Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.FC(F)(F)S(O[Si:22]([CH3:25])([CH3:24])[CH3:23])(=O)=O>C1(C)C=CC=CC=1>[CH3:23][Si:22]([N:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[Si:22]([CH3:25])([CH3:24])[CH3:23])([CH3:25])[CH3:24]
Reactant: CCOC(=O)CN
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN([Si](C)(C)C)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 19 h

Procedure:
About 6.02 g of ethyl glycinate hydrochloride, 14.39 g of triethylamine, and 10 ml of toluene were mixed in a round-bottom reaction flask cooled with an ice bath. To this mixture was added, in a dropwise fashion, a solution of 21.1 g of trimethylsilyl trifluoromethanesulfonate in 50 ml of toluene. The resulting mixture was stirred at room temperature for 19 hours to give a biphasic mixture. The top layer was transferred to another flask, and the bottom layer was extracted with 40 ml of toluene. The combined toluene solution was evaporated under vacuum. The residue was extracted with 100 ml of hexane, and the hexane layer was evaporated under vacuum, yielding ethyl [bis(trimethylsilyl)amino]acetate, also known as ethyl N,N-bis(trimethylsilyl)glycinate (BTMSEG), as a colorless liquid (9.23 g, 87% yield). The 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 3.89 (quartet, 2 H, OCH2 protons), 3.51 (singlet, 2 H, NCH2 protons), 0.90 (triplet, 3 H, CH3 protons), 0.14 (singlet, 18H, Si—CH3 protons). From the 1H NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH3:13])=[C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]2=[O:20])[N:10]=[N:9]1.[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:21]([NH:25][C:26]([N:17]1[CH2:18][CH2:19][N:14]([C:11]2[N:10]=[N:9][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:12]=2[CH3:13])[C:15](=[O:20])[CH2:16]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1c(N2CCNCC2=O)nnn1-c1ccccc1Cl
Reactant: CC(C)(C)N=C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1c(N2CCN(C(=O)NC(C)(C)C)CC2=O)nnn1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a nitrogen atmosphere, 4-[1-(2-chlorophenyl)-5-methyl-1H-[1,2,3]triazol-4-yl]-3-oxopiperazine prepared in 1) of Example 51 was dissolved in 1 ml of chloroform and 0.05 ml of tert-butyl isocyanate and 0.1 ml of triethylamine were added thereto followed by stirring at room temperature for 2 hours. After the solvent was evaporated in vacuo, the resulting residue was purified by a preparative thin-layer silica gel chromatography (chloroform:methanol=9:1) to give 5 mg of the title compound as a white solid.
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:20])=[C:5]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1)=O.[N+:21]([CH3:24])([O-:23])=[O:22].C([O-])(=O)C.[NH4+].C(O)(=O)C>>[CH3:20][C:4]1[C:3](/[CH:1]=[CH:24]/[N+:21]([O-:23])=[O:22])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[N+](=O)[O-]
Reactant: Cc1c(C=O)cccc1NC(=O)OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1c(/C=C/[N+](=O)[O-])cccc1NC(=O)OCc1ccccc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
A mixture of benzyl 3-formyl-2-methylphenylcarbamate (4.968 g, 18.45 mmol), nitromethane (2.478 mL, 46.1 mmol), and ammonium acetate (3.56 g, 46.1 mmol) in acetic acid (70 mL, 1223 mmol) was heated at 90° C. for 4.5 hr. The acetic acid was removed under vacuum. To the residue was added water (100 mL), and the mixture was stirred at room temperature for 30 min. The insoluble material was collected with suction filtration. The filter cake was mixed with water (100 mL) and the aqueous mixture was adjusted to pH 9 with saturated NaHCO3 solution and stirred at room temperature for 30 min. The insoluble product (4.13 g, 88% purity, 13.22 mmol, 71.7% yield) was collected as a yellow solid with suction filtration and dried over Drierite under vacuum.
Reaction SMILES: [OH-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:11]=[CH:12][C:13](=[CH2:15])[CH3:14].[BH4-].[Na+]>O>[CH2:3]([O:10][CH2:14][CH:13]([CH3:15])[CH2:12][OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=C(C)C=O
Reactant: OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(CO)COCc1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.59 g. of sodium hydroxide and 1.6 ml. of water in 402 ml. (420 g; 3.89 moles) of benzyl alcohol was stirred and cooled to -10° C. while 100 ml. (83.7 g.; 1.19 moles) of freshly distilled methacrolein were added dropwise keeping the temperature between -10° C. and -5° C. After the reaction mixture had stirred for 0.5 hr. at -10° C., a solution of 44.9 g. (1.19 moles) of sodium borohydride in 180 ml. of water was added dropwise over 1.75 hr. keeping the temperature below 5° C. Stirring was continued for an additional hour during which time the reaction mixture was allowed to warm to room temperature. The resulting mixture was poured into ice-water and the organic materials were extracted several times with ether. The ether extracts were worked up by first combining the extracts washing with saturated brine and drying over anhydrous magnesium sulfate. After filtration and removal of the solvents in vacuo, the residue was carefully fractionated, giving, after removal of low boiling materials, 39.6 g. of rac. 3-benzyloxy-2-methyl-1-propanol as a colorless liquid, b.p. 91°-98° C. (0.5 mm Hg.).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[C:15]([C:26]([NH:28][CH2:29][CH2:30][OH:31])=[O:27])[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[O:32]1[C:36](=[O:37])[CH2:35][CH2:34][C:33]1=[O:38]>N1C=CC=CC=1>[CH2:1]([NH:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:16]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[C:15]([C:26]([NH:28][CH2:29][CH2:30][O:31][C:36](=[O:37])[CH2:35][CH2:34][C:33]([OH:38])=[O:32])=[O:27])[N:14]=[N:13]2)=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)O1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NCCO)c2COc2cccc(F)c2)cc1
Solvent: c1ccncc1
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NCCOC(=O)CCC(=O)O)c2COc2cccc(F)c2)cc1
Temperature: 80 °C
Yield: 65.1 %

Procedure:
To a solution of 1-{4-[(ethylamino)carbonyl]phenyl}-5-[(3-fluorophenoxy)methyl]-N-(2-hydroxyethyl)-1H-1,2,3-triazole-4-carboxamide (500 mg) obtained in Example 498 in pyridine (10 ml) was added dihydrofuran-2,5-dione (234 mg), and the mixture was heated at 80° C. for 14 hr. The reaction solution was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate/hexane to give the title compound as a colorless powder (402 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][C:15]2[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]3[CH2:25][CH2:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH:12]3[C:11]=2[CH:10]=1.[Br:36]N1C(=O)CCC1=O>CN(C=O)C>[Br:36][C:16]1[C:15]2[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]3[CH2:25][CH2:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH:12]3[C:11]=2[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC2C(C1)c1cc(-c3ccc(Cl)cc3Cl)ccc1N2C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2C(C1)c1cc(-c3ccc(Cl)cc3Cl)cc(Br)c1N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 49 %

Procedure:
A dry 25 mL round bottom flask was charged with di(tert-butyl) 8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro-1H-pyrido[4,3-b]indole-2,5-dicarboxylate (0.38 g, 0.74 mmol), DMF (10 mL), N-bromosuccinimide (0.21 g, 1.11 mmol), and stirred at ambient temperature for 18 hours. The reaction was concentrated under high vacuum to remove DMF and partitioned between water and ethyl acetate (2X). The organics were combined, dried with MgSO4, filtered and concentrated to give 461 mg of a crude orange brown oil. Purification of the crude on a 40 gram silica Biotage column using 10% ethyl acetate in heptane gave 217 mg (50%) of di(tert-butyl) 6-bromo-8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro-1H-pyrido[4,3-b]indole-2,5-dicarboxylate as a pale yellow foam.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:26]=2[CH2:27][CH2:28][NH:29]3)[CH:20]=1>>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15](=[O:17])[N:29]3[C:30]4[C:26](=[C:25]([C:21]5[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=5)[CH:33]=[CH:32][CH:31]=4)[CH2:27][CH2:28]3)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: c1cncc(-c2cccc3c2CCN3)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(-c3cccnc3)cccc21
Yield: 71.9 %

Procedure:
The product is prepared by following the procedure described in example 10d using 26.7 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (example 1d, step 2d) and 25 mg of 4-pyridin-3-yl-2,3-dihydro-1H-indole in place of 4-pyridin-4-yl-2,3-dihydro-1H-indole. 30.7 mg of 6-(morpholin-4-yl)-2-{2-oxo-2-[4-(pyridin-3-yl)-2,3-dihydro-1H-indol-1-yl]ethyl}pyrimidin-4(3H)-one are obtained in the form of a pink powder, the characteristics of which are the following:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C(C)(C)c1cccc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)C(C)(C)c1cccc(O)c1
Temperature: -65 °C
Reaction time: 1.6 h
Yield: 39 %

Procedure:
The ester from Step 2 (29.1 g, 140 mmol) was dissolved in CH2Cl2 (170 mL) and cooled to −65° C. The reaction was treated with a 1.0 M solution of boron tribromide in CH2Cl2 (180 mL, 180 mmol). The reaction was stirred at −65° C. for 1.6 hours, then the cooling bath was removed and the reaction was warmed to room temperature. The reaction was added to ice water and the layers were separated. The organic layer was concentrated in vacuo, dissolved in ethyl acetate, washed with saturated NaHCO3, brine, dried over MgSO4 and concentrated in vacuo, to give methyl 2-(3-hydroxyphenyl)-2-methylpropionate as a brown oil (10.6 g, 42%): 1H NMR (CDCl3/300 MHz) 7.19 (m, 1H), 6.90 (d, 1H, J=7.9 Hz), 6.84 (m, 1H), 6.75 (d, 1H, J=8.1 Hz), 3.66 (s, 3H), 1.56 (s, 6H). The saturated NaHCO3 layer was acidified with concentrated HCl, extracted with ethyl acetate washed with the, dried over MgSO4 and concentrated in vacuo, to give 2-(3-hydroxyphenyl)-2-methylpropionic acid as a brown oil (15.8 g, 42%): 1H NMR (CDCl3/300 MHz) 7.20 (m, 1H), 6.97 (dd, 1H, J=7.9 Hz, 0.8 Hz), 6.88 (m, 1H), 6.75 (dd, 1H, J=8.1 Hz, 0.8 Hz), 1.57 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([OH:24])=[O:23])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH3:21])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH3:21])[CH:12]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCn1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCn1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)c2ccccc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 80.8 %

Procedure:
To DMF (80 mL) solution of the compound obtained in Example 137 (5,7 g) was added potassium carbonate (3.6 g) and iodomethane (1.6 mL) at 0° C., and the mixture was stirred for 17 hours at room temperature. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and thereafter the residue obtained by distilling off the solvent under a reduced pressure was purified with silica gel column chromatography (n-hexane:ethyl acetate=5:1), to give the captioned compound (4.8 g, 81%) as an oily product.
Reaction SMILES: [O:1]([C@H:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>[Fe](Cl)(Cl)Cl.C(OCC)(=O)C>[C:14]([C:5]1[CH:6]=[CH:7][C:2]([O:1][C@H:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:3][CH:4]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)[C@@H](C)Oc1ccccc1
Agent: Cl[Fe](Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](C)Oc1ccc(C(C)=O)cc1
Yield: 80 %

Procedure:
A mixture of 36 g (0.2 mol) of methyl (R)-2-phenoxypropionate (enantiomeric excess 94-95%), 81.6 g (0.8 mol) of acetic anhydride, 6.5 g (0.04 mol) of iron(III) chloride and 100 ml of ethyl acetate was heated at 70°-75° C. for 6 hours. The diluent and excess acetic anhydride were then removed under reduced pressure, after which the crude product was subjected to vacuum distillation. Yield: 80% (94-95% enantiomeric excess).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([OH:24])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:13]=[CH:12]2)C1C=CC=CC=1.[H][H]>C(O)C>[CH2:20]([C:19]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([OH:8])[CH:18]=[CH:17]2)([OH:24])[CH2:22][CH3:23])[CH3:21]
Reactant: CCC(O)(CC)c1ccc2cc(OCc3ccccc3)ccc2c1
Reactant: [H][H]
Solvent: CCO
Product: CCC(O)(CC)c1ccc2cc(O)ccc2c1
Yield: 87.2 %

Procedure:
Treat a mixture of 3-(6-benzyloxynaphthalen-2-yl)pentan-3-ol (1.5 g, 4.68 mmol) and 5% PdlAl2CO3 (0.90 g) in ethanol (750 mL) with hydrogen at 60 psi for 8 h at RT. Filter the catalyst from the reaction mixture and concentrate the filtrate to give the title compound as a yellow solid (0.94 g, 87%). MS (ES) m/e 229 (M−1).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([CH3:33])([CH3:32])[C:25](=[O:31])[NH:26][C:27]2=[O:30])=[CH:22][CH:21]=1>C(#N)C>[Cl:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:19][C:20]4[CH:29]=[C:28]5[C:23]([C:24]([CH3:33])([CH3:32])[C:25](=[O:31])[NH:26][C:27]5=[O:30])=[CH:22][CH:21]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC1(C)C(=O)NC(=O)c2cc(N)ccc21
Reactant: Clc1cccnc1N1CCc2c(Cl)ncnc2C1
Solvent: CC#N
Product: CC1(C)C(=O)NC(=O)c2cc(Nc3ncnc4c3CCN(c3ncccc3Cl)C4)ccc21
Yield: 50.1 %

Procedure:
A mixture of 4-chloro-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (7.5 mg), 7-amino-4,4-dimethylisoquinoline-1,3(2H,4H)-dione (30 mg) (prepared according to the reference: Snow, R. J. et al, J. Med. Chem. 2002, 45, 3394), and acetonitrile (0.5 mL) was heated with microwave at 180° C. for 60 min. The solvent was removed and the residue was purified by chromatography to give an off-white solid (6 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[NH:10][N:9]=[N:8][C:5]2=[N:6][CH:7]=1.[N:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([Sn](C)(C)C)[CH:25]=3)[N:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>O1CCOCC1>[N:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:2]4[CH:3]=[C:4]5[NH:10][N:9]=[N:8][C:5]5=[N:6][CH:7]=4)[CH:25]=3)[N:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: C[Sn](C)(C)c1ccc2nccc(-c3ccncc3)c2c1
Reactant: Brc1cnc2nn[nH]c2c1
Solvent: C1COCCO1
Product: c1cc(-c2ccnc3ccc(-c4cnc5nn[nH]c5c4)cc23)ccn1
Temperature: 100 °C
Yield: 13.6 %

Procedure:
A mixture of 6-bromo-1H-[1,2,3]triazolo[4,5-b]pyridine (100 mg, 0.5 mmol), 4-(4-pyridinyl)-6-(trimethylstannanyl)quinoline (204 mg, 0.55 mmol), and tetrakistriphenylphosphine palladium(0) (29 mg, 0.025 mmol) in 1,4-dioxane (3.0 mL) was heated at 100° C. for 18 h. The reaction was filtered to collect the precipitate. The solid was triturated in hot ethanol to give an off-white solid, which still contained some minor impurities. The off-white solid was triturated in hot ethanol to give the title product as a beige solid (22 mg, 14%). MS(ES)+ m/e 325.1 [M+H]+.
Reaction SMILES: [C:1]([CH:3]([C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][C:14]([N+:21]([O-:23])=[O:22])=[CH:13][N:12]=1)C(OC(C)(C)C)=O)#[N:2].Cl.CC(=O)OCC>CO>[N+:21]([C:14]1[CH:15]=[C:16]([C:17]([F:20])([F:18])[F:19])[C:11]([CH2:3][C:1]#[N:2])=[N:12][CH:13]=1)([O-:23])=[O:22]
Reactant: CC(C)(C)OC(=O)C(C#N)c1ncc([N+](=O)[O-])cc1C(F)(F)F
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: N#CCc1ncc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 100 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a solution of tert-butyl 2-cyano-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetate (7 g, 21.13 mmol) in MeOH (100 mL) was added aqueous HCl (40 mL, 1316 mmol). The resulting mixture was stirred at 100° C. overnight. After TLC analysis (PE/EA=10/1) showed the starting material was consumed, the solvent was removed in vacuo. The residue was dissolved in H2O (50 mL) and extracted by EA (100 mL). The organic layer was washed with aqueous NaHCO3 and brine and then dried over Na2SO4. After filtration, the filtrate was concentrated to give the crude product, which was purified by column chromatography (PE/EA=10/1) to yield a brown solid of 2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetonitrile (4.3 g, 17.77 mmol, 84% yield): 1H NMR (400 MHz, CD3OD) δ 9.59 (s, 1H), 8.88 (d, J=2.4 Hz, 1H), 4.86 (s, 2H); ES-LCMS m/z: 232.1 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][CH:9]([F:48])[O:10][CH2:11][C@@H:12]([O:14][C:15]1[CH:16]=[C:17]([CH:33]=[C:34]([O:36][C:37]2[CH:42]=[N:41][C:40]([C:43](=[O:47])[N:44]([CH3:46])[CH3:45])=[CH:39][N:38]=2)[CH:35]=1)[C:18]([NH:20][C:21]1[CH:25]=[CH:24][N:23](C(OC(C)(C)C)=O)[N:22]=1)=[O:19])[CH3:13]>C(Cl)Cl>[F:48][CH:9]([F:8])[O:10][CH2:11][C@@H:12]([O:14][C:15]1[CH:35]=[C:34]([CH:33]=[C:17]([C:18](=[O:19])[NH:20][C:21]2[CH:25]=[CH:24][NH:23][N:22]=2)[CH:16]=1)[O:36][C:37]1[N:38]=[CH:39][C:40]([C:43]([N:44]([CH3:46])[CH3:45])=[O:47])=[N:41][CH:42]=1)[CH3:13]
Reactant: C[C@@H](COC(F)F)Oc1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](COC(F)F)Oc1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(C(=O)Nc2cc[nH]n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl 3-[[3-[(2S)-1-(difluoromethoxy) propan-2-yl]oxy-5-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-benzoyl]amino]pyrazole-1-carboxylate (150 mg, 0.26 mmol) in DCM (16 mL) and stirred at RT for 2 hours. The solvent was removed in vacuo, DCM (20 mL) added and the mixture washed with water (20 mL), saturated sodium bicarbonate solution (20 mL), brine (20 mL), dried (MgSO4) and reduced in vacuo to give the desired compound (94 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]>C(O)C>[CH2:13]([O:12][C:10]([N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH2:2]1)=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: c1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C(OCc1ccccc1)N1C=CC=CC1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 74.3 %

Procedure:
A solution of pyridine (4.0 g., 0.050 mol) and NaBH4 (2.0 g, 0.026 mol) in 20 ml of absolute ethanol is treated with benzyl chloroformate (8.5 g, 0.05 mol) over about 1 hour followed by stirring for 1.5 hour at -78° C. The mixture is added to ice-water and extracted with ether, and the extract is washed with 3% HCl solution and 3% NaOH solution. After the extract is dried and evaporated, 8.0 g of N-benzyloxycarbonyl1,2-dihydropyridine is obtained in 74% yield. A 5% solution of N-benzyloxycarbonyl-1,2-dihydropyridine is then irradiated using a Rayonet photochemical reactor (RP-300 lamps) until NMR spectrum shows consumption of the starting materials. The solvent is evaporated to give the crude product, N-(benzyloxycarbonyl)-2-azabicyclo[2.2.0]hex-5-ene (VIII). Pure (VIII) is obtained by passing the crude product through basic alumina with ether. (VIII) is then reacted with ozone in methanol at -78° C. followed by reaction with peroxyacetic acid to form cis-N-(benzyloxycarbonyl)-azetidine-2,3- dicarboxylic acid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([C:20](O)=[O:21])[CH2:16][CH2:15]3)[NH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([S:32]([NH:35][C:20]([C@H:17]2[CH2:16][CH2:15][C@H:14]([C:11]3[NH:12][CH:13]=[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:4]=4)[N:10]=3)[CH2:19][CH2:18]2)=[O:21])(=[O:34])=[O:33])=[CH:30][CH:31]=1
Reactant: O=C(O)[C@H]1CC[C@H](c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)[C@H]2CC[C@H](c3nc(-c4cccc(C(F)(F)F)c4)c[nH]3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-water cooled mixture of trans-4-{4-[3-(trifluoromethyl)phenyl]imidazol-2-yl}cyclohexanecarboxylic acid (1.48 mmol), 4-methylbenzenesulfonamide (1.48 mmol), and DMAP (1.48 mmol) in dichloromethane (10 mL) under nitrogen, EDC (1.48 mmol) was added. The mixture was stirred at room temperature overnight, concentrated and chromatographed on silica gel (19:1 EtOAc-MeOH eluent) to give trans-N-[(4-methylphenyl)sulfonyl](4-{4-[3-(trifluoromethyl)phenyl]-imidazol-2-yl}cyclohexyl)carboxamide.
Reaction SMILES: [CH2:1]1[C:7]2=[CH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4][NH:3][CH2:2]1.C=O.[C:17]([BH3-])#N.[Na+]>CO>[CH3:17][N:3]1[CH2:2][CH2:1][C:7]2=[CH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4]1
Reactant: [BH3-]C#N
Reactant: c1ccc2c(c1)cc1n2CCNCC1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCc2cc3ccccc3n2CC1
Reaction time: 0.67 h
Yield: 58.4 %

Procedure:
A solution of 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole (372 mg, 2.0 mmol) in methanol (25 mL) is treated with a solution of 37% aqueous formaldehyde (24 mmol, 2.0 mL). The resulting clear solution is treated with a single portion of sodium cyanoborohydride (251 mg, 4.0 mmol) turning slightly a lighter yellow color. After 40 min, the reaction is quenched with 1M hydrochloric acid (15 mL), stirred over 10 min, basified to pH 13, volatiles removed under reduced pressure, and extracted twice with ethyl acetate (25 mL). The combined organics are washed with brine (20 mL), dried over MgSO4, filtered, and concentrated to give a crude oil. This material is purified by LC (230-400 silica gel) eluting with 70% acetone/heptane to afford 234 mg (58%) of 3-methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole as a white solid, mp 59-60° C. IR (drift) 2924, 2781, 2758, 2741, 1458, 1413, 1377, 1339, 1326, 1315, 1290, 1133, 1003, 799, 737 cm−1. MS (EI) m/z 200 (M+).