Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:4]=2[CH:3]=1.[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33].CCCCCC>CCN(CC)CC.[Cu]I.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:23]([C:5]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:4]2[CH:3]=[C:2]([C:36]#[C:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(Br)cc21
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(C#C[Si](C)(C)C)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To an ice-cold mixture of 2-bromo-9,9-dioctylfluorene (11.47 g, 24.4 mmol) in 100 mL Et3N was added copper (I) iodide (31.0 mg, 0.163 mmol), palladium (II) acetate (29.7 mg, 0.132 mmol) and triphenylphosphine (90.8 mg, 0.346 mmol). Trimethylsilyl acetylene (3.0 g, 30.5 mmol) was then added and the mixture stirred for 30 minutes followed by a further 30 minutes while warming to room temperature. The reaction mixture was next refluxed for 20 hours and then allowed to cool to room temperature. Thin layer chromatography (hexane as the mobile phase) showed the reaction to be complete and the formation of a reaction product with Rf value less than that of 2-bromo-9,9-dioctylfluorene. Petroleum ether was added to the reaction mixture and the insolubles filtered off. The filtrate was evaporated to dryness and the residual oil taken up in petroleum ether and washed successively with HCl (10%), NaHCO3 solution and water. Drying over magnesium sulfate and evaporation gave oil characterized as (9,9-Dioctyl-9H-fluoren-2-ylethynyl)-trimethylsilane (10.2 g, 86% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].S(=O)(=O)(O)O>O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+3].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[Fe+3]>[CH3:1][O:2][C:3]1[C:4]([O:9][CH3:10])=[CH:5][C:6]2[C:7]3[C:6](=[CH:5][C:4]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:8]=3)[C:7]3[C:6](=[CH:5][C:4]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:8]=3)[C:7]=2[CH:8]=1
Reactant: COc1ccccc1OC
Agent: [Fe+3]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: COc1cc2c3cc(OC)c(OC)cc3c3cc(OC)c(OC)cc3c2cc1OC
Temperature: 0 °C
Reaction time: 5 h
Yield: 83 %

Procedure:
In a 2-liter three-necked flask chilled with ice, 455 g of iron(III) sulfate hexahydrate and 193 ml of ice-water were placed, and vigorously stirred to completely dissolve iron(III) sulfate hexa-hydrate in water. Thereafter, 58.7 g of 1,2-dimethoxybenzene was further added to the solution and 882 ml of concentrated sulfuric acid was gradually added with cooling to prepare a mixture. After reaction of 24 hours, 9 liter of ice-water was gradually added to the reaction mixture. After stirring of 5 hours, the reaction mixture was filtered through a glass filter to obtain crude crystals of the above compound (TP-A) of 48.1 g (yield: 83%)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:18]=3)[C:13]([CH:24]=O)=[CH:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([BH3-])#N.[Na+].C(OCC)(=O)C>ClCCl.[I-].[Zn+2].[I-]>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:18]=3)[C:13]([CH3:24])=[CH:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2c(c1)c(C=O)cn2CCCCc1ccccc1
Agent: [BH3-]C#N
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)c(C)cn2CCCCc1ccccc1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 79.8 %

Procedure:
A solution of methyl 1-(4-phenylbutyl)-3-formylindole-5-carboxylate (600 mg, 1.79 mmol) in dry dichloromethane (15 ml) was added successively zinc iodide (857 mg, 2.69 mmol) and sodium cyanoborohydride (843 mg, 13.41 mmol). The resulting mixture was left under stirring at 85° C. for 1.5 h. After that the mixture was filtered through celite, washing the solid with dichloromethane (200 ml). The solvent was evaporated off under reduced pressure and the resulting crude was purified by chromatography through a silica gel column, eluting with n-hexane:ethyl acetate, 98:2, thereby recovering 459 mg of the title compound (80% yield).
Reaction SMILES: C[O:2][C:3]1[C:4]([C:21]2[N:26]=[N:25][C:24]([N:27]([CH3:38])[CH:28]3[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][C:30]([CH3:37])([CH3:36])[CH2:29]3)=[CH:23][CH:22]=2)=[CH:5][C:6]2[N:10]=[C:9]([CH3:11])[N:8](COCC[Si](C)(C)C)[C:7]=2[CH:20]=1.B(Br)(Br)Br>>[CH3:11][C:9]1[NH:8][C:7]2[CH:20]=[C:3]([OH:2])[C:4]([C:21]3[N:26]=[N:25][C:24]([N:27]([CH3:38])[CH:28]4[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][C:30]([CH3:37])([CH3:36])[CH2:29]4)=[CH:23][CH:22]=3)=[CH:5][C:6]=2[N:10]=1
Reactant: COc1cc2c(cc1-c1ccc(N(C)C3CC(C)(C)NC(C)(C)C3)nn1)nc(C)n2COCC[Si](C)(C)C
Agent: BrB(Br)Br
Product: Cc1nc2cc(-c3ccc(N(C)C4CC(C)(C)NC(C)(C)C4)nn3)c(O)cc2[nH]1
Yield: 50 %

Procedure:
From 6-(6-methoxy-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (44 mg, 0.082 mmol), following General Method 3.2 for methoxy deprotection using BBr3, 2-methyl-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-1H-benzo[d]imidazol-6-ol was obtained as a white solid after HPLC purification (16 mg, 50% yield). LCMS Rt=0.40 min [Method Q], MS (M+1)=395.4. 1H NMR (METHANOL-d4) δ 8.15 (d, J=10.1 Hz, 1H), 7.88 (s, 1H), 7.34 (d, J=9.6 Hz, 1H), 6.97 (s, 1H), 5.07 (t, J=11.9 Hz, 1H), 3.02 (s, 3H), 2.55 (s, 3H), 1.65-1.77 (m, 2H), 1.51-1.65 (m, 2H), 1.41 (s, 6H), 1.25 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([NH:14][C:15](C1ON=C(C3C=CC=CC=3)C=1C(F)(F)F)=[O:16])[CH2:7][CH2:6]2.[C:32]1([C:38]2[O:42][N:41]=[C:40](C(O)=O)[C:39]=2[C:46]([F:49])([F:48])[F:47])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([NH:14][C:15]([C:40]1[C:39]([C:46]([F:47])([F:49])[F:48])=[C:38]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:42][N:41]=1)=[O:16])[CH2:7][CH2:6]2
Reactant: O=C(O)c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: COc1ccc2c(c1)CCC(NC(=O)c1onc(-c3ccccc3)c1C(F)(F)F)C2=O
Product: COc1ccc2c(c1)CCC(NC(=O)c1noc(-c3ccccc3)c1C(F)(F)F)C2=O

Procedure:
The titled compound was prepared using the experimental protocol described for Preparation 43A employing 5-phenyl-4-(trifluoromethyl)isoxazole-3-carboxylic acid (Step D of Intermediate 5). 1H NMR (400 MHz, CDCl3) δ ppm 8.04 (1H, d, J=8.80 Hz), 7.85 (1H, d, J=5.28 Hz), 7.70 (2H, d, J=7.48 Hz), 7.52-7.62 (3H, m), 6.88 (1H, dd, J=8.80, 2.42 Hz), 6.74 (1H, d, J=2.20 Hz), 4.78 (1H, ddd, J=13.53, 4.95, 4.84 Hz), 3.89 (3H, s), 3.29 (1H, ddd, J=17.11, 12.93, 4.29 Hz), 2.93-3.08 (2H, m), 1.97-2.10 (1H, m).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[N:9]([C:17]1[C:22]([F:23])=[C:21](Cl)[N:20]=[C:19]([Cl:25])[N:18]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:40][NH:41][CH2:42][C:43]1[S:44][CH:45]=[CH:46][N:47]=1>C1COCC1.O>[CH3:4][C:2]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[N:9]([C:17]1[C:22]([F:23])=[C:21]([N:41]([CH3:40])[CH2:42][C:43]2[S:44][CH:45]=[CH:46][N:47]=2)[N:20]=[C:19]([Cl:25])[N:18]=1)[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[O:7])([CH3:3])[CH3:1]
Reactant: CNCc1nccs1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CN(Cc1nccs1)c1nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F
Reaction time: 8 h
Yield: 109.6 %

Procedure:
Tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (1.16 g, 2.339 mmol) was dissolved in THF (5 mL). To this solution was added triethylamine (0.39 mL, 2.8 mmol), followed by N-methyl-1-(1,3-thiazol-2-yl)methanamine (0.30 g, 2.3437 mmol) in THF (2 mL). The reaction was left to stir overnight. Then the reaction mixture was diluted with water, and the aqueous layer was extracted with ethyl acetate. The organics were dried (Na2SO4) and concentrated to produce tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[methyl(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate as a white solid (1.51 g). LCMS: (M+H−Boc)+=489.1.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[N+]([O-])=O)[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C=CC=1.[N+:39]([O-])([OH:41])=[O:40]>OS(O)(=O)=O>[N+:39]([C:11]1[C:10]2[C:9](=[O:22])[C:8]3[C:17](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=3)[C:16](=[O:18])[C:15]=2[CH:14]=[CH:13][CH:12]=1)([O-:41])=[O:40]
Reactant: O=[N+]([O-])O
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: O=C1c2ccccc2C(=O)c2ccccc21
Agent: O=S(=O)(O)O
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2cccc([N+](=O)[O-])c21
Yield: 30 %

Procedure:
Similarly, there has hitherto been no commercially and economically practicable process for the production of pure 1,8-dinitroanthraquinone. It is known that the commercially very important α,α-dinitration products of anthraquinone can be obtained in particularly high yields by nitration in concentrated nitric acid. Since the quantity of nitric acid required for this process is not appreciably higher than the quantity of sulphuric acid required for dinitration in H2SO4, nitric acid is economically superior to dinitration in sulfuric acid. The much simpler regeneration of the solvent is another factor in favour of nitric acid. According to Moiseva (Org.Polyprod, i. Krasitel, Moscow 1969, No. 4, 70-79), it is possible by the nitric acid process to obtain a 1,5-dinitroanthraquinone in a yield of 30 % of the theoretical amount. However, it is not possible under the conditions quoted by Moiseva (98 % HNO3, 24 hours at 24°-25°C) to obtain pure 1,5-dinitroanthraquinone. Instead the products obtained still contain at least 5 % of 1,8-dinitroanthraquinone (cf. Example 18 below). Even under more stringent conditions (filtration under suction at elevated temperature, increasing the quantity of nitric acid used for washing), we were unable to obtain 1,5-dinitroanthraquinone with a purity of more than 95 % in a yield of more than 20 % of the theoretical amount. In addition, it is subsequently no longer possible to isolate pure 1,8-dinitroanthraquinone from the mother liquors, because they then contain too much 1,5-dinitroanthraquinone.
Reaction SMILES: I[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([NH2:13])[CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:18]=[C:19]([CH2:21][O:22][C:23]([CH3:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])[CH:20]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([C:2]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:5]=[C:4]([NH2:13])[CH:3]=2)[CH:18]=[C:19]([CH2:21][O:22][C:23]([CH3:29])([CH3:28])[C:24]([F:25])([F:26])[F:27])[CH:20]=1
Reactant: Nc1cc(I)n(-c2ccccc2)n1
Reactant: CC(C)(OCc1cc(Cl)cc(B2OC(C)(C)C(C)(C)O2)c1)C(F)(F)F
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: COCCOC
Product: CC(C)(OCc1cc(Cl)cc(-c2cc(N)nn2-c2ccccc2)c1)C(F)(F)F
Temperature: 25 °C
Yield: 107.8 %

Procedure:
Under argon atmosphere, to a solution of 5-iodo-1-phenyl-1H-pyrazol-3-ylamine (40 mg) prepared according to the same procedures as Preparation 2 in 1,2-dimethoxyethane (1.0 ml) were sequentially added 2-[3-chloro-5-(2,2,2-trifluoro-1,1-dimethylethoxymethyl)phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (64 mg), palladium (II) acetate (3 mg), tricyclohexylphosphine (8 mg) and a 2M aqueous solution of sodium carbonate (0.5 ml) at room temperature, and the mixture was stirred at 100° C. for 13 hours. This reaction mixture was cooled to room temperature, and then purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 3/2 to 1/1) to give the titled compound (62 mg).
Reaction SMILES: [N:1]([C@@H:4]([CH3:18])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([NH2:17])=[O:16])[CH:13]=2)[CH:8]=[N:7]1)=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][C@@H:4]([CH3:18])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([NH2:17])=[O:16])[CH:13]=2)[CH:8]=[N:7]1
Reactant: C[C@@H](Cn1ncc2ccc(C(N)=O)cc21)N=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: C[C@H](N)Cn1ncc2ccc(C(N)=O)cc21
Yield: 75 %

Procedure:
To a solution of the product from Step B (0.14 g, 0.55 mmol) in ethanol (10 mL) was added Pd/C (10%, 0.01 g) under a nitrogen atmosphere at room temperature. The resultant suspension was stirred for 18 h under a hydrogen atmosphere. The reaction was filtered through a filter aide and the filtrate was concentrated in vacuo to give a solid (0.09 g, 75%): mp 170-172° C.; MS (ES) m/z 219 (M+); 1H NMR (DMSO-d6) 8.25 (1H, s), 8.12 (1H, s), 8.04 (1H, br s), 7.80 (1H, d, J=8.0 Hz), 7.63 (1H, d, J=8.0 Hz), 7.44 (1H, s), 4.27 (2H, m), 3.34 (1H, m), 0.96 (3H, d, J=6.0 Hz). Analysis. Calculated for C11H14N4O: C, 60.53; H, 6.47; N, 25.67. Found: C, 60.37; H, 6.33; N, 25.48.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]2[CH2:16][CH2:17][NH:18][C@@H:10]1[C@@H:11]([O:14]2)[O:12]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)[C:21]([OH:23])=[O:22]>O>[CH2:1]([O:8][C@H:9]1[C@H:15]([OH:14])[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:22])[C@@H:10]1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@H]1O[C@@H]2CCN[C@H]1[C@H]2OCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: O
Product: O=C[C@@H]1[C@@H](OCc2ccccc2)[C@H](O)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
A solution of methyl 3-O-benzyl-2,6-imino-2,5,6-trideoxy-β-D-lyxo-hexofuranoside (23β) (762 mg, 2.06 mmol) in a 1:1 mixture of trifluoroacetic acid and water (20 ml) was stirred at room temperature for 20 minutes. The solvents were removed in vacuo and the crude material purified by flash chromatography (ethyl acetate-hexane 1:2) to give 3-O-benzyl-N-benzyloxycarbonyl-2,6-imino-2,5,6-trideoxy-D-lyxo-hexose (640 mg, 87%) as a clear oil, [α]20D -17.2° (c, 0.73 in chloroform); νmax (film) 3400 (OH), 2920, 1690 (C=O), 1410, 1345 and 1060 cm-1 ; 1H NMR δ 1.50-1.71 (1H, m, H-5); 1.80 (1H, bs, OH); 2.02-2.20 (1H, m, H-5'); 3.08-3.27 (1H, m, H-6); 3.94-4.20 (2H, m, 6-H, H-3); 4.25-4.85 (4H, m, H-2, H-4, CH2 -Ph); 5.05-5.18 (2H, m, CH2 -Z); 5.50, 5.53 (0.75H, 2×s, H-1-hemiacetal); 7.20-7.40 (10H, m, 2×H-Ph); 9.68 (0.25H, s, H-1-aldehyde). 13C NMR δ 24.17 (t, C-5); 38.10 (t, C-6); 57.26, 57.77 (2×d, C-2); 67.30, 67.48, 67.58 (3×t, CH2 -Z); 71.38, 71.84, 72.12 (3×t, CH2Ph); 74.00, 74.63, 74.76 (3×d, C-3, C-4); 98.72, 98.88, 198.17 (3×d, C-1); 127.35, 127.58, 127.85, 128.01, 128.23, 128.63 (6×d, HC-Ph); 136.51, 136.62, 136.73, 137.46, 155.60 (s, C=O-Z); 137.74, 137.88 (6×s, C-Ph). m/z: 91 (100%), 262 (20%), 370 (M+H+, 15%). (Found C, 68.68; H, 6.40; N, 3.71. C21H23NO5 requires C, 68.28; H, 6.28; N, 3.79).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(=NC1CCCCC1)C.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH2:31][CH:30]3[CH2:32][CH:27]([CH2:28][CH2:29]3)[C:26]=2[CH:33]=O)=[CH:21][CH:20]=1.CC[O:37][CH2:38][CH3:39]>O>[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH2:31][CH:30]3[CH2:32][CH:27]([CH2:28][CH2:29]3)[C:26]=2[CH:33]=[CH:39][CH:38]=[O:37])=[CH:23][CH:24]=1
Reactant: O=CC1=C(c2ccc(F)cc2)CC2CCC1C2
Reactant: CCOCC
Agent: CC(C)[N-]C(C)C
Agent: CC=NC1CCCCC1
Agent: [Li+]
Solvent: O
Product: O=CC=CC1=C(c2ccc(F)cc2)CC2CCC1C2
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
To a 0°-5° C. solution of LDA (26.5 mmoles) in 25 ml anhydrous ether was added ethylidenecyclohexylamine (Org. Syn. 50 66) (3.32 g, 26.5 mmlles) in 25 ml anhydrous ether. The solution was stirred for 10 minutes, cooled to -70° C. and 3-(4-fluorophenyl)bicyclo[3.2.1]oct-2-ene-2-carboxaldehyde (5.55 g, 24.1 mmoles) in 25 ml ether was added. The solution was stirred for 60 minutes, warmed to 0°-5° C., stirred for 90 minutes and diluted with water. The organic layer was washed with water and brine and dried (MgSO4). Removal of the volatiles in vacuo provided a residue which was purified by HPLC using 3% ethyl acetate in hexanes as the eluent. Concentration in vacuo of the product rich fractions provided 2.53 g of the product as an orange oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[NH:16][C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:19])[O:3]1.I[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:19])[O:3]1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Reactant: CCCCCI
Product: CCCCCn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2

Procedure:
5-(4,4-Dimethyl-oxo-1,4-dihydro-2H-3,1-benzoxazine-6-yl)-1H-pyrrole-carbonitrile (1.94 g, 7.3 mmol) was reacted, according to General Method A, with 1-iodopentane (1.5 g, 7.6 mmol) to afford the title compound, m.p. 128-131° C. (0.2 g, 8%); 1H-NMR (DMSO-d6): δ 0.73 (t, J=7.3 Hz, 3H), 1.05 (m, 2H), 1.14 (m, 2H), 1.57 (m, 2H), 1.63 (s, 6H), 4.04 (t, J=7.5 Hz, 2H), 6.28 (d, J=4 Hz, 1H), 6.98 (d, J=7.9 Hz, 1H), 7.04 (d, J=4.5 Hz, 1H), 7.33 (dd, J=8.9, 2.0 Hz, 1H), 7.37 (d, J=2.2 Hz, 1H), 10.41 (s, 1H), MS (APCI (−)) m/z 336 (M−H)−
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][C:8]=1[C:9]([NH2:11])=O)([O-:3])=[O:2].C(Cl)(Cl)=O.O.Cl>ClCCl.N1C=CC=CC=1.C1(C)C=CC=CC=1.[Cl-].[Na+].O>[N+:1]([C:4]1[CH:5]=[N:6][NH:7][C:8]=1[C:9]#[N:11])([O-:3])=[O:2]
Reactant: NC(=O)c1[nH]ncc1[N+](=O)[O-]
Agent: Cl
Agent: O=C(Cl)Cl
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: N#Cc1[nH]ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.1 %

Procedure:
A suspension of 4-nitro-1H-5-pyrazolecarboxamide (7.80 g, 50 mmol) in dichloromethane (300 mL) and pyridine (30 mL) was treated with a solution of phosgene in toluene (20%, 50 mL). The mixture was stirred for 16 hours at ambient temperature then water (20 mL) was slowly added to the mixture, followed by 6 N aqueous hydrochloric acid (50 mL) and brine (15 mL). The mixture was extracted with dichloromethane (5×50 mL) and ethyl acetate (3×50 mL). The organic solutions were combined and dried over magnesium sulfate, filtered and the filtrate concentrated to a volume of about 150 mL then it was extracted with 1N aqueous hydrochloric acid (25 mL) and then brine (15 mL). The organic layer was dried over magnesium sulfate then filtered and the filtrate concentrated under reduced pressure to yield the title compound as a tan solid (6.36 g, 92%): 1H NMR (DMSO-d6, 400 MHz) δ 14.99 bs, 1H), 9.15 (s, 1H); RP-HPLC (Hypersil HS C18, 5 μm, 100 A, 250×4.6 mm; 5%-100% acetonitrile-0.05 M ammonium acetate over 25 min, 1 mL/min) tr 12.05 min; MS: MH+ 137.0
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[CH2:7][CH2:6][N:5]([C@@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]2[O:14][CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:4]1.O1C2(CCN([C@H]3CCCC[C@@H]3OCCCC3CCCCC3)C2)OCC1.CC(=O)CC>Cl>[ClH:1].[O:2]=[C:3]1[CH2:7][CH2:6][N:5]([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]2[O:14][CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:4]1
Reactant: O=C1CCN([C@@H]2CCCC[C@@H]2OCCCC2CCCCC2)C1
Agent: C1CCC(CCCO[C@H]2CCCC[C@@H]2N2CCC3(C2)OCCO3)CC1
Agent: Cl
Solvent: CCC(C)=O
Product: O=C1CCN([C@H]2CCCC[C@@H]2OCCCC2CCCCC2)C1

Procedure:
(1R,2S)/(1S,2R)-2-(3-Ketopyrrolidinyl)-1-[3-(cyclohexyl)propoxy]cyclohexane monohydrochloride: (1R,2R)/(1S,2S)-2-[1,4-Dioxa-7-azaspiro[4.4]non-7-yl]-1-[3-(cyclohexyl)propoxy]cyclohexane (ii) in a mixture of 6M HCl aqueous solution-butanone (1:4, v/v, 100 mL) was refluxed for 16 hours. The cooled reaction mixture was concentrated in vacuo and the residual aqueous solution was diluted with water (˜50 mL). The acidic aqueous solution was extracted with diethyl ether (50 mL) and then with dichloromethane (3×50 mL). The dichloromethane extracts were dried over sodium sulfate and the solvent was evaporated in vacuo to provide the crude title compound. The hydrochloride salt was crystallized by triturating in a mixture of diethyl ether-hexanes (1:1, v/v, ˜200 mL) and then precipitated from a mixture of dichloromethane-diethyl ether-hexanes to yield 0.8 g of the title compound, having the elemental analysis indicated in Table 1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[CH:16][CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1.C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccccc1C=CC=Cc1ccccc1OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCO
Product: Clc1ccccc1CCCCc1ccccc1OCc1ccccc1
Yield: 62.4 %

Procedure:
Following a procedure similar to that described in the latter part of Preparation 3, 4.53 g of this 1-(2-benzyloxyphenyl)-4-(2-chlorophenyl)butadiene were dissolved in a 4:1 by volume mixture of tetrahydrofuran and ethanol and were hydrogenated, whilst ice-cooling. The reaction mixture was then worked up as described in the latter part of Preparation 3, to give 2.86 g (yield 62%) of 1-(2-benzyloxyphenyl)-4-(2-chlorophenyl)butane.
Reaction SMILES: C(/S([O:12][C:13]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([CH2:31][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:26][CH:25]=3)=[C:18]2[C:14]=1[CH2:15][NH:16][C:17]2=[O:45])(=O)=O)=C\C1C=CC=CC=1.Cl.CO>>[OH:12][C:13]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([CH2:31][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:26][CH:25]=3)=[C:18]2[C:14]=1[CH2:15][NH:16][C:17]2=[O:45]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)/C=C/c3ccccc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 56.8 %

Procedure:
In a similar manner to Step 2 of Example 233, 4-(trans-β-styrenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0770 g, 0.0122 mmol) was treated with 10% hydrogen chloride-methanol solution (0.650 mL) to obtain Compound 276 (0.00320 g, yield 49%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][O:33]C1C=C(CCC(O)=O)C=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:32][O:33][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([CH:25]2[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: COc1cccc(CCC(=O)O)c1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: COc1cccc(CCCN(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCC(C)CC2)c1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 3-(3-methoxy-phenyl)-propionic acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.