Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH2:17][C:18]([OH:20])=[O:19])[N:15]=[N:14][N:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.[CH2:26](O)[CH2:27][OH:28]>>[OH:28][CH2:27][CH2:26][O:19][C:18](=[O:20])[CH2:17][N:16]1[C:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:11][CH:10]=2)=[N:13][N:14]=[N:15]1
Reactant: OCCO
Reactant: CCCCOc1ccc(-c2nnnn2CC(=O)O)cc1
Agent: O=S(=O)(O)O
Product: CCCCOc1ccc(-c2nnnn2CC(=O)OCCO)cc1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 69 %

Procedure:
To a solution of 0.5 g (1.81 mM) of [5-(4-butoxyphenyl) tetrazol-1-yl] acetic acid in 3 ml of ethylene glycol was added 0.3 ml of sulfuric acid. After the addition, the mixture was stirred at 90° C. for 2.5 hrs. The mixture was then poured into ice-water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent: chloroform/methyl alcohol=20/1) for separation and purification, to give 400 mg (yield 69%) of [5-(4-butoxyphenyl) tetrazol-1-yl] acetic acid 2-hydroxyethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:3]=1[NH2:4].[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[C:3]=1[NH2:4]
Reactant: [H][H]
Reactant: Cc1cccc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc(N)c1N
Yield: 97.4 %

Procedure:
2-Methyl-6-nitroaniline (15.2 g, 0.1 mol) was dissolved by heating in ethanol (150 mL). The solution was cooled, 10% palladium on carbon (1.0 g) was added and the solution was hydrogenated (50 lb initial hydrogen pressure) until uptake of hydrogen ceased (1 hour). The catalyst was filtered off and the ethanol was removed under reduced pressure to give 11.9 g (98%) of 3-methyl-1,2-benzenediamine as a solid which was used without purification.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(O)C.Cl(O)(=O)(=O)=O>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCO
Product: O=C(O)c1ccc(Cc2ccccc2)cc1
Reaction time: 8 h
Yield: 101.2 %

Procedure:
10% Palladium on carbon (0.5 g) was added to a solution of 4-benzoyl-benzoic acid (11.31 g, 50 mmol) in ethanol (250 mL) and 70% perchloric acid (10 mL). The suspension was hydrogenated under 40 psi at room temperature for 8 hours. The catalyst was removed by filtration and the filtrate made neutral with aqueous sodium bicarbonate. Solvents were evaporated, and the residue was partitioned into ethyl acetate and dilute aqueous potassium hydroxide. The aqueous phase was acidified with hydrochloric acid. The precipitated acid was filtered, washed, and dried to give 4-benzyl-benzoic acid (10.74 g, ˜100%).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][CH:40]=[C:41]([CH:44]=2)[C:42]#[N:43])O1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:21]=[C:2]([C:37]3[CH:38]=[N:39][CH:40]=[C:41]([C:42]#[N:43])[CH:44]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]3)=[N:4][CH:5]=2)=[O:8])=[CH:11][CH:12]=1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Product: N#Cc1cncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2N2CC[C@H](CO)C2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (S)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)nicotinamide (Stage 174.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford a yellow solid. UPLC-MS (Condition 3) tR=1.05 min, m/z=498.5 [M+H]+, m/z=500.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.66 (m, 1H) 1.78-1.92 (m, 1H) 2.17-2.30 (m, 1H) 2.96 (dd, J=11.00, 6.85 Hz, 1H) 3.11-3.28 (m, 4H) 3.32-3.42 (m, 1H) 4.60 (t, J=5.26 Hz, 1H) 7.34 (d, J=9.05 Hz, 2H) 7.81-7.91 (m, 2H) 8.08 (d, J=2.20 Hz, 1H) 8.40 (t, J=2.08 Hz, 1H) 8.79 (d, J=2.45 Hz, 1H) 8.91 (d, J=2.20 Hz, 1H) 9.01 (d, J=1.96 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:4][N:5]([C:7]2[N:28]=[CH:27][CH:26]=[CH:25][C:8]=2[C:9]([NH:11][CH:12]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]([OH:17])[C:14](O)=[O:15])=[O:10])[CH:6]=1.Cl.[CH3:36][O:37][NH2:38]>>[F:1][C:2]1[C:3]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:4][N:5]([C:7]2[N:28]=[CH:27][CH:26]=[CH:25][C:8]=2[C:9]([NH:11][CH:12]([CH:13]([OH:17])[C:14]([NH:38][O:37][CH3:36])=[O:15])[CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:10])[CH:6]=1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1cc(F)c(-c2ccccc2)n1
Reactant: CON
Agent: Cl
Product: CONC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc(F)c(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 3-(2-(4-fluoro-3-phenyl-1H-pyrazol-1-yl)nicotinamido)-2-hydroxy-4-phenylbutanoic acid with O-methylhydroxylamine hydrochloride. ESI-MS [M+H]+: 490.2
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[Li+].[CH3:12][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[Br:2][C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[NH2:10])[CH:6]=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: NNc1cccc(Br)c1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(N)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
To a solution of 3-bromophenylhydrazine hydrochloride (15 g, 67 mmol) in anhydrous THF (360 mL) was added LiHMDS (1.0 M solution in THF, 127 mL, 127 mmol) dropwise over a period of 1 h at 0° C. The reaction mixture was stirred for 30 min while warming to room temperature. The flask was recooled to −78° C., and MeI (4.1 mL, 67 mmol) was added. The reaction mixture was stirred for 2 h at 0° C. and then was quenched with water (600 mL). The aqueous layer was extracted with methylene chloride (3×200 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, hexanes/EtOAc, 60:40) gave the title compound (10.2 g, 76%) as yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.18 (t, J=3.5 Hz, 1H), 7.08 (t, J=13.5 Hz, 1H), 6.91-6.86 (m, 2H), 3.69 (br s, 2H), 3.11 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=O.Cl.[NH2:10][OH:11].[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[N:10][OH:11]
Reactant: O=Cc1sccc1Br
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1sccc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 22.3 %

Procedure:
3-Bromothiophene-2-carbaldehyde (28.7 g, 0.15 mol) in ethanol (50 mL) was added in one portion to a solution of hydroxylamine hydrochloride (13.8 g, 0.2 mol), sodium hydroxide (8 g, 0.2 mol) in water (30 mL) and ethanol (100 mL). The mixture was stirred at 0° C. for 2 hours and was kept at 0° C. overnight when a precipitate formed. The mixture was diluted with cold water (600 ml) and the solid was collected by filtration yielding 20.5 g, (67%). The aqueous solution was further extracted with ethyl acetate. The organic solution was washed with brine, dried with magnesium sulfate, filtered and evaporated yielding 6.9 g of additional product as a light yellow solid. The total yield was 27.4 g (89%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[CH3:54][C:55]1[O:59][N:58]=[CH:57][C:56]=1[C:60](Cl)=[O:61]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:60]([C:56]2[CH:57]=[N:58][O:59][C:55]=2[CH3:54])=[O:61])[CH2:48]1
Reactant: Cc1oncc1C(=O)Cl
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1oncc1C(=O)N1CC[C@@H](CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)C1
Yield: 91 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 5-methylisoxazole-4-carbonyl chloride as the starting materials in 91% yield. LCMS for C28H28ClN8O3 (M+H)+: m/z=559.0.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:31]1[C:43]2[CH:42]([CH2:44][O:45][C:46]([NH:48][C@H:49]([C:54](O)=[O:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]=2[CH:34]=[CH:33][CH:32]=1>>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)[CH:14]=1)[C:54](=[O:55])[C@H:49]([CH2:50][CH:51]([CH3:52])[CH3:53])[NH:48][C:46]([O:45][CH2:44][CH:42]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:43]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:47])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: COc1cc(-c2cc(CNCCO[Si](C)(C)C(C)(C)C)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN(CCO[Si](C)(C)C(C)(C)C)C(=O)[C@H](CC(C)C)NC(=O)OCC3c4ccccc4-c4ccccc43)ccn2)cc(OC)c1OC

Procedure:
N-[2-(tert-Butyldimethylsilyloxy)ethyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amine (1.40 g) and N-(9-fluorenylmethoxycarbonyl)-L-leucine (1.16 g) were treated in the same manner as in Preparation Example 9 to obtain the title compound.
Reaction SMILES: Cl.[CH2:2]([N:5]1[C:10](=[O:11])[C:9]([NH2:12])=[CH:8][N:7]=[C:6]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:3]=[CH2:4].C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27].C(=O)(O)[O-].[Na+]>O1CCCC1>[C:26]([NH:12][C:9]1[C:10](=[O:11])[N:5]([CH2:2][CH:3]=[CH2:4])[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][CH:8]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: C=CCn1c(-c2ccccc2)ncc(N)c1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCn1c(-c2ccccc2)ncc(NC(C)=O)c1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1-Allyl-5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidine hydrochloride was dissolved in tetrahydrofuran (27 ml) and triethylamine (1.16 ml, 8.33 mmol), and acetyl chloride (0.284 ml, 3.99 mmol) was added to it under cooling on ice, and the mixture was stirred at 0° C. for 30 minutes and at room temperature for 2 hours. After saturated aqueous sodium bicarbonate was added, the reaction solution was extracted with ethyl acetate, and it was washed with saturated saline. After dried over anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) whereby the title compound (617 mg, 69%) was obtained.
Reaction SMILES: [C:1]([O:7]C(C)(C)C)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[N:14]=1>C1(C)C=CC=CC=1>[Si:21]([O:20][CH2:19][C:15]1[N:14]=[C:13]([NH:12][C:1](=[O:7])[CH2:2][C:3](=[O:4])[CH3:5])[CH:18]=[CH:17][CH:16]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N)n1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)Nc1cccc(CO[Si](C)(C)C(C)(C)C)n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
6.6 mL of tert-butyl acetoacetate was dissolved in 10 mL of toluene and the mixture was stirred at 100° C. for 1 hour. To the reaction solution was added a solution of 1.9 g (8.1 mmol) of 2-amino-6-(tert-butyldimethylsilyloxymethyl)pyridine in 5 mL of toluene and the mixture was stirred at the same temperature for 15 hours. The reaction solution was concentrated and the resulting residue was purified by a silica gel column chromatography to give 2.2 g of the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH:15]2[CH:17]([CH:18]=[O:19])[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.O.O.O.O.C(OO)(=O)C1C(=CC=CC=1)C(O)=[O:30].[Mg]>CCO.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:17]([C:18]([OH:30])=[O:19])[CH:15]([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC2CCCCC(C1)C2C=O
Reactant: O=C(O)c1ccccc1C(=O)OO
Agent: [Mg]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2CCCCC(C1)C2C(=O)O

Procedure:
2.86 g of 10-formyl-8-aza-bicyclo[4.3.1]decane-8-carboxylic acid tert-butyl ester and 5.8 g of magnesium monoperoxyphthalic acid hexahydrate in 170 ml of EtOH/H2O (1:1) are stirred at RT. The mixture obtained is diluted with EtAc. The mixture obtained is extracted with aqueous 1M HCl and brine. The organic layer obtained is dried, solvent is evaporated and the evaporation residue is crystallized from MeOH/H2O. 8-aza-bicyclo[4.3.1]decane-8,10-dicarboxylic acid 8-tert-butyl ester is obtained. m.p.: 218-222°; 13C-NMR: 179.88, 155.31, 80.00, 52.43, 50.98, 47.63, 33.14, 32.31, 28.91, 27.06.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([O:14][CH:15]([F:17])[F:16])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:21]([O:23]CC)=[O:22])=[CH:6][N:7]2[CH:18]1[CH2:20][CH2:19]1.C(O)(=O)C.S(=O)(=O)(O)O>O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([O:14][CH:15]([F:16])[F:17])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:21]([OH:23])=[O:22])=[CH:6][N:7]2[CH:18]1[CH2:20][CH2:19]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(F)c(F)c(N)c2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(F)c(F)c(OC(F)F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reaction time: 1 h
Yield: 90.3 %

Procedure:
A suspension of 3.58 g (0.0096 moles) of ethyl 5-amino-1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate [(XXII), R1 =--OCHF2, R17 =C2H5, X=F] [prepared as described in step (f) or (f') above], 21 ml of acetic acid, 2.8 ml of concentrated sulfuric acid and 15 ml of water was heated under reflux, with stirring, for 1 hour, after which it was cooled by allowing it to stand. Water was then added to the reaction mixture, and the insoluble materials were removed by filtration and washed with water and with diethyl ether, in that order, to give 3.0 g of 5-amino-1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid as a pale yellowish green powder, melting at 284°-286° C.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH2:13][CH:14]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][N:24]3[CH2:23][CH2:22][N:21]([CH2:20][C:19]4[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=4[C:17]([F:31])([F:32])[F:16])[CH2:26][CH2:25]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)(F)c1ccccc1CN1CCNCC1
Reactant: O=CCCc1cc(-c2ccccc2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)c1ccccc1CN1CCN(CCCc2cc(-c3ccccc3)no2)CC1
Yield: 46.6 %

Procedure:
About 2 min after dissolving 3-(3-phenylisoxazol-5-yl)propanal (10 mg, 0.05 mmol) and 1-[2-(trifluoromethyl)benyl]piperazine (10.4, 0.05 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (32 mg, 0.15 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 2.1 hr and followed the same processes as in Example 1 to obtain 10 mg (46.6%) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:5][N:6]=1.[NH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14]>>[OH:14][CH2:13][C:12]([NH:11][S:7]([C:4]1[S:3][C:2]([Cl:1])=[N:6][CH:5]=1)(=[O:9])=[O:8])([CH3:16])[CH3:15]
Reactant: O=S(=O)(Cl)c1cnc(Cl)s1
Reactant: CC(C)(N)CO
Product: CC(C)(CO)NS(=O)(=O)c1cnc(Cl)s1
Yield: 67.7 %

Procedure:
Prepared by general procedure III from 2-chloro-thiazole-5-sulfonyl chloride (2.0 g, 9 mmol, example B.13, step 1) and 2-amino-2-methyl-1-propanol (0.95 g, 9 mmol) to give the title compound (1.65 g, 33%) as an off-white solid. MS (EI) 269.2[(M)+] and 271.2[(M+2)+].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=[O:2].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]C#N)=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:2][N:1]=[C:4]3[CH:9]=[CH:8][C:7]([C:10]4[N:14]([C:15]5[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=5)[N:13]=[CH:12][CH:11]=4)=[CH:6][C:5]=23)=[CH:26][CH:25]=1
Reactant: COc1ccc(CC#N)cc1
Reactant: Cc1ccc(-n2nccc2-c2ccc([N+](=O)[O-])cc2)cc1
Product: COc1ccc(-c2onc3ccc(-c4ccnn4-c4ccc(C)cc4)cc23)cc1

Procedure:
The title compound, light brown solid (17 mg, 12%), MS (ISP) m/z=382.4 [(M+H)+], mp 165° C., was prepared in accordance with the general method of example 1 from 5-(4-nitro-phenyl)-1-p-tolyl-1H-pyrazole (intermediate E) (100 mg, 353 μmol) and commercially available 2-(4-methoxy-phenyl)-acetonitrile.
Reaction SMILES: CN1CCOCC1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:33])[CH2:16][NH:17][C:18]([CH2:20][N:21]([CH2:29][C:30](O)=[O:31])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:19])=[CH:11][CH:10]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:59][O:60][C:61](=[O:67])[C@@H:62]([CH:64]([CH3:66])[CH3:65])[NH2:63]>CN(C)C=O>[CH3:59][O:60][C:61](=[O:67])[CH:62]([NH:63][C:30](=[O:31])[CH2:29][N:21]([CH2:20][C:18](=[O:19])[NH:17][CH2:16][C:15]([C:12]1[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][CH:11]=1)=[O:33])[C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH:64]([CH3:66])[CH3:65]
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)CC(=O)NCC(=O)c1ccc(Br)cc1
Reactant: COC(=O)[C@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)C(NC(=O)CN(CC(=O)NCC(=O)c1ccc(Br)cc1)C(=O)OC(C)(C)C)C(C)C
Yield: 87.1 %

Procedure:
4-Methylmorpholine (4.1 mL, 37.3 mmol) was added to a suspension of ({[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-methyl}-tert-butoxycarbonyl-amino)-acetic acid (4 g, 9.3 mmol), and HATU (4.61 g, 12.1 mmol) in dimethylformamide (25 mL). After 5 minutes d-valine methyl ester hydrochloride (1.56 g, 9.3 mmol), was added to the solution. After 1 hour the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (150 mL), and washed with water (100 mL), aqueous hydrogen chloride (0.5 N, 2×100 mL), saturated sodium bicarbonate (100 mL), and saturated sodium chloride (100 mL). The organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography with eluent of (10% methanol in ethyl acetate) and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to yield 2-[2-({[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-methyl}-tert-butoxycarbonyl-amino)-acetylamino]-3-methyl-butyric acid methyl ester (4.37 g, 8.1 mmol, 87%). C23H32BrN3O7 calculated 541.1 observed [M+1]+431.1; rt=2.65 min.
Reaction SMILES: N[C:2](N)=[S:3].[CH3:5][CH:6]([CH2:8][CH2:9][CH2:10][C@H:11]([C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@H:27]([CH2:28][CH2:29]2)[C@:25]2([CH3:26])[C:20]([CH2:21][C@@H:22]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]CI)[CH2:23][CH2:24]2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)[CH3:12])[CH3:7]>O1CCCC1>[CH3:7][CH:6]([CH2:8][CH2:9][CH2:10][C@H:11]([C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@H:27]([CH2:28][CH2:29]2)[C@:25]2([CH3:26])[C:20]([CH2:21][C@@H:22]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:2][SH:3])[CH2:23][CH2:24]2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)[CH3:12])[CH3:5]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: NC(N)=S
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCS)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 86.5 %

Procedure:
Thiourea (7.5 g) is added to a solution of 6-(5-cholesten-3β-yloxy)hexyl iodide (15 g, 25.3 mmol) in tetrahydrofuran (200 ml) and the mixture is heated with stirring under reflux for 6 hours. The solution is concentrated to a residue which is triturated with anhydrous ether. The solid is filtered and dissolved in chloroform (100 ml). This solution is added to a solution of potassium metabisulfite (15 g) in water (100 ml). The mixture is heated under reflux in a nitrogen atmosphere for 20 minutes. The organic layer is washed with water, dried, and concentrated to dryness. The crude material is put on a silica gel column and eluted with 5% ethyl ether in peteroleum ether. The dried fractions are pooled and concentrated to give the title compound (11 g, 86% yield), m.p. 89°-90°.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([O:18]C)=[O:17])[CH:15]=[C:10]3[C:9]([CH2:20][O:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][C:25]3=[O:29])=[CH:8]2)=[CH:4][CH:3]=1.[Li+].[OH-].Cl>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([OH:18])=[O:17])[CH:15]=[C:10]3[C:9]([CH2:20][O:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][C:25]3=[O:29])=[CH:8]2)=[CH:30][CH:31]=1
Reactant: COC(=O)c1cc2c(COCCN3CCCC3=O)cn(Cc3ccc(F)cc3)c2cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc2c(COCCN3CCCC3=O)cn(Cc3ccc(F)cc3)c2cn1
Temperature: 50 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To a stirring solution of methyl 1-(4-fluorobenzyl)-3-{[2-(2-oxopyrrolidin-1-yl)ethoxy]methyl}-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (0.915 g, 2.15 mmol) in methanol (25 mL) was added 3M LiOH(aq) (2.15 mL, 6.45 mmol). The clear reaction was warmed to 50° C. for 16 hours. After 16 hours a 50° C. the reaction was acidified to pH 4 by the addition of 1M HCl(aq). The solvent was evaporated in vacuo and the white residue stirred in water (50 mL) for 1 hour. The solid was filtered, washed with water, and dried under heat and vacuum to yield 1-(4-fluorobenzyl)-3-{[2-(2oxopyrrolidin-1-yl)ethoxy]methyl}-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid as a white solid (0.829 g, 94% yield). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.76-1.85 (m, 2H) 2.13 (t, J=8.08 Hz, 2H) 3.31 (ddd, J=13.77, 6.69, 6.32 Hz, 4H) 3.52 (t, J=5.43 Hz, 2H) 4.66 (s, 2H) 5.57 (s, 2H) 7.16 (t, J=8.84 Hz, 2H) 7.35 (dd, J=8.46, 5.68 Hz, 2H) 7.86 (s, 1H) 8.33 (s, 1H) 8.95 (s, 1H).