Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:40][CH:41]([CH2:43][C@H:44]([OH:48])[C:45](O)=[O:46])[CH3:42]>C(Cl)Cl>[OH:48][C@@H:44]([CH2:43][CH:41]([CH3:42])[CH3:40])[C:45]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:11])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:46]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)C[C@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](O)CC(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 87.6 %

Procedure:
To a solution of L-leucine methyl ester hydrochloride (1.97 g) dissolved in DCM (32 mL) was added NMM (1.9 mL) and the mixture was stirred for 5 minutes before being cooled to 0° C. HOBt (4.0 g), EDAC (3.8 g) and L-α-hydroxyisocaproic acid (1.35 g) were then added sequentially to the reaction mixture. After 30 minutes at 0° C., the reaction was allowed to warm to room temperature and continued stirring overnight. The reaction mixture was concentrated and the resulting crude product was dissolved in EtOAc and washed 2×1.2N HCl, 2× saturated NaHCO3, brine, dried (MgSO4) and concentrated to yield the desired product (2.32 g, 82%). 1H NMR (300 MHz, CDCl3) δ 0.93-0.96 (m, 12H), 1.50-1.67 (m, 5H), 1.82-1.93 (m, 1H), 3.73 (s, 3H), 3.83 (bs, 1H), 4.11-4.18 (m, 1H), 4.57-4.64 (m, 1H), 7.07 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[C:30]#[CH:31]>C(#N)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH2:31][C:30]#[CH:29])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1
Reactant: C#CCBr
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: C#CCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
To a solution of 200 mg (0.59 mmol) of 3-[4-chloro-2-fluoro-5-(hydroxy)phenyl]-1-methyl-6- (trifluoromethyl)-2,4 (1H,3H) -pyrimidinedione in 3 mL of acetonitrile was added 162 mg of potassium carbonate (1.18 mmol) and 131 mL (1.18 mmol) of an 80% solution of propargyl bromide in toluene. It was warmed under reflux for 2 h. The resulting mixture was filtered and the filtrate was concentrated in vacuo to give colorless oil which was flash chromatographed over silica gel, eluting with a 1:4 v:v mixture of ethyl acetate and hexane to give 204 mg of title compound as a white foam: 1H-NMR (CDCl3, 200 MHz) ppm 7.35 (d, 1H), 7.0 (d, 1H), 6.4 (s, 1H), 4.78 (d, 2H), 3.58 (s, 3H), 2.6 (d, 1H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[N:14]3[CH:15]=[CH:16][N:17]=[C:18]([NH2:19])[C:13]3=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:21]=3)[N:11]=2)[CH2:6][CH2:5]1.[CH3:33]NC>>[CH3:1][N:2]([CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[N:14]3[CH:15]=[CH:16][N:17]=[C:18]([NH2:19])[C:13]3=[C:12]([C:20]3[CH:21]=[CH:22][C:23]([O:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:24][CH:25]=3)[N:11]=2)[CH2:6][CH2:5]1)[CH3:33]
Reactant: CNC
Reactant: CNC[C@H]1CC[C@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn32)CC1
Product: CN(C)CC1CCC(c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn23)CC1

Procedure:
Prepared according to the procedure described above for the synthesis of trans-3-(4-methylaminomethyl-cyclohexyl)-1-(4-phenoxy-phenyl)-imidazo[1,5-a]pyrazin-8-ylamine, except using dimethyl-amine.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[C:13]([OH:19])=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1>N1C=CC=CC=1>[Cl:11][C:12]1[C:13]([O:19][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:14][C:15]([O:18][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=2)=[N:16][CH:17]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Oc2cc(OC(=O)c3ccc(C)cc3)c(Cl)cn2)cc1
Reaction time: 6 h

Procedure:
A 2.66 g quantity of 4-methylbenzoyl chloride was added dropwise to 50 ml of a solution of 1.00 g of 5-chloro-4-hydroxy-2-pyridone in pyridine. The mixture was subjected to reaction at room temperature overnight. The pyridine was distilled off and the residue was stirred in ether for 6 hours. The solids thus precipitated were dried, giving 1.71 g of the title compound. The ether was concentrated and the residue was applied to silica gel column chromatography using as an eluent petroleum ether-chloroform (1:2), affording 0.85 g of the same compound (total amount 2.56 g, total yield 97%).
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:3].F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][C:27]=1[O:35][CH3:36].CCN(C(C)C)C(C)C.CNC>C1COCC1>[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:2]([CH3:3])[CH3:1])=[O:31])=[CH:28][C:27]=1[O:35][CH3:36]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N(C)C)ccc1N
Reaction time: 18 h
Yield: 59.4 %

Procedure:
HATU (0.296 g, 0.778 mmol) was added to a solution of 4-amino-3-methoxybenzoic acid (0.1 g, 0.598 mmol), DIPEA (0.156 mL, 0.897 mmol) and dimethylamine (2M in THF, 0.598 mL, 1.196 mmol) in THF (1.617 ml). The reaction mixture was stirred for 18 hours. The reaction was partitioned between EtOAc and water, the organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by Biotage silica gel column chromatography eluting with DCM/EtOAc 60/40 to 40/60 followed by filtration through an SCX-2 column eluting with 2M NH3/MeOH to afford the title compound as a colourless oil (69 mg, 59%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([N:12]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:13][C@H:14]([OH:23])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][OH:11])=[CH:4][CH:3]=1.[CH2:31]([N:33]=[C:34]=[O:35])[CH3:32]>ClCCl>[CH2:24]([N:12]([C@H:9]([CH2:10][OH:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:34]([NH:33][CH2:31][CH3:32])=[O:35])=[CH:3][CH:4]=1)[CH2:13][C@H:14]([OH:23])[CH2:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccccc2)cc1
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)Nc1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To an ice-cooled solution of (2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-1-propanol (83 mg) in dichloromethane (0.8 ml) was added dropwise ethyl isocyanate (0.016 ml). The mixture was stirred at the same temperature for 1.5 hours and partitioned between chloroform and saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, chloroform/methanol) to give N-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]-N′-ethylurea (84 mg) as a white amorphous powder.
Reaction SMILES: C(OC(N=NC(OC(C)C)=O)=O)(C)C.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([OH:26])[CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=1.[C:27]1(O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]([CH3:24])[CH3:25])=[CH:20][CH:21]=1
Reactant: Oc1ccccc1
Reactant: CC(C)C(O)c1ccc(Br)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)C(Oc1ccccc1)c1ccc(Br)cc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 42836.4 %

Procedure:
Azodicarboxylic acid diisopropyl ester (824 mg, 4.1 mmol) was added to the mixture of 1-(4-bromophenyl)-2-methylpropan-1-ol (620 mg, 2.7 mmol), phenol (307 mg, 3.2 mmol), triphenylphosphine (1.07 g, 4.1 mmol) and tetrahydrofuran (15 mL) at 20° C. Then the mixture was stirred at 20° C. for 12 hours. The resultant mixture was washed with water (20 mL×2). The organic phase was separated, dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10:1) to gave 1-bromo-4-(2-methyl-1-phenoxypropyl)benzene as a colorless oil (353 g, 44%). 1H NMR (300 MHz, CDCl3): δ 8.07-7.98 (m, 2H), 7.56-7.48 (m, 2H), 7.32-7.28 (m, 2H), 6.84-6.77 (m, 3H), 4.49 (d, J=6.6 Hz, 1H), 2.35-2.30 (m, 1H), 1.01 (d, J=6.6 Hz, 6H).
Reaction SMILES: CC(C)(C)C(Cl)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][C:10]=1[F:19].[Li]CCCC.[CH2:25]([C@@H:32]1[CH2:36][O:35][C:34](=[O:37])[NH:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH2:25]([C@@H:32]1[CH2:36][O:35][C:34](=[O:37])[N:33]1[C:16](=[O:18])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([Cl:8])=[C:10]([F:19])[CH:11]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)Cc1ccc(Cl)c(F)c1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)c(F)c1)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60.3 %

Procedure:
Trimethylacetyl chloride (1.68 g, 13.9 mmol) was added to a solution of 2-(4-chloro-3-fluorophenyl)acetic acid (2.50 g, 13.3 mmol) and TEA (d. 0.726; 2.00 mL, 14.3 mmol) in dry THF (100 mL) at 0° C. and stirred at room temperature. In a separate flask, n-BuLi (6.424 mL, 14.58 mmol) was added to (R)-4-benzyloxazolidin-2-one (2.47 g, 13.9 mmol) in dry THF (100 mL) at −78° C. The reaction was strirred for 20 minutes at −78° C., and then the (R)-4-benzyloxazolidin-2-one solution was added dropwise to the 0° C. mixed anhydride solution. The reaction was allowed to stir overnight at room temperature. The reaction was quenched with water (100 mL) and diluted with ethyl acetate (100 mL). The layers were separated, and the organics were washed with brine, dried (MgSO4) and concentrated to a residue. The resulting residue was purified by flash chromatography to give (R)-4-benzyl-3-(2-(4-chloro-3-fluorophenyl)acetyl)oxazolidin-2-one (2.79 g, 8.02 mmol, 60.5% yield). 1H NMR (400 MHz, CDCl3) 7.37 (t, J=8.2 Hz, 1H), 7.33-7.26 (m, 3H), 7.18-7.12 (m, 3H), 7.07 (d, J=8.2 Hz, 1H), 4.73-4.65 (m, 1H), 4.33-4.18 (m, 4H), 3.27 (dd, J1=3.5 Hz, J2=13.3 Hz, 1H), 2.77 (dd, J1=9.4 Hz, J2=13.7 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][C@@H:28]1[NH:33][CH2:32][CH2:31][N:30]([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]=2)[CH2:29]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:33]2[CH2:32][CH2:31][N:30]([C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)[CH2:29][C@@H:28]2[CH3:27])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: C[C@H]1CN(c2ccc3ccccc3n2)CCN1
Product: C[C@H]1CN(c2ccc3ccccc3n2)CCN1CCCCC1(C(=O)NCC(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-[(S)-3-methyl-piperazin-1-yl]-quinoline
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[F:7][C:8]([F:29])([F:28])[O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[N:19][C:18]([C:21]3[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=3)=[N:17]2)=[CH:12][CH:11]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:1]([CH2:3][C:4]([NH:25][C:24]1[CH:26]=[CH:27][C:21]([C:18]2[N:19]=[CH:20][N:16]([C:13]3[CH:14]=[CH:15][C:10]([O:9][C:8]([F:7])([F:29])[F:28])=[CH:11][CH:12]=3)[N:17]=2)=[CH:22][CH:23]=1)=[O:6])#[N:2]
Reactant: Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: N#CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: N#CCC(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reaction time: 2 h
Yield: 67.9 %

Procedure:
Cyanoacetic acid (0.30 g, 3.53 mmol) and 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline (1.00 g, 3.12 mmol) were dissolved in 30 mL of dichloromethane, and then dicyclohexylcarbodiimide (0.695 g, 3.37 mmol) was added in one portion as a solid. The solution was allowed to stir for 2 h, then the solvent was removed and the residue was heated in 75 mL of EtOAc, cooled and filtered to remove dicyclohexyl urea. The filtrate was concentrated and the solid was recrystallized from EtOH to give 0.82 g (66%) of 2-cyano-N-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acetamide (B11) as a white solid, mp 250-252° C. 1H NMR (DMSO-d6) δ 10.51 (s, 1H), 9.39 (s, 1H), 8.13-8.00 (m, 4H), 7.75-7.66 (m, 2H), 7.62 (d, J=8.3 Hz, 2H), 3.95 (s, 2H). ESIMS m/z 388 (M+H).
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[Cl:14][C:15]1[N:20]=[C:19]([CH:21](O)[CH3:22])[CH:18]=[CH:17][N:16]=1>ClCCl>[Cl:14][C:15]1[N:20]=[C:19]([CH:21]([F:11])[CH3:22])[CH:18]=[CH:17][N:16]=1
Reactant: CC(O)c1ccnc(Cl)n1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: CC(F)c1ccnc(Cl)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Bis(2-methoxyethyl)aminosulfur trifluoride (7.70 g, 17.4 mmol) was added drop wise to a solution of 1-(2-chloropyrimidin-4-yl)ethanol (2.30 g, 14.5 mmol) in dichloromethane (20 mL) at 0° C. and the mixture was stirred at 0° C. for 15 minutes. The mixture was diluted with dichloromethane and washed with aqueous sodium bicarbonate. The organic layers were separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-50% EtOAc/Hexane) to afford 2-chloro-4-(1-fluoroethyl)pyrimidine. 1H NMR (500 MHz, DMSO-d6) δ 8.66 (d, J=5.0 Hz, 1H), 7.45 (d, J=5.0 Hz, 1H), 5.65-5.51 (m, 1H), 1.71-1.65 (m, 3H).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][S:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24]C(C(NC3C=C4C(=CC=3)NC(C(OC(C)(C)C)=O)=C4)=O)=[CH:22][C:21]=2[CH:44]=1>>[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][S:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:2]([C:3]([OH:5])=[O:4])=[CH:22][C:21]=2[CH:44]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)c1cc2cc(NC(=O)c3cc4cc(CSSc5ccccn5)ccc4o3)ccc2[nH]1
Product: O=C(O)c1cc2cc(CSSc3ccccn3)ccc2o1
Reaction time: 2 h

Procedure:
To 4 mL trifluoroacetic acid, cooled to 0° C. and stirred under argon, was added 16 (120 mg, 0.23 mmol). After 2 h, trifluoroacetic acid was removed under reduced pressure to give 15 as an off-white solid: NMR (acetone-d6) d 4.3 (2,2H), δ7.3-8.7 (m, 12H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([C:35]1[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[C:37]([F:43])[CH:36]=1)([C:11]1[N:12]=[CH:13][N:14](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:15]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:44]([O:48][CH3:49])(=[O:47])[CH2:45]O.C(N(CC)C(C)C)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]([C:11]1[N:12]([CH2:45][C:44]([O:48][CH3:49])=[O:47])[CH:13]=[N:14][CH:15]=1)([C:35]1[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[C:37]([F:43])[CH:36]=1)[CH3:10])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)CO
Reactant: CC(C)(C)OC(=O)NC(C)(c1ccc(C#N)c(F)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Cn1cncc1C(C)(NC(=O)OC(C)(C)C)c1ccc(C#N)c(F)c1
Temperature: 25 °C

Procedure:
To a stirred solution of N-(tert-butoxycarbonyl)-1-(4-cyano-3-fluoro-phenyl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethylamine, as described above in Step B, (2.6 g, 4.5 mmol), methyl glycolate (532 mg, 5.9 mmol), and N,N-diisopropylethyl-amine (1.6 g, 11.7 mmol) in dry CH2Cl2 (100 mL), under argon, at −78° C., was added trifluoromethanesulfonic anhydride (1.7 g, 5.9 mmol) dropwise. The mixture was allowed to warm slowly to ambient temperature, then the solvent was removed in vacuo. The residue was dissolved in MeOH (50 mL) and the solution was heated to reflux for 1 hour, then concentrated to dryness. The residue was purified by silica gel chromatography, eluting with EtOAc—2% MeOH—0.2% NH4OH. The product was further purified by preparative HPLC using a C-18 column and eluting with a gradient of H2O—0.2% triethylamine—0.1% AcOH—0% to 60% CH3CN to yield the titled product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH:14]=[CH:13][C:11]([OH:12])=[CH:10][CH:9]=1)[OH:8].[Br:15][CH2:16][CH2:17]Br>CC(C)=O>[Br:15][CH2:16][CH2:17][O:8][C:7]1[CH:14]=[CH:13][C:11]([OH:12])=[CH:10][CH:9]=1
Reactant: BrCCBr
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Oc1ccc(OCCBr)cc1

Procedure:
Potassium carbonate (7.53 g, 0.05448 mol) was added to the acetone solution (50 ml) of hydroquinone (2.00 g, 0.01816 mol) and 1,2-dibromoethane (3.39 g, 0.01805 mol). The mixture was heated at reflux for 6 h under nitrogen. The resulting mixture was filtered, water was added and pH was adjusted to 2-3. The mixture was extracted with ethyl acetate. The extracts were washed with water, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography on silica gel, using heptane/ethyl acetate as a gradient eluent (95:5-70:30) to afford the pure desired compound as white crystals. 1H NMR (400 MHz, DMSO-d6): 3.74 (2H, t, 3J=5.5 Hz), 4.19 (2H, t, 3J=5.5 Hz), 6.67 (2H, d, 3J=8.9 Hz), 6.78 (2H, d, 3J=8.9 Hz), 8.95 (1H, s, —OH).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[NH:10][C@@H:11]([C@@H:13]([OH:26])[CH2:14][O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:28]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)([O-:30])=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[N+:28]([C:31]1[CH:32]=[CH:33][C:34]([C:35]([O:26][C@H:13]([CH2:14][O:15][Si:16]([CH:20]([CH3:22])[CH3:21])([CH:23]([CH3:25])[CH3:24])[CH:17]([CH3:19])[CH3:18])[C@@H:11]([CH3:12])[NH:10][C:9](=[O:27])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:36])=[CH:38][CH:39]=1)([O-:30])=[O:29]
Reactant: CC(C)[Si](OC[C@H](O)[C@@H](C)NC(=O)OCc1ccccc1)(C(C)C)C(C)C
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)[Si](OC[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)[C@@H](C)NC(=O)OCc1ccccc1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 81.9 %

Procedure:
Benzyl {(2R,3R)-3-hydroxy-4-[(tripropan-2-ylsilyl)oxy]butan-2-yl}carbamate (7.00 g, 17.7 mmol) synthesized in Example (89b) was dissolved in toluene (80 mL), and 4-nitro benzoic acid (6.10 g, 36.5 mmol) and triphenylphosphine (11.85 g, 45.2 mmol) were added, followed by cooling to 0° C. Under nitrogen atmosphere, diethyl azodicarboxylate (40% toluene solution, 20.3 mL, 44.7 mmol) was added dropwise over 10 minutes, and stirring was carried out at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-15%) to afford the desired compound (7.90 g, yield 82%) as a yellow liquid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][C:15]=2[N+:23]([O-:25])=[O:24])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[CH3:33][S:34]([N:37]1[CH2:42][CH2:41][C:40]2[N:43]([CH2:56][CH:57]3C[O:58]3)[N:44]=[C:45]([C:46]3[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=3)[C:39]=2[CH2:38]1)(=[O:36])=[O:35]>C(Cl)Cl>[N+:23]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([N+:20]([O-:22])=[O:21])[C:14]=1[N:11]1[CH2:10][CH2:9][N:8]([CH2:6][CH:57]([OH:58])[CH2:56][N:43]2[C:40]3[CH2:41][CH2:42][N:37]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:38][C:39]=3[C:45]([C:46]3[CH:51]=[CH:50][C:49]([C:52]([F:54])([F:55])[F:53])=[CH:48][CH:47]=3)=[N:44]2)[CH2:13][CH2:12]1)([O-:25])=[O:24]
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c([N+](=O)[O-])cccc2[N+](=O)[O-])CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCN(c3c([N+](=O)[O-])cccc3[N+](=O)[O-])CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
4-(2,6-Dinitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (220 mg, 0.63 mmol) was dissolved in 5.0 mL of CH2Cl2 and treated with 3.0 mL of trifluoroacetic acid. The reaction mixture was stirred at 25° C. for 1 h before all volatiles were removed. The solid was treated with CH2Cl2 (20 mL) and aqueous KOH (4 N, 10 mL). The organic layer was separated, dried over Na2SO4, and concentrated. The crude oil (67 mg) was dissolved in absolute EtOH (1.2 mL) and treated with 141 mg (0.35 mmol, 1.3 eq) of 5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. The reaction mixture was refluxed at 85° C. for 3 h and then the solvent was removed. Column chromatography purification (silica, 10-20% acetone/CH2Cl2) provided 150 mg (85%) of 1-[4-(2,6-dinitro-phenyl)-piperazin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol. TLC (silica, 10% acetone/CH2Cl2): Rf=0.3. MS (electrospray): exact mass calculated for C27H30F3N7O7S, 653.19; m/z found, 654.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.71 (d, J=8.2 Hz, 2H), 7.64 and 7.58 (AB pattern, J=8.4 Hz, 4H), 7.20 (t, J=8.2 Hz, 1H), 4.54 (s, 2H), 4.29-4.12 (m, 2H), 3.66 (t, J=5.3 Hz, 2H), 3.70-2.95 (m, 9H), 2.91 (s, 3H), 2.67-2.32 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9]O)[CH:5]=[CH:4][N:3]=1.CN(C=O)C.O=P(Cl)(Cl)[Cl:18]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][Cl:18])[CH:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(CO)ccnc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(CCl)ccnc1Cl
Temperature: 25 °C
Reaction time: 17 h

Procedure:
(2-Chloro-3-methyl-pyridin-4-yl)-methanol (12-4, impure, 0.200 g) was dissolved in 5 mL anhydrous DCM under N2. Anhydrous DMF (0.098 mL, 1.3 mmol) and POCl3 (0.118 mL, 1.27 mmol) were added and the reaction was stirred at RT for 17 h. The reaction was quenched with sat NaHCO3 (aq) and extracted 3× with DCM. The organic phases were dried over Na2SO4, filtered and concentrated to provide 2-chloro-4-chloromethyl-3-methyl-pyridine still contaminated with a major by-product. 2-Chloro-4-chloromethyl-3-methyl-pyridine (impure, 0.215 g) was stirred in 3 mL DMSO. 1-Acetylpiperazine (0.626 g, 4.88 mmol was added and the reaction was stirred at RT overnight. The solution was purified by directly loading onto a preparative reverse phase column to afford an oil which slowly crystallizes. TFA salt: 1H NMR (CD3OD) δ8.30 (d, 1H, J=5.0 Hz), 7.53 (d, 1H, J=5.0 Hz), 4.48 (s, 2H), 3.84 (bs, 4H), 3.39-3.30 (m, 4H), 2.14 (s, 3H).