Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:5]1[N:10]=[C:9]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2S(C)(=O)=O)=[O:12])[C:8]([OH:26])=[C:7]([OH:27])[N:6]=1)([CH3:4])[CH3:3].[CH2:28]([O:35][CH2:36][CH2:37][CH:38]=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([BH3-])#N.[Na+]>>[CH2:28]([O:35][CH2:36][CH2:37][CH2:38][NH:1][C:2]([C:5]1[N:10]=[C:9]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:12])[C:8]([OH:26])=[C:7]([OH:27])[N:6]=1)([CH3:4])[CH3:3])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(N)c1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2S(C)(=O)=O)n1
Reactant: O=CCCOCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)(NCCCOCc1ccccc1)c1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A methanolic solution of 2-(1-amino-1-methylethyl)-N-(4-fluorobenzyl)-5,6-dihydroxypyrimidine-4-carboxamide (prepared as described in WO2003035076 A1) was treated with 3-(benzyloxy)propanal (1.5 eq.) and sodium cyanoborohydride (1.5 eq.). The mixture was stirred at room temperature overnight, solution was applied on a cation exchange resin. The resin was washed with methanol and desired product was eluted with 2 N ammonia solution in methanol. Evaporation of appropriate fractions followed by trituration with Et2O gave intermediate 2-(1-{[3-(benzyloxy)propyl]amino}-1-methylethyl)-N-(4-fluorobenzyl)-5,6-dihydroxypyrimidine-4-carboxamide. MS (ES) C25H29FN4O4 requires 468. Found: 469 (M+H+). The crude organic product was taken in methanol, treated with 1 eq. of 6N HCl and stirred under hydrogen atmosphere in the presence of catalytic amount of 10% palladium on charcoal. After overnight stirring, mixture was filtered through celite, filtrate was concentrated under reduced pressure and purified by cation exchange resin. The resin was washed with methanol and desired product was eluted with 2 N ammonia solution in methanol. Evaporation of appropriate fractions followed by trituration with Et2O gave title compound as a pink solid. MS (ES) C18H23FN4O4 requires 378. Found: 379 (M+H+).
Reaction SMILES: [C:1]([N:5]1[C:9]([Cl:10])=[C:8]([CH:11]=[O:12])[C:7]([C:13]([F:16])([F:15])[F:14])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O.C(OCC)(=O)C>CO>[C:1]([N:5]1[C:9]([Cl:10])=[C:8]([CH2:11][OH:12])[C:7]([C:13]([F:14])([F:16])[F:15])=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1nc(C(F)(F)F)c(C=O)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)n1nc(C(F)(F)F)c(CO)c1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
A solution of 39.9 g (156.9 mmoles) of 1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 300 ml of methanol was cooled to 0° C. Thereto was gradually added 6.5 g (172.6 mmoles) of sodium borohydride. The mixture was stirred at room temperature for 3 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water and extraction with ethyl acetate was conducted. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein, to obtain 37.7 g (yield: 93.6%) of (1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[NH:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:2]1.[Na].Cl.[CH2:19]([N:21]([CH2:26][CH3:27])[CH2:22][CH2:23][CH2:24]Cl)[CH3:20]>CN(C=O)C.C(O)C>[CH2:19]([N:21]([CH2:26][CH3:27])[CH2:22][CH2:23][CH2:24][N:12]1[C:11](=[O:16])[CH:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[NH:14][C:13]1=[O:15])[CH3:20]
Reactant: CCN(CC)CCCCl
Reactant: O=C1NC(=O)C(c2c[nH]c3ccccc23)N1
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCN(CC)CCCN1C(=O)NC(c2c[nH]c3ccccc23)C1=O
Reaction time: 18 h

Procedure:
A solution of 5-(indol-3-yl)hydantoin (5.2 g, 0.024 mole) in 100 ml of DMF was added to a solution of sodium (1.1 g) in 100 ml of anhydrous C2H5OH. The solution was warmed warmed 3-diethylaminopropyl chloride hydrochloride (4.5 g, 0.024 mole) was added and the mixture was heated to reflux with stirring for 18 hours, filtered and diluted with H2O. The crude free base (2.5 g) and oxalic acid (1.5 g) was dissolved in methanol and diluted with ethyl acetate. The solid was collected and dried, yield 1.0 g, mp 231°-2°.
Reaction SMILES: [CH3:1][C:2]([NH2:15])([CH3:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1.ClC(Cl)(Cl)C1O[N:19]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C(Cl)Cl>[CH3:14][C:2]([NH:15][NH:19][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([CH3:1])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:8][CH:9]=1
Reactant: CC(C)(N)Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1OC1C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(Cc1ccc(C(F)(F)F)cc1)NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4.2 g of 2-methyl-1-(4-(trifluoromethyl)phenyl)propan-2-amine was dissolved in 30 mL of methylene chloride and mixed with 5.6 g (21 mmol) of separately prepared t-butyl 3-(trichloromethyl)-1,2-oxaziridine-2-carboxylate under cooling with ice. The reaction solution was stirred at room temperature for 30 minutes, washed with 10% aqueous citric acid, with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride successively and dried over anhydrous sodium sulfate, and methylene chloride was removed under reduced pressure. The resulting residue was purified by intermediate pressure silica gel column chromatography (silica gel 100 g, ethyl acetate:hexane) to give 1.38 g of the desired product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8].[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15])([O-:11])=[O:10].N1C=CC=CC=1>O1CCCC1>[Cl:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:1][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1cnccc1Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1cnccc1Cl)c1ccccc1[N+](=O)[O-]

Procedure:
A solution of 3-amino-4-chloropyridine (5 g, 39 mmol), 2-nitrobenzoyl chloride (5.1 mL, 39 mmol) and pyridine (11 mL) in tetrahydrofuran (50 mL) was stirred for 20 hours. The reaction mixture was partitioned between water (200 mL) and dichloromethane (600 mL). The phases were separated and the organic phase was washed with water (150 mL) then brine (150 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 10% ethyl acetate in dichloromethane). The N-(4-chloropyridin-3-yl)-2-nitrobenzamide was obtained as a brown solid (2.0 g). LCMS [M+H]: 279.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:36].[NH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41].C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[CH:28]=[CH:29][C:30]=3[CH3:31])[C:13]=2[CH2:12][NH:11][C:10]1=[O:36]
Reactant: NCCC(=O)O
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)(=O)=O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCNC(=O)c1ccc(C)c(-c2nc(NCCC(=O)O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Temperature: 100 °C
Yield: 42.9 %

Procedure:
To 3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (100 mg, 0.2 mmol) in DMF (1 mL) was added β-alanine (35.6 mg, 0.4 mmol) and triethylamine (56.2 uL, 0.4 mmol). The mixture was heated with microwave at 100° C. for 2 hrs. The mixture was separated by HPLC to afford the title compound (45 mg, 43%). LC-MS m/z 525 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20](C(OC)=O)[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)OC(=O)Cl
Reactant: COC(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Product: CC(C)OC(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 42 %

Procedure:
According to the procedure for compound 476 using isopropyl chloroformate (20 mg, 0.21 mmol) afforded 11.3 mg (42% yield) of 477, as a trifluoroacetic acid salt after preparatory HPLC purification.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]2=[O:21])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[F:23][C:24]([F:34])([F:35])[C:25]1[CH:26]=[C:27]([NH:31][C:32]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][C:10]([N:8]3[CH2:7][CH2:6][C:3]4([CH2:5][CH2:4]4)[C@H:2]([OH:1])[CH2:9]3)=[O:22])[C:15](=[O:21])[C@@H:16]2[CH3:20])=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: C[C@@H]1NCCN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Product: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1cccc(C(F)(F)F)c1
Yield: 24 %

Procedure:
In analogy to the procedure described in Example 25, (S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (intermediate 13) and 3-(trifluoromethyl)phenyl isocyanate gave the titled compound in 24% yield as white foam. MS: 497.2 (MH+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[CH:12]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[N+:34]([C:36]([CH3:39])([CH3:38])[CH3:37])#[C-:35]>CO>[C:36]([NH:34][C:35]1[N:7]2[CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=[CH:5][C:6]2=[N:9][C:12]=1[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18])([CH3:39])([CH3:38])[CH3:37]
Reactant: N#Cc1cccc(C=O)c1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: [C-]#[N+]C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)(C)Nc1c(-c2cccc(C#N)c2)nc2ccc(C(F)(F)F)cn12
Reaction time: 0.33 h
Yield: 27.2 %

Procedure:
5-(trifluoromethyl)pyridin-2-amine (200 mg, 1.23 mmol, Eq: 1.00), 3-formylbenzonitrile (170 mg, 1.3 mmol, Eq: 1.05) and p-toluenesulfonic acid monohydrate (70.4 mg, 370 μmol, Eq: 0.3) were dissolved in MeOH (2.00 mL) and the intensive yellow solution was stirred for 20 min. To this yellow solution was added dropwise 2-isocyano-2-methylpropane (103 mg, 140 μL, 1.23 mmol, Eq: 1.00) and the corresponding yellow solution was stirred for 1 h whereupon a white precipitate was formed. The precipitate was filtered off, washed with MeOH (4 mL) and dried under vacuum to give the product as an off-white solid (120 mg, 27.1%). MS: 359.2 [M+H]+; 1H-NMR (D6-DMSO): δ 8.91 (s, 1H), 8.64 (s, 1H), 8.54 (d, 1H), 7.81 (d, 1H), 7.74 (d, 1H), 7.68 (t, 1H), 7.48 (dd, 1H), 5.03 (s, 1H), 1.03 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1.[C:12](OC(C)=C)(=[O:14])[CH3:13]>C(OCC)(=O)C>[C:12]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH2:9]1)(=[O:14])[CH3:13]
Reactant: C=C(C)OC(C)=O
Reactant: Nc1ccc2c(c1)CNCC2
Solvent: CCOC(C)=O
Product: CC(=O)N1CCc2ccc(N)cc2C1

Procedure:
A mixture of 2.5 g. (16.8 mmol) 7-amino-1,2,3,4-tetrahydroisoquinoline, 30 ml. ethyl acetate and 2 ml. isopropenyl acetate was refluxed for approximately 16 hours and was then concentrated to dryness at reduced pressure. The residue was then recrystallized from a mixture of ethyl acetate and petroleum ether to afford 2-acetyl-7-amino-1,2,3,4-tetrahydroisoquinoline with a melting point of 98°-100° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]#[C:10][C:11]([O:13][CH3:14])=[O:12].[N-:15]=[N+:16]=[N-:17].[Na+].I[CH3:20]>O.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]([CH3:20])[N:16]=[N:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CI
Reactant: COC(=O)C#Cc1ccccc1OC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nnn(C)c1-c1ccccc1OC
Temperature: 100 °C
Yield: 54.9 %

Procedure:
A mixture of methyl 3-(2-methoxyphenyl)propiolate (3, 932 mg, 4.90 mmol), sodium azide (478 mg, 7.35 mmol), and iodomethane (0.458 ml, 7.35 mmol) in Water (7 ml) and DMF (3 ml) was heated to 100° C. in a Microwave reactor for 6 hrs. Purified by Prep-HPLC (Varian, 15-90B in min., B=90% MeOH/10% H2O) to afford methyl 5-(2-methoxyphenyl)-1-methyl-1H-1,2,3-triazole-4-carboxylate (701 mg, 2.69 mmol, 55.0% yield), 1H-NMR (500 MHz, CD3OD), δ: 7.52-7.56 (m, 1H), 7.30 (dd, 1H), 7.12, (td, 1H), 7.06, (d, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.82 (s, 3H). and methyl 4-(2-methoxyphenyl)-1-methyl-1H-1,2,3-triazole-5-carboxylate (185 mg, 0.711 mmol, 14.51% yield), 1H-NMR (500 MHz, CD3OD), δ: 7.49-7.46 (m, 2H), 7.10-7.07 (m, 2H), 4.32 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H).
Reaction SMILES: Cl.O1CCOCC1.C(OC(=O)[NH:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25]([N:27]1[CH2:41][C:30]2=[C:31]3[N:36]([N:37]=[C:29]2[CH2:28]1)[C:35]([CH3:38])=[C:34]([Cl:39])[C:33]([CH3:40])=[N:32]3)=[O:26])(C)(C)C>C(Cl)Cl>[ClH:39].[NH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25]([N:27]1[CH2:41][C:30]2=[C:31]3[N:36]([N:37]=[C:29]2[CH2:28]1)[C:35]([CH3:38])=[C:34]([Cl:39])[C:33]([CH3:40])=[N:32]3)=[O:26]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1OCCNC(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1OCCN)C3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 181.7 %

Procedure:
A 4M solution of HCl in 1,4-dioxane (1.67 mL; 6.7 mmol; 15 eq.) was added to a solution of Example 174 (225 mg; 0.45 mmol; 1 eq.) in DCM (10 mL) and the reaction mixture was stirred at room temperature for 15 minutes then concentrated in vacuo to afford the title compound (180 mg, 92%) as a yellow solid. 1H NMR (DMSO-d6) δ 7.92 (br s, 3H), 7.44 (ddd, J=8.4, 6.8, 4.3 Hz, 1H), 7.18 (dd, J=11.3, 2.4 Hz, 1H), 6.95 (td, J=8.4, 2.3 Hz, 1H), 4.85 (d, J=8.6 Hz, 2H), 4.59 (d, J=14.9 Hz, 2H), 4.32-4.26 (m, 2H), 3.15 (t, J=5.0 Hz, 2H), 2.86 (s, 1.6H), 2.82 (s, 1.4H), 2.62 (s, 1.4H), 2.56 (s, 1.6H). HPLC (max plot) 99.4%, Rt 2.69 min. UPLC/MS: (MS+) 404.3 ([M+H]+).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24](O)=[O:25])[CH2:9]2)=[O:7])[CH2:2]1.O[N:28]=[C:29]([NH2:34])[CH2:30][CH2:31][O:32][CH3:33]>>[CH3:33][O:32][CH2:31][CH2:30][C:29]1[N:34]=[C:24]([CH:10]2[CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=3)[CH2:13][N:8]([C:6]([N:3]3[CH2:4][CH2:5][S:1][CH2:2]3)=[O:7])[CH2:9]2)[O:25][N:28]=1
Reactant: COCCC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCSC2)C1
Product: COCCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCSC3)C2)n1
Yield: 12.5 %

Procedure:
250 mg (0.644 mmol) of 1-(1,3-thiazolidin-3-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 102A) and 112 mg (0.708 mmol, 75% pure) of N′-hydroxy-3-methoxypropanimidamide (Example 64A) were reacted according to the General Method 1. Enantiomer separation of the racemate according to Method 16D gave 35.0 mg of the title compound from Example 317 and 38.0 mg of the title compound from Example 318 (24% of theory).
Reaction SMILES: [C:1]([Si:5]([CH3:28])([CH3:27])[O:6][CH2:7][CH2:8][C@H:9]([N:13]1[CH2:17][C:16]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:15][C:14]1=[O:26])[C:10](O)=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH3:29][C:30]1([CH3:42])[O:34][C@H:33]([CH2:35][N:36]2[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]2)[CH2:32][O:31]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[C:1]([Si:5]([CH3:27])([CH3:28])[O:6][CH2:7][CH2:8][C@H:9]([N:13]1[CH2:17][C:16]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:15][C:14]1=[O:26])[C:10]([NH:41][C:38]1[CH:39]=[CH:40][N:36]([CH2:35][C@@H:33]2[CH2:32][O:31][C:30]([CH3:42])([CH3:29])[O:34]2)[N:37]=1)=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H](C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)[C@H](CCO[Si](C)(C)C(C)(C)C)N3CC(Oc4ccccc4Cl)=CC3=O)n2)O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.1 %

Procedure:
In a round bottom flask under argon was placed (S)-4-(t-butyl-dimethyl-silanyloxy)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-butyric acid (190 mg, 0.45 mmol) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 105 mg, 0.54 mmol) in N,N-dimethylformamide (3 mL). To this mixture was added N,N-diisopropyethylamine (220 μL, 1.34 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (295 mg, 0.57 mmol) and stirred for 5 h at 25° C. After this time, the mixture was diluted with ethyl acetate (25 mL) and washed with a saturated aqueous solution of ammonium chloride (25 mL), saturated aqueous solution of sodium bicarbonate (25 mL) and saturated aqueous sodium chloride solution (25 mL) dried over sodium sulfate, and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (Aspire 40 g column, 80% ethyl acetate/hexanes) afforded (S)-4-(t-butyl-dimethyl-silanyloxy)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-butyramide (131 mg, 49%) as a white foam: HR-ES-MS m/z calculated for C29H41N4O6ClSi [M+H]+ 605.2557, observed 605.2559.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([CH3:40])[C:34]=1[S:41](Cl)(=[O:43])=[O:42]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:41]([C:34]4[C:35]([CH3:40])=[CH:36][C:37]([Cl:39])=[CH:38][C:33]=4[Cl:32])(=[O:43])=[O:42])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4c(C)cc(Cl)cc4Cl)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2,4-dichloro-6-methyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=644.6)=85%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)(O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCCl>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:11][CH:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:19][CH:20]=2)[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2ccc(CN3CCCC3)cc2)CC(COCc2ccccc2)C1
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(COCC2CC(c3ccc(CN4CCCC4)cc3)C2)cc1
Temperature: 25 °C

Procedure:
To a stirring solution of 3-benzyloxymethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutanol (1.0 g, 2.8 mmol) in 10 mL of 1,2-dichlorethane was added triethyl silane (4.5 mL, 28.5 mmol) followed by the addition of trifluoroacetic acid (4.4 mL, 57.0 mmol). The reaction was then heated to 75 C (oil bath). After 1 hour the reaction was cooled to room temperature and then concentrated under reduced pressure. The crude material was taken up in EtOAc and washed with an aqueous solution of 1M NaOH. The layer were separated and the organic layer was dried over magnesium sulfate, filtered through a fritted funnel and concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography using a 45 g ISCO column, eluting with a gradient of 2% MeOH/CH2Cl2 w/0.1% NH4OH, through 10% MeOH/CH2Cl2 w/0.1% NH4OH. The product containing fractions were collected and concentrated to give the title compound (yield not determined due to presence of TFA) as a colorless oil and a 1:1 mixture of cis:trans isomers. Further purification of this material is not required.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12]([C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:24]=1[OH:25])[C:19](Cl)=[O:20])([CH3:15])([CH3:14])[CH3:13]>COCCOC>[C:7]([C:6]1[CH:10]=[C:2]([NH:1][C:19](=[O:20])[C:18]2[CH:22]=[C:23]([C:26]([CH3:27])([CH3:28])[CH3:29])[C:24]([OH:25])=[C:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:17]=2)[CH:3]=[CH:4][C:5]=1[Cl:11])([OH:9])=[O:8]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Solvent: COCCOC
Product: CC(C)(C)c1cc(C(=O)Nc2ccc(Cl)c(C(=O)O)c2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 34.7 %

Procedure:
A suspension of 6.90 g (0.04 mole) of 5-amino-2-chlorobenzoic acid in 100 ml of 1,2-dimethoxyethane was mixed with a solution of 5.08g (0.02 mole) of 3,5-di-t-butyl-4-hydroxybenzoyl chloride in 100 ml of 1,2-dimethoxyethane, and the mixture was stirred at 25° C. for about 72 hours. The reaction mixture was heated gently for 30 minutes and then allowed to cool before being filtered to remove the hydrochloride salt of the excess starting amine. The filtrate was concentrated under vacuum and then diluted with water. The resulting precipitate was collected, and was then recrystallized twice from a mixture of ethanol and water to give 2.8g of off-white solid N-(3-carboxy-4-chlorophenyl)-3,5-di-t-butyl-4-hydroxybenzamide, m.p. 265°-267° C. Analysis: Calculated for C22H26NO4Cl: %C, 65.4; %H, 6.5; %N, 3.4; Found: %C, 65.8; %H, 6.6; %N, 3.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=O)[CH3:16].C([O-])(=O)C.[NH4+].C([BH3-])#[N:24].[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([NH2:24])[CH3:16]
Reactant: CC(=O)c1ccccc1-c1ccc(F)cc1F
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)c1ccccc1-c1ccc(F)cc1F
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1-(2′,4′-difluoro-1,1′-biphenyl-2-yl)ethanone (3.67 g, 15.8 mmol) in anhydrous methanol (200 mL) was added solid ammonium acetate (12.2 g, 158 mmol). The reaction mixture was heated at 60° C. for one hour, followed by the addition of a methanolic solution of sodium cyanoborohydride (5 mL, 1.99 g, 31.6 mmol). After 16 hours, the methanol was removed in vacuo and aqueous ammonium hydroxide was added. The aqueous phase was extracted with diethyl ether (3×200 mL) until the amine was no longer present in the aqueous phase. The combined organic phase was washed with 2 N aqueous hydrochloric acid (3×100 mL) and the aqueous phases combined. The solid formed during the acid wash was determined to be the dialkyated amine and was segregated from the aqueous phase. Aqueous sodium hydroxide was added to the acidic aqueous phase until the solution was neutralized to pH 8 to 9. The basic aqueous phase was extracted with diethyl ether until the primary amine was no longer detected in the aqueous phase. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford a clear oil that was used without further purification;