Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: CCCCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Product: CCCCCCCCCCCCCCCC(=O)NCCn1cc(CCCCCc2cn(C(=O)OC(C)(C)C)c(N)n2)nn1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.087 g, 0.313 mmol) was reacted with N-(2-azidoethyl)palmitamide (0.102 g, 0.313 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-palmitamidoethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.29 (s, 1H), δ 6.78 (t, J=4.5 Hz, 1H), δ 6.41 (s, 1H), δ 6.19 (s, 2H), δ 4.39 (t, J=5.4 Hz, 2H), 83.67 (q, J=5.5, 4.8 Hz, 2H), δ 2.61 (t, J=6.9 Hz, 2H), δ 2.12 (t, J=6.5 Hz, 2H), δ 2.07 (t, J=7.5 Hz, 2H), δ 1.42 (m, 13H), δ 1.42 (m, 2H), δ 1.32 (m, 22H), 0.81 (t, J=5.4 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 176.8, 174.3, 173.9, 149.5, 148.3, 121.9, 106.4, 85.0, 67.2, 51.1, 49.5, 39.5, 39.1, 38.1, 36.8, 36.7, 32.1, 29.9, 29.8, 29.7, 29.6, 29.5, 29.3, 28.9, 28.3, 28.2, 27.9, 25.9, 25.6, 22.9, 14.3 ppm; HRMS (ESI) calcd for C33H59N7O3(M+) 601.4679. found 601.4671, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)palmitamide hydrochloride (0.155 g, 92% yield). 1H NMR (300 MHz, CD3OD) δ 8.59 (s, 1H), δ 6.53 (s, 1H), δ 4.72 (s, 2H), δ 3.75 (s, 2H), δ 2.90 (s, 2H), δ 2.54 (s, 2H), δ 2.16 (t, J=7.2 Hz, 2H), δ 1.80 (s, 2H), δ 1.69 (s, 2H), δ 1.51 (s, 4H), δ 1.28 (bs, 24H), δ 0.71 (t, J=6.3 Hz, 3H) ppm; 13C NMR (75 MHz, CD3OD) δ 175.7, 147.2, 145.6, 128.4, 127.6, 108.6, 67.2, 52.7, 37.4, 36.5, 35.8, 31.9, 29.7, 29.5, 29.4, 29.2, 28.0, 27.9, 27.8, 27.7, 25.8, 24.1, 23.6, 23.2, 22.6 ppm; HRMS (ESI) calcd for C28H51N7O (M+) 501.4155. found 501.4143.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].Cl[C:10]([CH3:18])([CH2:12][CH2:13][C:14](Cl)([CH3:16])[CH3:15])[CH3:11].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl.CCCCCC.Cl>[Br:1][C:2]1[C:3]([CH3:8])=[CH:4][C:5]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][C:10]([CH3:18])([CH3:11])[C:6]=2[CH:7]=1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: Cc1ccccc1Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.3 %

Procedure:
To a solution of 20 g (117 mmol) of 2-bromotoluene and 14.4 g (97.4 mmol) of 2,5-dichloro-2,5-dimethylhexane in 100 mL of dichloromethane was added 1.56 g (16.9 mmol) of aluminum chloride and the mixture heated at reflux. After 16 hours, the mixture was cooled to room temperature, diluted with 150 mL of hexane and 100 mL of 1 N HCl was added. The organic layer was separated and the aqueous layer was extracted with hexane. The combined organic layers were washed with saturated NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. The product was purified by filtration through a pad of silica gel with elution with hexane and afforded 23.9 g (87%) of 2-bromo-3-methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene as a solid. (m.p.: 81.1-85° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C@@H:25]([OH:26])[CH2:24][C:23]([CH3:28])([CH3:27])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.CCN(CC)CC.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:36]([O:26][C@@H:25]1[C:10]2[C:11](=[N:12][C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH:9]=2)[O:22][C:23]([CH3:28])([CH3:27])[CH2:24]1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC1(C)C[C@H](O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C[C@H](OC(=O)c2ccccc2)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Reaction time: 2 h

Procedure:
To a solution of the product of Step A (21.6 mg, 0.05 mmol), NEt3 (21 μL, 0.15 mmol), and catalytic amount of DMAP in 10 mL of CH2Cl2 at rt was added benzoyl chloride (11.5 μL, 0.10 mmol). After stirring for 2 h, the reaction was quenched by adding saturated aq NaHCO3 (5 mL) and the resulting mixture was stirred at rt for 30 min. The reaction mixture was partitioned between CH2Cl2 (50 mL) and saturated aq NaHCO3 (50 mL). The aq layer was separated and extracted with CH2Cl2 (3×10 mL). The organic layers were combined, dried over MgSO4, and concentrated. Chromatography on Biotage 40+S cartridges using 3:17 v/v EtOAc/hexanes as the eluant afforded the title compound: 1H NMR δ 1.57 (s, 3H), 1.65 (s, 3H), 2.24 (dd, J=6.7, 14.2, 1H), 2.46 (dd, J=5.9, 14.3, 1H), 6.40 (t, J=6.2, 1H), 7.00 (d, J=8.4, 2H), 7.16-7.28 (m, 5H), 7.45-7.60 (m, 3H), 7.77 (s, 1H), 8.07 (d, J=7.5, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:10]([C:15](=[O:25])[N:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[N:17]=3)=[CH:11][NH:12][C:13]=2[CH3:14])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(O)CO.COC>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([N:16]2[C:15](=[O:25])[C:10]3=[CH:11][NH:12][C:13]([CH3:14])=[C:8]([C:4]4[CH:3]=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:7]=[CH:6][CH:5]=4)[C:9]3=[N:17]2)=[CH:19][CH:20]=1
Reactant: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1cccc(N)c1
Reactant: CS(=O)(=O)Cl
Agent: COC
Solvent: OCCO
Solvent: c1ccncc1
Product: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1cccc(NS(C)(=O)=O)c1
Yield: 91.5 %

Procedure:
To a stirred solution of 7-(3-aminophenyl)-2-(4-chlorophenyl)-2,5-dihydro-6-methylpyrazolo[4,3-c]pyridin-3-one (0.100 g, 0.285 mmol) in anhydrous ethylene glycol, dimethyl ether (5 ml) was added portionwise, over a few hours, pyridine (0.228 ml, 2.82 mmol) and methanesulphonyl chloride (0.174 ml, 2.25 mmol), and the mixture was heated at 50° C. for 1.5 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, 5-10% MeOH/CH2Cl2) to leave 0.1119 g (92%) of the title compound as a yellow solid; mp 332-341° C. (CH2Cl2-MeOH-EtOAc); 1H NMR (360 MHz, DMSO-d6) δ2.28 (3H, s), 3.06 (3H, s), 7.24 (2H, dd, J 7.9, J′1.8 Hz), 7.40 (1H, m), 7.43 (2H, d, J 9.0 Hz), 7.46 (1H, t, J 8.0 Hz), 8.13 (2H, d, J 9.0 Hz), 8.56 (1H, s); MS (ES+) m/z 429/431[MH]+. Anal. found: C, 55.89; H, 4.06; N, 12.60. C20H17CLN4O3S.0.2H2O requires: C, 55.54; H, 4.06; N, 12.95%.
Reaction SMILES: [CH2:1]([C:3]1([C:16]([O-:18])=[O:17])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)C.[CH:19]([N-]C(C)C)(C)[CH3:20].[Li+].CI.[Cl-].[NH4+]>C1COCC1>[CH3:1][C:3]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:4]1
Reactant: CCC1(C(=O)[O-])CCCN(C(=O)OC(C)(C)C)C1
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
A THF (5 mL) solution of 1-tert-butyl 3-ethylpiperidine-1,3-dicarboxylate (1 g, 3.89 mmol) was added dropwise to a THF (15 mL) solution of lithium diisopropylamide (5.83 mmol) in a nitrogen atmosphere at −78 degrees over 5 minutes. The mixture was raised to room temperature, and stirred for 50 minutes. The temperature of the reaction mixture was lowered to −78 degrees again, and methyl iodide (1.21 mL, 19.43 mmol) was added dropwise at −78 degrees over 5 minutes. The reaction mixture was then raised to room temperature, and stirred for 5 hours. After being added to a saturated ammonium chloride aqueous solution, the reaction mixture was stirred for a while, and extracted with diethyl ether. The organic layer was collected, washed once with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was then purified using silica gel column chromatography to obtain the target (698 mg, 66%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[N+:6]([O-:8])[CH:7]=1.[H-].[Na+].[CH3:13]I>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][O:10][CH3:13])=[N+:6]([O-:8])[CH:7]=1
Reactant: [O-][n+]1cc(Br)ccc1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccc(Br)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a solution of 5-bromo-2-hydroxymethyl-pyridine-1-oxide (6.43 g, 31.5 mmol) in THF (200 ml) was added sodium hydride (1.51 g, 63.1 mmol) at 0° C., and then the reaction mixture was stirred at ambient temperature for 1 h. After cooling to 0° C., MeI (2.90 ml, 46.6 mmol) was added. The temperature was raised to ambient temperature and the reaction mixture was heated to 70° C. for 1 h. After cooling to 0° C. the reaction mixture was quenched with MeOH. The solvents were removed, and the crude product was purified by silica gel chromatography using an ethyl acetate/hexane eluent to yield 4.8 g (70%) of the title compound.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[CH2:8][CH2:7][N:6]([CH2:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:5](=[O:26])[C:4]=2[CH:3]=1.[Li]CCCC.[C:32]1(=[O:38])[O:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C1COCC1>[OH:38][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([C:2]1[S:10][C:9]2[CH2:8][CH2:7][N:6]([CH2:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:5](=[O:26])[C:4]=2[CH:3]=1)=[O:37]
Reactant: O=C1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2CCc3sc(Br)cc3C2=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCN2CCc3sc(C(=O)CCCCO)cc3C2=O)CC1
Reaction time: 0.5 h

Procedure:
A solution of 3-1 (0.66 g, 1.5 mmoles) in THF (30 ml) was cooled to -78° and treated with n-BuLi (3.0 mmoles) and the resulting yellow brown solution was stirred for 30 minutes. Then, valerolactone (0.16 g, 1.65 mmoles) was added and this was stirred at -70° for 6 hours and then overnight at ambient temperature. The reaction mixture was cooled to -10°, quenched with 10% KHSO4 and concentrated. The residue was taken up in H2O/EtOAc and the organic phase was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on silica gel eluting with hexane (3)/acetone(2) to give 4-1, Rf 0.35.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[C:10]=1[Cl:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][C:18]1=[O:23]>>[CH2:1]([S:8][C:9]1[C:10]([Cl:16])=[C:11]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C:18]2=[O:23])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1c(Br)cccc1SCc1ccccc1
Reactant: O=C1COCCN1
Product: O=C1COCCN1c1cccc(SCc2ccccc2)c1Cl

Procedure:
Intermediate 16 (10 g, 31.38 mmol) was treated with morpholin-3-one (389 mg, 3.85 mmol) according to the procedure described in 1.6).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[CH:16]([C:27](=[CH2:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:36]([OH:44])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[C:36]([O:44][CH2:35]/[C:27](/[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: C=C(C(=O)OC(C)(C)C)C(O)CCCCc1ccccc1
Reactant: O=C(O)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C(=C/CCCCc1ccccc1)COC(=O)c1ccccc1
Temperature: 0 °C
Yield: 81.4 %

Procedure:
Diisopropyl azodicarboxylate (5 mL, 25 mmol) is added dropwise over 5 minutes to a solution of t-butyl 2-(1-hydroxy-5-phenylpentyl)acrylate (5.59 g, 19.3 mmol), benzoic acid (3 g, 25 mmol) and triphenyl phosphine (6.5 g, 25 mmol) in THF (100 mL) at -55° C. The reaction is maintained between -55 and -50° C. for 45 minutes and then the reaction is allowed to warm to 0° C. The solution is diluted with ether (300 mL) and washed with 1 N NaOH (2×40 mL) and brine (70 mL). The resulting solution is dried (MgSO4) and concentrated in vacuo. The crude reaction product is partially dissolved in 20% ether/petroleum ether and applied to a silica gel column as a slurry. The column is eluted using gradient elution (silica, 10 to 20% ether in petroleum ether) to obtain (E)-2-t-Butoxycarbonyl-7-phenylhept-2-enyl benzoate (6.2 g, 82%): 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J=7.0 Hz, 2H), 7.53-7.49 (m, 1 H), 7.41 (t, J=7.5 Hz, 2H), 7.28-7.23 (m, 2H), 7.20-7.10 (m, 3H), 6.99 (t, J=7.8 Hz, 1H), 5.05 (s, 2H), 2.61 (t, J=7.5 Hz, 2H), 2.36 (q, J=7.5 Hz, 2H), 1.72-1.46 (m, 4H), 1.47 (s, 9H); MS (FAB) m/e 395 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([NH:13][CH3:14])=[C:7]([NH2:15])[C:6]=1[CH3:16])(=O)C.CO[C:19]([CH2:21][O:22][C:23]1[CH:36]=[CH:35][C:26]([CH2:27][CH:28]2[S:32][C:31](=[O:33])[NH:30][C:29]2=[O:34])=[CH:25][CH:24]=1)=O.Cl.C(=O)([O-])O.[Na+]>C(OCC)C.O1CCOCC1>[OH:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]2[N:13]([CH3:14])[C:19]([CH2:21][O:22][C:23]3[CH:24]=[CH:25][C:26]([CH2:27][CH:28]4[S:32][C:31](=[O:33])[NH:30][C:29]4=[O:34])=[CH:35][CH:36]=3)=[N:15][C:7]=2[C:6]=1[CH3:16]
Reactant: COC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CNc1c(C)c(C)c(OC(C)=O)c(C)c1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1c(O)c(C)c2nc(COc3ccc(CC4SC(=O)NC4=O)cc3)n(C)c2c1C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 27.2 %

Procedure:
A mixture of 1.0 g of 4-acetoxy-N-methyl-3,5,6-trimethyl-1,2-phenylenediamine (prepared as described in Preparation 19), 2.7 g of 5-(4-methoxycarbonylmethoxybenzyl)thiazolidine-2,4-dione (prepared as described in Preparation 21), 5 ml of 1,4-dioxane and 25 ml of concentrated aqueous hydrochloric acid was heated under reflux for 2 days. At the end of this time, the reaction mixture was added to ice-water and the resulting mixture was neutralized by the addition of sodium hydrogencarbonate. It was then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, after which the residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent. Fractions containing the title compound were collected and the solvent was removed by distillation under reduced pressure, to give a red residual oil. 150 ml of diethyl ether were added to the oil, and the mixture was agitated ultrasonically for 5 minutes. The precipitate which separated out was collected by filtration and dissolved in 300 ml of tetrahydrofuran. The resulting solution was concentrated to a volume of between about 10 ml and 20 ml by evaporation under reduced pressure. 200 ml of ethyl acetate were added to the concentrate, and the mixture was agitated ultrasonically for 20 minutes. The precipitate which separated out was collected by filtration, to give 0.52 g of the title compound, melting at 240°-244° C. and having an Rf value=0.44 (on thin layer chromatography on silica gel; developing solvent: ethyl acetate).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH:11]([C:15]([OH:17])=[O:16])[CH:12]([CH3:14])[CH3:13].[OH-].[Na+].S(=O)(=O)(O)O>O1CCCC1>[C:1]([NH:10][CH:11]([C:15]([OH:17])=[O:16])[CH:12]([CH3:14])[CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(N)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)c1ccccc1)C(=O)O
Reaction time: 3 h

Procedure:
5.1 kg. (36.28 moles) of benzoyl chloride is added portionwise to a mixture of 3.5 kg. (29.88 moles) of DL-valine, 39.0 1. of 2N. sodium hydroxide solution (78 moles) and 7 1. of tetrahydrofuran stirred at ~10° C. at a rate such that the temperature is maintained at 10° -15° C., and the reaction mixture is warmed to ~20° C. and stirred at ~20° C. for 3 hours, the reaction mixture being stirred under nitrogen throughout. 1.4 1. of concentrated sulfuric acid is carefully added at a rate such that the temperature does not exceed 25° C., and the mixture is cooled to ~5°-10° C. and stirred at this temperature for about 30 minutes to obtain a solid. (If necessary, the mixture is seeded.) The resulting solid is collected by filtration, washed three times with 20 1. portions of hot water, washed three times with 20 1. portions of hexane and dried at 40° C. and reduced pressure for ~12 hours to obtain the product (6.4 kg.), m.p. 123°-126° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[O:7]2)[CH2:3][CH2:2]1.Cl[CH2:17][CH2:18][CH2:19][CH:20]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH:20]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[CH2:19][CH2:18][CH2:17][N:1]2[CH2:6][CH2:5][C:4]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8](=[O:15])[O:7]3)[CH2:3][CH2:2]2)=[CH:26][CH:25]=1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: O=C1OC2(CCN(CCCC(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c2ccccc21

Procedure:
A mixture of 4.0 g. of 1,3-dihydrospiro[isobenzofuran-1,4'-piperidine]-3-one, 6.4 g. of 4-chloro-1,1-di(4-fluorophenyl)butane, 10 g. of potassium carbonate, and 25 ml. of 1-butanol is heated under reflux for 48 hours and filtered. The filtrate is diluted with water and extracted with benzene. The benzene solution is dried over potassium carbonate and concentrated to an oil, 1,3-dihydro-1'-[4,4-di(4-fluorophenyl)butyl]spiro[isobenzofuran-1,4'-piperidine]-3-one. The oil is converted to a crystalline hydrochloride salt, m.p. 182°-183° (from benzene).
Reaction SMILES: [K].[CH:2]([CH:4]([CH2:7][C:8]#[N:9])[C:5]#[N:6])=O.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH2:18])=[CH:13][CH:12]=1.C(O)(=O)C>O>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]([NH:18][CH:2]=[C:4]([CH2:7][C:8]#[N:9])[C:5]#[N:6])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:16]=1
Reactant: N#CCC(C#N)C=O
Reactant: NC(c1ccccc1)c1ccc(F)cc1
Agent: [K]
Solvent: O
Solvent: CC(=O)O
Product: N#CCC(C#N)=CNC(c1ccccc1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of formyl succinonitrile potassium salt (7.26 g, 49.7 mmol) and 1-(4-fluorophenyl)-1-phenylmethaneamine (11.0 g, 54.7 mmol) in water-(20 ml) was added acetic acid (20 ml) at room temperature, the mixture was stirred at 100° C. for 30 minutes, and the solvent was distilled off under reduced pressure. The residue was poured into iced water, made basic by adding potassium carbonate and then extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the objective product as a solid material.
Reaction SMILES: [CH3:1][C@@:2]12[C@H:11]3[CH2:12][CH2:13][C@:14]4([CH3:20])[C:18](=O)[CH2:17][CH2:16][C@H:15]4[C@@H:10]3[C@H:9](O)C[C@H:7]1[CH2:6][C@H:5]([OH:22])[CH2:4][CH2:3]2.C[C:24]([CH3:27])([O-:26])[CH3:25].[K+].O>O1CCCC1.[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH3:9]/[CH:10]=[C:15]1/[CH2:16][CH2:17][C@@H:18]2[C@:14]/1([CH3:20])[CH2:13][CH2:12][C@H:11]1[C@H:25]2[C@H:24]([OH:26])[CH2:27][C@H:7]2[C@:2]1([CH3:1])[CH2:3][CH2:4][C@@H:5]([OH:22])[CH2:6]2
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1C[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(C)(C)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C/C=C1/CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 72 h
Yield: 82 %

Procedure:
A solution of 1.282 g (ca. 0.0034 mol) of 3α,5β,7α-3,7-dihydroxyandrostan-17-one in 5 ml of tetrahydrofuran was added to a room temperature solution of 113 ml of tetrahydrofuran, 1.875 g (0.0167 mol) of potassium t-butoxide and 6.215 g (0.0167 mol) of ethyltriphenylphosphonium bromide. The mixture was stirred under argon for 72 hr. and then was poured into 750 ml of water containing 250 g of ice. After 30 min., the mixture was collected by suction filtration and washed with water. The dried, crude material (3.0 g) was chromatographed on 200 g of silica gel to afford, on elution with ethyl acetate--hexane (2:1), 0.888 g of material (82%). Trace amounts of impurities were removed by dissolving in a mixture of hexane and methylene chloride. The methylene chloride was distilled, the mixture was cooled, and the solid product, (Z)-3α,5β,7α-pregn-17(20)-ene-3,7-diol, was collected by filtration. The analytical sample was recrystallized from ethyl acetate then acetonitrile, mp 160°-161° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][NH:11][C:12]2[C:17]([NH2:18])=[N:16][CH:15]=[C:14]([Br:19])[N:13]=2)=[CH:2]1.[N:20]([O-])=O.[Na+].OS(O)(=O)=O.[OH-].[Na+]>CC(O)=O.O.O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][N:11]2[C:12]3=[N:13][C:14]([Br:19])=[CH:15][N:16]=[C:17]3[N:18]=[N:20]2)=[CH:2]1
Reactant: Nc1ncc(Br)nc1NCc1c[nH]c2ncccc12
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Brc1cnc2nnn(Cc3c[nH]c4ncccc34)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
To the ice-cooled mixture of N2-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-6-bromopyrazine-2,3-diamine (48 mg, 0.15 mmol) in HOAc/H2O (1.5 mL/1.5 mL) was added NaNO2 (31 mg, 0.45 mmol) in water (0.2 mL). The reaction was stirred for 1.5 h in an ice bath, then aqueous H2SO4 (49%, 0.1 mL) was added. The resulting mixture was allowed to warm to room temperature and stir overnight, then was adjusted to pH>8 with 3 N aqueous NaOH solution, and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated to give the title compound (46 mg) MS (m/z): 332 (M+1)+.