Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[CH:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[N:14]=2)=[CH:9][CH:8]=1)=[O:5])#[N:2].[CH:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]=[C:39]=[S:40])([CH3:31])[CH3:30].[H-].[Na+].Cl>CN(C=O)C>[C:1](/[C:3](=[C:39](\[NH:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH:29]([CH3:31])[CH3:30])/[SH:40])/[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[CH:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[N:14]=2)=[CH:9][CH:8]=1)=[O:5])#[N:2]
Reactant: N#CCC(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC(C)c1ccccc1N=C=S
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1ccccc1N/C(S)=C(\C#N)C(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
The cyanoacetanilide from Step 1 (0.30 g, 0.775 mmol) and 2-isopropylphenyl isothiocyanate (0.16 g, 0.903 mmol) were dissolved in 5 mL of DMF and stirred under N2 while NaH (60%; 62 mg, 1.55 mmol) was added in one portion. The solution was allowed to stir at ambient temperature for 1 h, then it was poured into 20 mL of 1 N HCl. The gummy solid was collected and crystallized from EtOH/water to give 0.32 g (71%) of the title compound as a light yellow solid, mp 159-162° C. 1H NMR (CDCl3) δ 12.56 (s, 1H), 8.56 (s, 1H), 8.18 (d, J=8.7 Hz, 2H), 7.85-7.77 (m, 2H), 7.68-7.60 (m, 3H), 7.45-7.36 (m, 4H), 7.32-7.27 (m, 1H), 7.20 (d, J=7.7 Hz, 1H), 4.42 (s, 1H), 3.11 (heptet, J=6.9 Hz, 1H), 1.26 (d, J=6.9 Hz, 6H); ESIMS m/z 565 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([O:22]C)[CH:19]=[C:18]([O:24]C)[CH:17]=2)=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].B(Br)(Br)Br.O>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([OH:24])[CH:19]=[C:20]([OH:22])[CH:21]=2)=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C(=O)NCc2cc(OC)cc(OC)c2)cc1Cl
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NCc2cc(O)cc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
A solution of 2-chloro-4-[[(3,5-dimethoxybenzyl)amino]carbonyl]benzoic acid, methyl ester (0.50 g, 1.4 mmol) in dry dichloromethane (20 mL) was cooled to −78° C. A solution of boron tribromide (1 M in dichloromethane; 10 mL, 10 mmol) was added and the solution was allowed to warm to room temperature and stir overnight. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (200 mL), dried (MgSO4), filtered, and evaporated to give 2-chloro-4-[[[(3,5-dihydroxyphenyl)methyl]amino]carbonyl]benzoic acid, methyl ester (400 mg, 90%) as a white solid, mp 152-155° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([Cl:14])[C:12]=1[Cl:13])[C:9](=[O:15])[CH2:8][CH2:7][CH2:6]2.Cl.N1C=CC=CC=1>O>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([Cl:14])[C:12]=1[Cl:13])[C:9](=[O:15])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)CCC2
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C1CCCc2cc(O)c(Cl)c(Cl)c21
Yield: 43.3 %

Procedure:
A mixture of 6-methoxy-7,8-dichloro-1-tetralone (2.45 g.) and pyridine hydrochloride (25 g.) is heated at 180°-190° C. for two hours and then poured into water (500 ml.). The product is collected, washed with water, dried and crystallized from ethanol-water (3:2) to obtain 6-hydroxy-7,8-dichloro-1-tetralone (1 g.), melting point 243.5°-245.5° C.
Reaction SMILES: O[NH:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1.S(=O)(=O)(O)O>[Fe].COCCO>[NH2:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)c2c(NO)cccc21
Agent: [Fe]
Agent: O=S(=O)(O)O
Solvent: COCCO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 75 °C

Procedure:
50 Parts of 1-hydroxylaminoanthraquinone was stirred into a mixture of 1,000 parts of ethyleneglycol monomethyl ether and 30 parts of conc. sulfuric acid. After heated to 75°C, the mixture was added with 17 parts of iron dust little by little over 1 hour and maintained at 75°C for additional 3 hours. The reaction mixture was then filtered while hot and the residue was washed with 100 parts of ethyleneglycol monomethyl ether heated at 80°C. Thus, unreacted metallic iron and iron sulfate were separated as residue. The filtrate was added with 200 parts of water and then cooled to 25°C to precipitate crystals. The crystals were recovered by filtration, washed with water and dried to obtain 43.5 parts of 1-aminoanthraquinone of a purity of 95 %.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:9])=[CH:5][C:6]=1[CH:7]=[O:8].[CH:10]1([Mg]Br)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[CH:10]1([CH:7]([C:6]2[CH:5]=[C:4]([CH3:9])[S:3][C:2]=2[CH3:1])[OH:8])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Br[Mg]C1CCCCC1
Reactant: Cc1cc(C=O)c(C)s1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(C(O)C2CCCCC2)c(C)s1
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of 2,5-dimethylthiophene-3-carbaldehyde (562 mg) synthesized above in tetrahydrofuran (10 mL) was added dropwise 1.0M cyclohexylmagnesium bromide-tetrahydrofuran solution (6.02 mL) at 0° C., and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, tetrahydrofuran was evaporated using evaporator, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title compound (643 mg, 72%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 100 °C
Yield: 53.3 %

Procedure:
To a mixture of 2-bromo-5-nitropyridine (0.5 g, 2.46 mmol) and N-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (0.913 g, 2.95 mmol) in toluene (4 mL) and ethanol (1.0 mL) was added potassium carbonate solution (2M, 2 mL) and PdCl2dppf (180 mg, 0.246 mmol). The mixture was degassed with argon and heated to 100° C. in a microwave for 40 minutes with stirring. The solvents were evaporated and the residue was extracted with ethyl acetate. After evaporation of the solvents, the residue was purified using flash chromatography (eluting with ethyl acetate and hexanes) to give 5-nitro-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester as a solid (400 mg). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].CC(O)C.C(=O)=O.[Br:17]Br.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:17][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=1[OH:9]
Reactant: BrBr
Reactant: Cc1ccc(O)cc1C
Agent: O=C=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: Cc1cc(O)c(Br)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of 3,4-dimethylphenol (2.48 g, 20.3 mmol, 1 equiv) in DCM (200 mL) at −78° C. (IPA/dry ice) was added dropwise bromine (1.05 mL, 20.3 mmol, 1 equiv). After 1 h, 1 N Na2SO3 was added and the cold bath was removed. After warming to ambient temperature, the DCM layer was separated, dried (Na2SO4), and concentrated in vacuo to provide the product (4.09 g, 100%) as a yellow solid. Regioselectivity>10:1, use as is. 1H NMR (400 MHz, CDCl3) δ 7.21 (s, 1H), 6.83 (s, 1H), 5.26 (s, 1H), 2.20 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:3])[NH2:2].[O:18]1CCOC[CH2:19]1>>[Cl:10][C:7]1[CH:6]=[C:5]2[C:4]([C:1](=[O:3])[NH:2][C:19](=[O:18])[N:11]2[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:8]=1
Reactant: C1COCCO1
Reactant: CCOC(=O)CNc1cc(Cl)ccc1C(N)=O
Product: CCOC(=O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
Ethyl N-(2-carbamoyl-5-chlorophenyl)aminoacetate (357 g) and N,N'-carbonyldiimidazole (451 g) were dissolved in 1,4-dioxane (1.5 l) and 1,4-dioxane was concentrated to a bout 0.5 l by distillation. The resulting mixture was stirred at 150° C. for 30 minutes. After cooling, the precipitated crystals were collected by filtration and washed with ethanol to give ethyl 2-(7-chloro-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl)acetate (353 g).
Reaction SMILES: [C:1]([O:5]O)([CH3:4])([CH3:3])C.[Cl-].[Na+].[C:9]([O:26][CH:27]1[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]1)(=[O:25])[CH2:10][CH2:11][C:12]([O:14][CH:15]1[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]1)=[O:13]>[Mo]=O.C1CCCCC1>[C:9]([O:26][CH:27]1[CH2:32][C:31]([CH3:34])([CH3:33])[N:30]([O:5][CH:1]2[CH2:4][CH2:20][CH2:15][CH2:16][CH2:3]2)[C:29]([CH3:36])([CH3:35])[CH2:28]1)(=[O:25])[CH2:10][CH2:11][C:12]([O:14][CH:15]1[CH2:16][C:17]([CH3:24])([CH3:23])[N:18]([O:5][CH:1]2[CH2:4][CH2:11][CH2:10][CH2:9][CH2:3]2)[C:19]([CH3:22])([CH3:21])[CH2:20]1)=[O:13]
Reactant: CC1(C)CC(OC(=O)CCC(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: CC(C)(C)OO
Agent: O=[Mo]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCCCC1
Product: CC1(C)CC(OC(=O)CCC(=O)OC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)CC(C)(C)N1OC1CCCCC1
Temperature: 140 °C
Reaction time: 4 h
Yield: 137.6 %

Procedure:
A two-phase mixture of 70% aqueous t-butyl hydroperoxide (103.9 g, 807 mmol), cyclohexane (200 ml) and sodium chloride (15 g) is shaken in a separatory funnel. The organic phase is dried over magnesium sulfate, filtered, and added to 40.0 g (101 mmol) of di-(2,2,6,6-tetramethylpiperidin-4-yl) succinate. Molybdenum oxide (2.0 g) is added, and the mixture is refluxed for one hour. Water is collected in a Dean-Stark trap. The entire reaction mixture is then transferred to a Fischer-Porter bottle and heated at 140° C. for 6 hours. Additional t-butyl hydroperoxide (90%, 10.1 g, 101 mmol) is added and heating is resumed for another 4 hours. The colorless reaction mixture is filtered, concentrated, and dissolved in heptane (20 0 ml). The heptane solution is passed through a short column of silica gel with heptane. Subsequent evaporation affords an oil which is crystallized from ethanol to yield 41.2 g (69%) of a white powder, m.p. 122°-6° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([P:9](=[O:24])([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1.C([Li])CCC.CCCCCC.CC1(C)CCCC(C)(C)N1.[I:46]I.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[I:46][C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[P:9](=[O:24])([C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1)[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1
Reactant: II
Reactant: COc1cccc(P(=O)(c2ccc(C)cc2)c2ccc(C)cc2)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(P(=O)(c2ccc(C)cc2)c2ccc(C)cc2)c1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
dc) 16.8 g (50 mmol) of (3-methoxyphenyl)-di-p-tolylphosphine oxide were dissolved in 100 ml of dry THF in a 1 l four-necked sulphonation flask provided with a stirrer, dropping funnel, thermometer and argon gasification. In a separate Schlenk tube 34.0 ml of 1.6N n-butyllithium solution in hexane (54.4 mmol) were added dropwise under argon and while stirring at -78° C. to a solution of 9.98 g (70.6 mmol) of 2,2,6,6-tetramethylpiperidine in 50 ml of THF. The solution was warmed to 0° C. for a short period, then again cooled to -78° C. and then added dropwise via a canula at ≤-70° C. to the solution of the phosphine oxide in THF. The resulting red-brown solution was stirred at -78° C. for a further 30 minutes and then treated dropwise with a solution of 15.0 g (59.1 mmol) of iodine in 50 ml of THF, whereby a beige precipitate formed. The reaction mixture was left to warm to 0° C., treated with aqueous sodium pyrosulphite solution and extracted with ethyl acetate. The extracts were washed with sat. NaHCO3 solution and sat. NaCl solution, dried over Na2SO4, filtered and evaporated. The residue was chromatographed on silica gel (200 g, ethyl acetate), whereby 15.3 g of (2-iodo-3-methoxyphenyl)-di-p-tolylphosphine oxide were obtained. After recrystallization from t-butyl methyl ether there was obtained a white powder with a m.p. of 146°-148° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:11][CH3:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:13])[CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([F:26])([F:25])([F:24])([F:23])[F:22])=[CH:17][CH:16]=1.N>C(O)C>[CH3:13][C:4]1[CH:3]=[C:2]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([F:26])([F:22])([F:23])([F:24])[F:25])=[CH:17][CH:16]=2)[N:7]2[N:8]=[C:9]([S:11][CH3:12])[N:10]=[C:6]2[N:5]=1
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: CSc1nc2nc(C)cc(Cl)n2n1
Agent: N
Solvent: CCO
Product: CSc1nc2nc(C)cc(Nc3ccc(S(F)(F)(F)(F)F)cc3)n2n1
Temperature: 25 °C

Procedure:
To a suspension of 7-chloro-5-methyl-2-(methylthio)[1,2,4]triazolo[1,5-a]pyrimidine (Intermediate 8, (0.2 g, 0.932 mmol)), in ethanol (10 mL), 4-aminophenylsulfur pentafluoride (MANCHESTER, 0.204 g, 0.932 mmol) was added and the mixture was stirred at room temperature until reaching completion. Anhydrous ammonia (0.133 mL, 0.932 mmol) was then added to the mixture and solvent was removed in vacuo. The crude mixture was purified by flash chromatography (Si, eluting with Hexane/EtOAc mixtures form 95:5 to 40:60%). Upon collection of the appropriate fractions, the title compound was obtained as a light yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].C(N(CC)CC)C.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>CN(C=O)C>[N:44]1([CH2:2][CH2:3][CH2:4][S:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:22]4[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]5[S:24][CH:25]=[CH:26][CH:27]=5)[CH:21]=4)[NH:16][N:15]=3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1
Reactant: NC(=O)c1cc(-c2cccs2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(-c2cccs2)cc2c(C3CCN(S(=O)(=O)CCCN4CCOCC4)CC3)n[nH]c12
Yield: 56.8 %

Procedure:
The title compound was prepared according to the general procedure of Example 38b. Thus, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(2-thienyl)-1H-indazole-7-carboxamide (Example 48a) (0.1 mmol) in DMF (2 mL) was reacted with K2CO3 (27.6 mg, 0.2 mmol), triethyl amine (83 uL, 0.6 mmol) and morpholine (43 uL, 0.5 mmol) to afford the title compound (29.4 mg, 57%).
Reaction SMILES: [OH:1][C:2]([CH:4]([C:6]1[CH:15]=[CH:14][C:9]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=1)[CH3:5])=[O:3].[OH-].[Na+].O.O.O.O.O.O.[Cl-].[Sr+2:25].[Cl-]>O>[O-:3][C:2]([CH:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][CH:11]([CH3:12])[CH3:13])=[CH:14][CH:15]=1)[CH3:5])=[O:1].[Sr+2:25].[O-:3][C:2]([CH:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][CH:11]([CH3:12])[CH3:13])=[CH:14][CH:15]=1)[CH3:5])=[O:1]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)Cc1ccc(C(C)C(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Ibuprofen (2.59 g, 12.5 mmol) was dissolved in water (100 ml) containing sodium hydroxide (0.503 g, 12.5 mmol). A solution of strontium chloride hexahydrate (1.68 g, 6.3 mmol) in water (5 ml) was added. The mixture was stirred for 10 minutes at room temperature and the title compound was isolated by filtration and dried. Yield 1.30 g (44%). Melting point >300° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([OH:24])([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].CO>[OH:24][C:11]1([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: OC1(c2cccc3ccccc23)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: OC1(c2cccc3ccccc23)CCNCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.2 %

Procedure:
A mixture of 1.5 gm (4.7 mMol) 1-benzyl-4-hydroxy-4-(naphth-1-yl)piperidine and 0.1 gm 5% palladium on carbon in 45 mL methanol was stirred under a hydrogen atmosphere for 2 days at room temperature. The reaction mixture was then filtered through a bed of celite and the filtrate concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with dichloromethane containing 17% methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 0.526 gm (49%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[C:13]([O:17][C:18]([N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.COCCOC>[NH2:5][C:4]1[CH:3]=[C:2]([C:21]2[N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH:24]=[CH:23][CH:22]=2)[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)n1cccc1-c1cc(N)cc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 74.6 %

Procedure:
A mixture of 3-bromo-5-(trifluoromethyl)aniline (1.50 mL, 10.6 mmol), water (15.0 mL), 1,2 dimethoxyethane (75 mL), [1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl]boronic acid (3.36 g, 15.9 mmol) and sodium carbonate (4.50 g, 42.4 mmol) was degassed with nitrogen for 5 min. Tetrakis(triphenylphosphine)palladium(0) (0.74 mg, 0.64 mmol) was added to the mixture and the slurry was heated at 80° C. for 3 h. Water was added and the mixture was extracted with EtOAc. The organic solutions were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on basic alumina to give tert-butyl 2-[3-amino-5-(trifluoromethyl)phenyl]-1H-pyrrole-1-carboxylate (2.58 g, 74%). LCMS: (FA) ES+ 327.3.
Reaction SMILES: [Cl:1][C:2]1[C:7](NC(=O)C)=[CH:6][CH:5]=[C:4]([Cl:12])[N:3]=1.[N:13]1C=CC=C[CH:14]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[C:7]([C:14]#[N:13])=[CH:6][CH:5]=[C:4]([Cl:12])[N:3]=1
Reactant: c1ccncc1
Reactant: CC(=O)Nc1ccc(Cl)nc1Cl
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
To a mixture of 2,6-dichloro-3-acetamidopyridine (6.3 g, 55% pure) and pyridine (4.93 ml, 61 mmole) in dichloromethane (100 ml), trifluoroacetic anhydride (4.23 ml, 30 mmole) was added. The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The crude product was purified by flash chromatography, eluting with 85% hexane: 15% ethyl acetate to give a pale yellow product (1.77 g, 90%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH2:4][O:3]1.[CH2:13]([N:15]([CH2:20][CH3:21])[CH2:16][CH2:17][NH:18][CH3:19])[CH3:14]>>[CH2:13]([N:15]([CH2:20][CH3:21])[CH2:16][CH2:17][N:18]([CH2:11][C:7]1[N:6]=[C:5]2[CH2:4][O:3][C:2](=[O:1])[C:10]2=[CH:9][CH:8]=1)[CH3:19])[CH3:14]
Reactant: CCN(CC)CCNC
Reactant: O=Cc1ccc2c(n1)COC2=O
Product: CCN(CC)CCN(C)Cc1ccc2c(n1)COC2=O
Yield: 63.6 %

Procedure:
In a process similar to that described in Preparation 8, 5-oxo-5,7-dihydro-furo[3,4-b]pyridine-2-carbaldehyde (110 mg, 0.68 mmol) and N,N-diethyl-N′-methylethylenediamine (109 μL, 0.68 mmol) are reacted to provide the title compound as white solid (120 mg, 64%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH:15]=[CH2:16])[C:8]([O:10][CH3:11])=[O:9])C=C>C(Cl)Cl.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[O:4]1[C:5]2[C:14](=[CH:13][CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:6]=2)[CH:15]=[CH:16][CH2:1]1
Reactant: C=CCOc1cc(C(=O)OC)ccc1C=C
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)OCC=C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
To a stirred solution of methyl 3-(allyloxy)-4-vinylbenzoate (0.67 g, 3.1 mmol) in CH2Cl2 (20 mL) at rt is added benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (63 mg, 0.076 mmol). The mixture is stirred at rt for 2 h. The reaction mixture is concentrated in vacuo to a dark residue. The crude product is purified by flash chromatography on SiO2. Elution with hexanes-EtOAc (95:5) gives 372 mg (64%) of methyl 2H-chromene-7-carboxylate as a clear oil: 1H NMR (400 MHz, CDCl3) δ 7.56, 7.46, 7.01, 6.46, 5.91, 4.89, 3.91.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([CH3:11])[N:6]([C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5]2.C([Li])CCC.C([O:39][B:40](OC(C)C)[O:41]C(C)C)(C)C.Cl>O1CCCC1.CCCCCC>[CH3:11][CH:7]1[C:8]2[C:4](=[CH:3][C:2]([B:40]([OH:41])[OH:39])=[CH:10][CH:9]=2)[CH2:5][N:6]1[C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC1c2ccc(Br)cc2CN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1c2ccc(B(O)O)cc2CN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -72 °C
Reaction time: 0.25 h
Yield: 80.9 %

Procedure:
In 75 ml of anhydrous tetrahydrofuran was dissolved 15.0 g of (+)-5-bromo-1-methyl-2-trityliso-indoline, and the solution was cooled to -72° C. under a nitrogen atmosphere, after which 22.3 ml of a 1.63 M solution of n-butyllithium in n-hexane was added dropwise thereto over a period of 15 minutes, and the resulting mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added dropwise 7.45 g of triisopropoxyborane at -72° C. over a period of 20 minutes, and the resulting mixtuere was stirred at the same temperature for 30 minutes. The reaction mixture was added to 75 ml of ice water and the pH was adjusted to 6.8 with lN hydrochloric acid, after which the organic layer was separated. The organic layer obtained was washed with water, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. Cyclohexane was added to the resulting residue and the crystals were collected by filtration to obtain 11.2 g ofcolorless (+)-1-methyl-2-tritylisoindoline-5-boronic acid.