 (d, 1H). 4.44 (br s, 1H), 4.54 (s, 2H), 5.34 (m, 1H), 6.78 (m, 1H), 0.84 (m, 1H), 7.30 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([Mg]Br)[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23]>C1COCC1>[C:1]1([C:7]2[S:11][CH:10]=[C:9]([CH:12]([C:18]3[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:16]([O:15][CH3:14])[CH:17]=3)[OH:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1csc(-c2ccccc2)c1
Reactant: COc1cc([Mg]Br)cc(OC)c1OC
Solvent: C1CCOC1
Product: COc1cc(C(O)c2csc(-c3ccccc3)c2)cc(OC)c1OC
Reaction time: 0.5 h

Procedure:
At −78° C., to a solution of 38f (2.5 mmol) in 5 mL THF under argon protection was added a solution of LiAlH4 in THF (1 N, 1.42 mL) and stirring continued at 1 h at −20° C. The reaction mixture was placed on an ice bath and quenched by 20% H2SO4 solution, extracted with ethyl acetate and dried over MgSO4. The solvent was removed under reduced pressure and purified by column chromatography to yield 5-phenylthiophene-3-carbaldehyde (not shown) (84.8%). 1H NMR (CDCl3) δ 9.98 (s, 1H), 8.04 (d, 1H, J=1.5 Hz), 7.86 (br, 1H), 7.61-7.58 (br, 2H), 7.47-7.33 (m, 3H), 7.35-7.32 (m, 1H), 6.78 (d, 1H, J=4.0 Hz); MS (ESI) m/z 210.9 (M+Na)+. To a solution of 5-phenylthiophene-3-carbaldehyde (0.195 g, 1.04 mmoL) in 5 mL THF was added a THF solution of 3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 2.3 mL, 1.14 mmol) at 0° C. The mixture was allowed to stir for 30 min and quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 40f. (70.5%). 1H NMR (CDCl3) δ 7.55-7.52 (m, 2H), 7.40-7.35 (m, 3H), 7.30 (br, 1H), 7.20 (br, 1H), 6.72 (s, 2H), 6.01 (d, 1H, J=3.9 Hz), 3.86 (s, 6H), 3.85 (s, 3H), 2.42 (d, 1H, J=3.9 Hz); MS (ESI) m/z 339.1 (M-OH)−.
Reaction SMILES: [CH:1](=[O:3])[CH3:2].[Si](O[C@H:12]1[CH2:17][CH2:16][C@H:15]([N:18]2[C:22](=[O:23])[C:21]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]3[C:19]2=[O:28])[CH2:14][CH2:13]1)(C(C)(C)C)(C)C.[Bi](Br)(Br)Br.C([SiH](CC)CC)C>C(#N)C>[CH2:1]([O:3][C@H:12]1[CH2:13][CH2:14][C@H:15]([N:18]2[C:22](=[O:23])[C:21]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]3[C:19]2=[O:28])[CH2:16][CH2:17]1)[CH3:2]
Reactant: CC=O
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1
Agent: Br[Bi](Br)Br
Agent: CC[SiH](CC)CC
Solvent: CC#N
Product: CCO[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C

Procedure:
Acetaldehyde (10 mL; 0.17 mol) in acetonitrile (50 mL) was added over 30 minutes to a solution of trans-N-(4-tert-butyldimethylsilyloxycyclohexyl)phthalimide (D63; 50.0 g; 0.14 mol), bismuth tribromide (6.7 g; 0.015 mol) and triethylsilane (27 mL; 0.18 mol) in acetonitrile (500 mL) stirred at ice bath temperature and the mixture was allowed to warm to room temperature overnight. The mixture was filtered and the resulting grey solid and filtrate were worked up separately. The filtrate was evaporated and treated with hexane to give the title compound as a white solid (16.35 g). The grey solid was washed with dichloromethane, the dichloromethane extract was evaporated and the residue was stirred with hexane (200 mL) to give a second crop of the title compound as a white solid (17.47 g).