Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][CH:4]=1.[H-].[Na+].[CH2:25](Cl)[C:26]1[CH:34]=[CH:33][C:32]2[O:31][CH2:30][O:29][C:28]=2[CH:27]=1>CN(P(N(C)C)(N(C)C)=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:25][C:26]3[CH:34]=[CH:33][C:32]4[O:31][CH2:30][O:29][C:28]=4[CH:27]=3)[C:10]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1[nH]c2ncccc2c1-c1ccc(OC)cc1
Reactant: ClCc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1c(-c2ccc(OC)cc2)c2cccnc2n1Cc1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
To a solution of ethyl 3-(4-methoxyphenyl)pyrrolo[2,3-b]pyridine-2-carboxylate in HMPA stirred at ice bath temperature under an argon atmosphere is added NaH. A solution of piperonyl chloride in HMPA is added and the ice bath removed. The reaction mixture is stirred at room temperature then partitioned between 3 N HCl and EtOAc. The organic extract is washed successively with H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (Na2SO4). The solvent is removed in vacuo. The residue is purified by chromatography to afford the title compound.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:15][CH2:14][C@H:13]2[NH:16][C@:10]1([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:11][CH2:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:23](Br)[CH:24]=[CH2:25].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)C>[Si:1]([O:8][C@H:9]1[CH2:15][CH2:14][C@H:13]2[N:16]([CH2:25][CH:24]=[CH2:23])[C@:10]1([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:11][CH2:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=CCBr
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H]2CC[C@@]1(c1ccccc1)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCN1[C@@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@]1(c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A mixture of (1S,2S,5S)-2-(tert-butyldimethylsilyloxy)-1-phenyl-8-azabicyclo[3.2.1]octane (Description 55; 237 mg), allyl bromide (0.4 ml), potassium carbonate (230 mg) and N,N-dimethylformamide (2 ml) was stirred at room temperature for 2 hours. The reaction mixture was treated with diethyl ether, washed with water and brine, then dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 0-25%) to give the title compound (230 mg, 98% two steps).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[CH2:12]([Li])[CH2:13][CH2:14][CH3:15].C[Si](Cl)(C)C.Cl>O1CCCC1>[CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8]/[C:7](=[C:14](/[C:13]3[CH:12]=[CH:1][C:2]([CH3:11])=[CH:3][CH:4]=3)\[CH3:15])/[C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: [Li]CCCC
Reactant: Cc1ccnc2c1CCCC2
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: C1CCOC1
Product: C/C(=C1\CCCc2c(C)ccnc21)c1ccc(C)cc1
Temperature: 0 °C

Procedure:
5,6,7,8-Tetrahydro-4-methylquinoline (7.5 g) in tetrahydrofuran (THF) (25 ml) was added to a solution of n-butyl lithium (1.37M, 37 ml) in THF (40 ml) maintained at 0° C. After 30 minutes the solution was blown over with nitrogen onto a solution of trimethylsilyl chloride (5.6 g) in THF (25 ml) at 0° C. Further n-butyl lithium (1.37M, 37 ml) was added and after 30 minutes the reaction mixture was blown over with nitrogen onto 4-methylacetophenone (15 g) in THF (25 ml) at 0° C. After 10 minutes 2M HCl (150 ml) was added.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[O:14][N:13]=[C:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18])[CH:11]=3)=[N:7][C:6]=2[CH:27]=1.I[CH:29]([CH3:31])[CH3:30]>>[CH3:18][C@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH2:16][O:15][C:12]1[CH:11]=[C:10]([C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([O:1][CH:29]([CH3:31])[CH3:30])=[CH:27][C:6]=3[N:7]=2)[O:14][N:13]=1
Reactant: CC(C)I
Reactant: C[C@@H](COc1cc(-c2nc3cc(O)ccc3o2)on1)NC(=O)OC(C)(C)C
Product: CC(C)Oc1ccc2oc(-c3cc(OC[C@H](C)NC(=O)OC(C)(C)C)no3)nc2c1

Procedure:
Using tert-butyl [(1S)-2-{[5-(5-hydroxy-1,3-benzoxazol-2-yl)isoxazol-3-yl]oxy}-1-methylethyl]carbamate (200 mg) and 2-iodopropane (0.106 mL), and in the same manner as in Example 2, step E, the title compound was obtained (246 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:8](=[O:21])[NH:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:36])[CH2:31][C:32]([F:35])([F:34])[F:33])=[CH:25][CH:24]=1.Cl>CN1C(=O)CCC1>[F:33][C:32]([F:34])([F:35])[CH2:31][C:30]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:2]2[C:11]3[CH2:10][N:9]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)[C:8](=[O:21])[NH:7][C:6]=3[N:5]=[CH:4][CH:3]=2)=[CH:24][CH:25]=1)=[O:36]
Reactant: COc1ccc(CN2Cc3c(Cl)ccnc3NC2=O)cc1
Reactant: Nc1ccc(NC(=O)CC(F)(F)F)cc1
Agent: Cl
Solvent: CN1CCCC1=O
Product: COc1ccc(CN2Cc3c(Nc4ccc(NC(=O)CC(F)(F)F)cc4)ccnc3NC2=O)cc1
Temperature: 150 °C
Reaction time: 1.67 h
Yield: 39 %

Procedure:
1 (52 mg, 0.17 mmol), N-(4-aminophenyl)-3,3,3-trifluoropropanamide (44 mg, 0.17 mmol), and HCl (43 μL, 4.0M in dioxane, 0.17 mmol) were suspended in NMP (1 mL), and stirred in a microwave at 150° C. for 100 min. The crude product was purified directly via HPLC to provide 100 (39% yield). LC-MS (M+H=486, obsd.=486).
Reaction SMILES: [C:1]1([S:7]([NH:10][CH2:11][CH2:12][S:13][CH:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][O:17][C:16]3[CH:25]=[CH:26][C:27]([C:29]([O:31]C)=[O:30])=[CH:28][C:15]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[C:1]1([S:7]([NH:10][CH2:11][CH2:12][S:13][CH:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][O:17][C:16]3[CH:25]=[CH:26][C:27]([C:29]([OH:31])=[O:30])=[CH:28][C:15]2=3)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2c(c1)C(SCCNS(=O)(=O)c1ccccc1)c1ccccc1CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(c1)C(SCCNS(=O)(=O)c1ccccc1)c1ccccc1CO2

Procedure:
Compound 1a, 9.90 g, obtained in Example 1 was dissolved in a solvent mixture of 200 ml of methanol and 20 ml of water and 2.70 g of sodium hydroxide was added to the solution. The mixture was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure and the resulting residue was dissolved in 200 ml of water. A pH was adjusted to 1.5 with 4N hydrochloric acid aqueous solution. The crystallized crude product was taken out by filtration and dried. The crude product was recrystallized from 300 ml of isopropanol to give 6.44 g of the desired compound.
Reaction SMILES: [CH2:1]([C:5]1[NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>>[CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CCCCc1nc2ccccc2[nH]1
Product: CCCCc1nc2ccccc2n1Cc1ccc(C#N)cc1
Yield: 117 %

Procedure:
Using the procedure of Step B of Example 1, 3.5 g of 2-butyl -1H-benzimidazol [POOL et al., Am. Soc., Vol. 59, p. 178 (1937)] and 4.3 g of 4-bromomethyl benzonitrile were reacted to obtain 6.8 g of the desired product melting at 130° C. which was dissolved in methylene chloride, treated with activated charcoal, filtered and evaporated to dryness to obtain 6 g of product melting at 130° C. which was crystallized from isopropyl ether to obtain 4.7 g of the expected product melting at 148° C. The analytical sample was obtained by two successive crystallizations of 1.2 g of the product from isopropyl ether to obtain 700 mg of purified product melting at 150° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:5]=[C:6]([N+:15]([O-])=O)[CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:14])([F:13])[F:12].[H][H]>CO.[Ni]>[F:1][C:2]([F:18])([F:19])[O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:12])([F:13])[F:14])[NH2:15]
Reactant: O=[N+]([O-])c1ccc(OC(F)(F)F)c(OC(F)(F)F)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(OC(F)(F)F)c(OC(F)(F)F)c1
Yield: 92.7 %

Procedure:
291 g of the 3,4-bistrifluoromethoxynitrobenzene thus obtained were hydrogenated with 20 bar of hydrogen in the course of 3 hours at 40° C. in 500 ml of methanol with the addition of 10 g of Raney nickel. After filtering off the catalyst with suction, the filtrate was fractionally distilled and 242 g of 3,4-bistrifluoromethoxyaniline were obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]1[C:15]([C:16](OCC)=[O:17])=[CH:14][C:13]([C:21](OCC)=[O:22])=[N:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][N:11]1[C:15]([CH2:16][OH:17])=[CH:14][C:13]([CH2:21][OH:22])=[N:12]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc(C(=O)OCC)n(CCO[Si](C)(C)C(C)(C)C)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCn1nc(CO)cc1CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a solution of diethyl 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-pyrazole-3,5-dicarboxylate (0.74 g, 2 mmol) in methylene chloride (8 ml), under nitrogen, was added 12 ml of a 1.0 M solution of diisobutylaluminum hydride in methylene chloride at 0° C. After stirring at 0° C. for 0.5 hr, the mixture waas warmed to room temperature for 0.5 hr. It was then quenched with 15 ml of saturated ammonium chloride solution and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and evaporated to give 0.44 g of a white solid; mp 82–83° C.; MS m/e 287 (MH+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[CH:8]=1)[CH3:2].[Br:15]Br.O>C(O)(=O)C>[CH2:1]([O:3][CH2:4][CH2:5][S:6][C:7]1[CH:8]=[C:9]([CH3:14])[C:10]([Br:15])=[C:11]([CH3:13])[CH:12]=1)[CH3:2]
Reactant: CCOCCSc1cc(C)cc(C)c1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CCOCCSc1cc(C)c(Br)c(C)c1
Temperature: 25 °C
Yield: 65.1 %

Procedure:
To a solution of 2-[(3,5-dimethylphenyl)thio]ethyl ethyl ether (2.69 g, 12.8 mmol) in acetic acid (60 mL) was slowly added dropwise a solution of bromine (0.68 mL, 13.2 mmol) in acetic acid (30 mL) under stirring at room temperature. The reaction mixture was stirred at the same temperature for 2 hr, poured into cold water, and the mixture was extracted with diethyl ether. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane/ethyl acetate=20/1) to give the title compound (2.41 g, yield 65%) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:23](O)=[O:24]>>[CH3:32][O:31][C:27]1[CH:26]=[C:22]([CH:21]=[C:20]([O:19][CH3:18])[C:28]=1[O:29][CH3:30])[C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:24]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Product: COc1cc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3c2)cc(OC)c1OC
Yield: 74.1 %

Procedure:
Beginning with 10.0 mg (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 27.8 mg (0.131 mMol) 3,4,5-trimethoxybenzoic acid, 13.8 mg (75%) of the title compound were recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:28]([OH:30])=[O:29])[N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH:16]=2)=[O:10])=[C:4]([CH3:31])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:44](O)[CH2:45][OH:46].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:28]([O:30][CH2:44][CH2:45][OH:46])=[O:29])[N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH:16]=2)=[O:10])=[C:4]([CH3:31])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)O)n1
Reactant: OCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)OCCO)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.36 g (3 mmol) of 4-({[(4-chloro-2-methylphenyl)amino]carbonyl}amino)-1-[4-(trifluoromethyl)benzyl]-1H-imidazole-2-carboxylic acid (Example 20A) are dissolved in 6 ml of absolute DMF, and 0.58 g (3.6 mmol) of N,N-carbonyldiimidazole is added. The reaction mixture is stirred at RT for 3 h. Then 18.4 g (16.5 ml, 297 mmol) of 1,2-ethanediol and 303 mg (418 μl, 3 mmol) of triethylamine are added. The reaction mixture is stirred at 50° C. for 1.5 h and at RT overnight. Dilution with water is followed by extraction twice with ethyl acetate. The combined extracts are washed twice with saturated sodium bicarbonate solution, once with water and twice with saturated sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The residue from evaporation is purified by chromatography on silica gel with cyclohexane/ethyl acetate as eluent.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH2:18])[CH2:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>>[CH2:32]([O:31][C:29](=[O:30])[NH:18][CH2:17][CH:14]1[CH2:13][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)[C:16]=2[O:15]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1ccc(-c2cccc3c2OC(CN)C3)cc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cccc3c2OC(CNC(=O)OCc2ccccc2)C3)cc1
Yield: 92.6 %

Procedure:
Treatment of (±)-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.385 g, 1.396 mmol) with diisopropylethylamine (0.270 g, 2.09 mmol) and benzyl chloroformate (0.285 g, 1.675 mmol) generally according to the procedure described for Intermediate 12 provided 0.483 g (93%) of (±)-benzyl[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as colorless oil. Rf=0.47 (silica, ethyl acetate:hexane 2:8); mp 83-86° C.; Anal. calcd. for C24H23NO3: C, 77.19; H, 6.21; N, 3.75. Found: C, 76.97; H, 5.99; N, 3.68. Chiral HPLC separation of (±)-benzyl[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralpak OD, methanol:carbon dioxide 1:1) provided two fractions. Fraction 1 (Rt=3.788 min Chiralpak OD, methanol:carbon dioxide 1:1); Fraction 2 (Rt=4.398 min, Chiralpak OD, methanol:carbon dioxide 1:1).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[C:12]1([CH:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19](=[O:21])[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:20][C:19](=[O:21])[CH:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)C(Cc1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=Cc1ccc(Cl)cc1)C(Cc1ccccc1)c1ccccc1

Procedure:
A 20% sodium hydroxide solution (10 ml.) is added to a stirred solution of p-chlorobenzaldehyde (19.4 g., 0.138 mole) and 3,4-diphenyl-2-butanone (31.06 g., 0.138 mole) in ethanol (400 ml.). The cream-colored solid that separates is collected, washed with water, and dried at 90°C., yield 41.13 g., m.p. 113°-115°C. Recrystallization from ethanol gives material with m.p. 117°-118.5 C.
Reaction SMILES: [OH-].[Na+].CO.[Br:5][C:6]1[N:18]=[C:9]2[CH2:10][CH:11]([C:14]([O:16]C)=[O:15])[CH2:12][CH2:13][N:8]2[N:7]=1>O>[Br:5][C:6]1[N:18]=[C:9]2[CH2:10][CH:11]([C:14]([OH:16])=[O:15])[CH2:12][CH2:13][N:8]2[N:7]=1
Reactant: COC(=O)C1CCn2nc(Br)nc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CCn2nc(Br)nc2C1
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
A 2 N sodium hydroxide aqueous solution (6.9 ml) was added to a mixed solution of methanol (20 ml) and water (10 ml) containing the methyl 2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (2.4 g) obtained in (Example 5.16) <Step 3>. The obtained mixture was stirred for 1 hour 30 minutes. Thereafter, methanol was distilled away under reduced pressure, and the obtained aqueous solution was then washed with ethyl acetate (2 ml). Insoluble substances were removed by filtration. The filtrate was adjusted to pH 1 with concentrated hydrochloric acid, and was then extracted with a mixed solution (50 ml) of 20% isopropanol and methylene chloride five times. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure, so as to obtain a crude product (1.87 g) of the title compound in the form of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:15])[C:6]=2[CH:5]=[C:4]([O:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:3]=1.C[Si](C)(C)[C:27]([F:30])([F:29])[F:28].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C1COCC1>[Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C@:7]([OH:15])([C:27]([F:30])([F:29])[F:28])[C:6]=2[CH:5]=[C:4]([O:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCOC(=O)CCCOc1cc(Cl)c2c(c1)C(=O)c1ccccc1-2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)CCCOc1cc(Cl)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Reaction time: 0.25 h

Procedure:
Under an argon atmosphere, ethyl 4-(4-chloro-9-oxo-9H-fluorene-2-yloxy)butyrate (69.4 g) was dissolved in THF (700 ml), and N-(4-tert-butylbenzyl)cinchonidium 4-methoxyphenoxide (6.4 g) was added. To the reaction mixture was added dropwise a solution of trimethyl(trifluoromethyl)silane (52.0 ml) in THF (140 ml) at −16° C., and the mixture was stirred at the same temperature for 15 min. To the reaction mixture were successively added acetic acid (23.0 ml) and 1M tetrabutylammonium fluoride/THF solution (222 ml), and the mixture was stirred at room temperature for 1 hr. The solvent in the reaction mixture was evaporated, and to the obtained residue were added toluene (500 ml) and saturated aqueous sodium hydrogen carbonate (200 ml) to allow for layer separation. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate (150 ml, twice), 1N aqueous sodium hydroxide (100 ml), water (100 ml), 1N hydrochloric acid (100 ml), water (100 ml) and saturated brine (100 ml). To the obtained organic layer were added anhydrous magnesium sulfate and silica gel (150 g), and the mixture was stirred for 10 min. The insoluble material was filtered off, and the insoluble material was washed successively with toluene (300 ml) and ethyl acetate (800 ml). The obtained filtrate and the toluene washing were combined and the solvent was evaporated to give the title compound (72.1 g). Also, the solvent in the ethyl acetate washing was evaporated, to the obtained residue were added silica gel (40 g) and a mixed solvent of hexane and ethyl acetate (ethyl acetate:hexane 2:1, 300 ml), and the mixture was stirred at room temperature. The insoluble material was filtered off, and the insoluble material was washed with a mixed solvent of hexane and ethyl acetate (ethyl acetate:hexane=2:1, 300 ml). The solvent in the obtained filtrate was evaporated to further give the title compound (20.3 g).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[O:13])[S:10][CH:11]=1>O.CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[Br:6][C:7]1[CH:8]=[C:9]([C:12]([OH:2])=[O:13])[S:10][CH:11]=1
Reactant: O=S(=O)(O)O
Reactant: O=Cc1cc(Br)cs1
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1cc(Br)cs1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Chromium (VI) oxide (20 g), and concentrated sulfuric acid (32 g) were dissolved in water (50 mL) and when dissolution was complete, the volume was made up to 100 mL with water. 55 mL of the resulting solution was added dropwise to a solution of 4-bromothiophene-2-carboxaldehyde (19.1 g) in acetone (200 mL) stirred at 0° C. After 2 h, the solution was diluted with water and extracted with chloroform. The organic extracts were washed with water, then extracted with aqueous sodium hydroxide. The alkaline mixture was acidified by cautious addition of concentrated hydrochloric acid then extracted with chloroform. The organic layer was then dried (Mg2SO4), filtered, and evaporated. The resulting solid was recrystallised from diethyl ether/hexane to give a colourless solid; MS (ES+) 207, 209 (MH+).
Reaction SMILES: C[C:2]([CH3:15])([CH3:14])[C:3]#[C:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.[C:16](C1CCCC1)#[CH:17]>>[CH:2]1([C:3]#[C:4][C:5]2[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:12][CH:13]=2)[CH2:14][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)C#Cc1ccc(C(=O)O)cc1
Reactant: C#CC1CCCC1
Product: O=C(O)c1ccc(C#CC2CCCC2)cc1

Procedure:
The same procedure was followed as for 4-(3,3-dimethylbut-1-ynyl)benzoic acid, with the exception that ethynylcylopentane was used in place of 3,3-dimethylbut-1-yne.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCO.[F:32][C:33]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:34]=1[C:35](=[S:38])[NH:36][NH2:37]>C(Cl)Cl>[Si:1]([O:18][CH2:19][CH2:20][C:21]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:37][N:36]=[C:35]([C:34]2[CH:39]=[C:40]([F:43])[CH:41]=[CH:42][C:33]=2[F:32])[S:38]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NNC(=S)c1cc(F)ccc1F
Reactant: CC(C)(C)[Si](OCCC(=O)c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1)(c1ccccc1)c1ccccc1
Reaction time: 48 h

Procedure:
To a solution of 3-(tert-butyldiphenylsilyloxy)-1-phenylpropan-1-one (1.98 g, 5.10 mmol) in 20 mL of a 3:1 mixture of EtOH:DCM was added 2,5-difluorobenzothiohydrazide (0.800 g, 4.25 mmol). The mixture was allowed to stir capped, at room temperature for 60 hours, then uncapped for 48 hours and then concentrated in vacuo. The residue was purified by flash column chromatography (Hexanes) to afford the desired product as an orange oil, 2.19 g, 92% which was contaminated with 3-(tert-butyldiphenylsilyloxy)-1-phenylpropan-1-one. The compound was carried forward to the next step without further purification.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[ClH:5].NC(N)=N.C[O-].[Na+].[NH:13]([CH:20]=[C:21]([CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([O:35][CH3:36])=[CH:27][CH:26]=1)[C:22]#N)C1C=CC=CC=1>C(O)C.COCCO>[ClH:5].[NH2:3][C:2]1[N:4]=[C:20]([NH2:13])[C:21]([CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([O:35][CH3:36])=[CH:27][CH:26]=2)=[CH:22][N:1]=1
Reactant: N=C(N)N
Reactant: COc1ccc(CC(C#N)=CNc2ccccc2)c2ccccc12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCO
Solvent: CCO
Product: COc1ccc(Cc2cnc(N)nc2N)c2ccccc12

Procedure:
To 65 mL of ethanolic guanidine solution prepared from 3.42 g (35.8 mmol) of guanidine hydrochloride and 2.00 g (37.0 mmol) of sodium methoxide was added 9.00 g (28.6 mmol) of 3-anilino-2-(4-methoxy--naphthylmethyl)acrylonitrile. The solution was heated under reflux for 1.5 hr, and then 60 mL of 2-methoxyethanol was added. The internal temperature was allowed to gradually increase to 108° by distillation of the ethanol, after which it was heated at this temperature for 2.5 hr. The hot mixture was filtered, and the precipitate (7.04 g, 87% of crude product) recrystallized from 30% ethanol in the presence of hydrochloric acid, to give the title compound; mp 312°-314° dec. Anal. Calcd for C16H16N4O.HCl: C, 60.66; H, 5.41; N, 17.69; Cl, 11.19. Found: C, 60.67; H, 5.45; N, 17.70; Cl, 11.19.