Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[C:10]([NH2:12])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[Cl:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([Cl:32])[C:30]=1Cl>C1(C)C=CC=CC=1>[Cl:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([Cl:32])[C:30]=1[NH:12][C:10](=[O:11])[C:9]1[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: COc1ccc(C(N)=O)cc1OC1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1CCCC1

Procedure:
Alternatively, a suspension of 3-cyclopentyloxy-4-methoxybenzamide (2.58 g; that is prepared as described in Reference Example 73) in dry toluene (40 mL) is heated at reflux and treated with potassium t-butoxide (1.4 g), followed by 3,4,5-trichloro-pyridine (1.82 g). The mixture is then heated at reflux for 3 hours and 45 minutes, and is then treated with a further quantity of potassium t-butoxide (1.4 g) and heated at reflux for a further period of 7 hours. The mixture is allowed to cool and is then filtered. The filtrate is evaporated and the resulting residue is extracted with aqueous sodium hydroxide solution (2 M). The alkaline solution is then acidified by treatment with acetic acid, and the solid which separates is collected by filtration, washed with water and dried, to give N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxy-benzamide (2.09 g) in the form of a buff solid, m.p. 153-155° C.
Reaction SMILES: C(OC1C=C([C@@H]2C[C@H]2CO)C=NC=1)C1C=CC=CC=1.[C:20]([O:24][C:25]([N:27]1[CH2:30][CH2:29][C@H:28]1[CH2:31][O:32][C:33]1[CH:34]=[C:35]([C@H:39]2[CH2:41][C@@H:40]2[CH2:42][OH:43])[CH:36]=[N:37][CH:38]=1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(OC1C=C([C@H]2C[C@@H]2CO)C=NC=1)C1C=CC=CC=1>>[C:20]([O:24][C:25]([N:27]1[CH2:30][CH2:29][C@H:28]1[CH2:31][O:32][C:33]1[CH:34]=[C:35]([C@@H:39]2[CH2:41][C@H:40]2[CH2:42][OH:43])[CH:36]=[N:37][CH:38]=1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@H]2C[C@@H]2CO)c1
Agent: OC[C@@H]1C[C@H]1c1cncc(OCc2ccccc2)c1
Agent: OC[C@H]1C[C@@H]1c1cncc(OCc2ccccc2)c1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@@H]2C[C@H]2CO)c1

Procedure:
This compound is prepared from (1R,2R)-2-[5-(benzyloxy)-3-pyridyl]cyclopropylmethanol in the same manner as its diastereoisomer, (1S,2S)-2-[5-[[1-(tert-butoxycarbonyl)-(2S)-azetidinyl]methoxy]-3-pyridyl]cyclopropylmethanol, is prepared in Example 1 from (1S,2S)-2-[5-(benzyloxy)-3-pyridyl]cyclopropylmethanol.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH2:17]Br)[N:3]=1.[C-:19]#[N:20].[Na+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH2:17][C:19]#[N:20])[N:3]=1
Reactant: [C-]#N
Reactant: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(CBr)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1nc(N)nc(N)c1-c1ccc(Cl)cc1Cl

Procedure:
This compound was prepared from 2,4-diamino-5-(2,4-dichlorophenyl)-6- bromomethyl-pyrimidine (Example 53) by reaction with sodium cyanide in DMF at room temperature, mp. 249°-251° C.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:6][N:5]=1.[CH2:20]([NH:27][C:28](=[O:31])[CH2:29]Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[O:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:6][N:5]1[CH2:29][C:28]([NH:27][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:31]
Reactant: Oc1nnc(-c2ccccc2)c2ccccc12
Reactant: O=C(CBr)NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(Cn1nc(-c2ccccc2)c2ccccc2c1=O)NCc1ccccc1
Reaction time: 0.25 h
Yield: 40.3 %

Procedure:
1N NaOH (4.5 mmol) is added to 1-hydroxy-4-phenyl-phthalazine (1 g, 4.5 mmol) in ethanol (20 ml). After 15 minutes, N-benzyl bromoacetamide (1.32 g, 4.5 mmol) is added, the reaction mixture is diluted with ethanol (20 ml) and is stirred overnight. Filtration followed by washing with ethanol (50 ml) and then with water (50 ml) yields the title compound (0.67 g). (R1=benzyl, R2=phenyl, A=benzene, Y1=—CH2—C(O)—NH—, m=0, p=0).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]([CH2:11][CH2:12][CH2:13][OH:14])[C:8](=[O:15])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([OH:26])(=[O:14])=[O:25].[Cl:1][C:2]1[C:10]2[N:9]([CH2:11][CH2:12][CH2:13][OH:14])[C:8](=[O:15])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Agent: O=c1[nH]c2cccc(Cl)c2n1CCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O
Reaction time: 1 h

Procedure:
To a stirred mixture of 9 parts of 4-chloro-1,3-dihydro-3-(3-hydroxypropyl)-2H-benzimidazol-2-one, 7 parts of N,N-diethylethanamine and 130 parts of dichloromethane are added dropwise 12 parts of methanesulfonyl chloride (exothermic reaction: temperature rises to reflux). Upon completion, stirring is continued for 1 hour at reflux temperature. The reaction mixture is cooled and poured onto water. The organic phase is separated, washed with acidified water, dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 9 parts (75%) of 4-chloro-1,3-dihydro-3-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate.
Reaction SMILES: [CH3:1][N:2]([S:6][C:7]1([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])[C:3](Cl)=[O:4].[CH3:14][N:15]1[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[S:17][C:16]1=[N:23][OH:24].C(N(CC)CC)C>O1CCOCC1>[CH3:1][N:2]([S:6][C:7]1([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])[C:3]([O:24][N:23]=[C:16]1[N:15]([CH3:14])[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[S:17]1)=[O:4]
Reactant: CN1C(=O)C(C)(C)SC1=NO
Reactant: CN(SC1(C)CCCC1=O)C(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(SC1(C)CCCC1=O)C(=O)ON=C1SC(C)(C)C(=O)N1C
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 3.93g 0.0225m) of 3,5,5-trimethyl-2-oximino-thiazolidin-4-one and 2.28g (0.0225m) of triethylamine in 75 ml of dioxane was added dropwise with stirring 5.0g (0.0225m) of N-methyl-N-(2-methyl-1-oxo-2-cyclopentanesulfenyl)carbamoyl chloride whilst maintaining the temperature between 10°-15° C. The reaction mixture was left standing for 16 hours at 5° C, and then diluted with ice water. The product was extracted in ethylacetate, dried and concentrated to yield 0.66g of white solid, m.p. 119°-121° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([O:7][C:8](=[O:22])[CH2:9][CH:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20]C)=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)[CH3:6].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:5]([O:7][C:8](=[O:22])[CH2:9][CH:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:20])=[C:17]([C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:18]=2)[CH2:13][CH2:12][CH2:11]1)[CH3:6]
Reactant: CCOC(=O)CC1CCCc2cc(OC)ccc21
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)CC1CCCc2cc(O)c(C(=O)c3ccccc3)cc21
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
26.6 g of finely powdered aluminium chloride are added in portions to a solution of 10 g of 6-methoxy-1,2,3,4-tetrahydro-1-naphthyl-acetic acid ethyl ester in 50 ml of absolute methylene chloride whilst stirring at 5° C., and thereafter 16.9 g of benzoyl chloride are added sufficiently slowly that the reaction solution boils gently under reflux. After completion of the addition, the reaction mixture is allowed to boil for a further 30 minutes and is then allowed to cool to room temperature, after which it is poured onto 300 g of ice. The mixture is extracted with 3 times 100 ml of methylene chloride and the organic phases are washed until neutral, dried over sodium sulphate and evaporated to dryness in vacuo. Chromatography of the evaporation residue on 500 g of silica gel, using methylene chloride as the eluting agent, gives 6-hydroxy-7-benzoyl-1,2,3,4-tetrahydro-1-naphthylacetic acid ethyl ester of boiling point 190° C./0.04 mm Hg.
Reaction SMILES: [Cl-:1].[NH2:2][N+:3]1[CH:7]=[CH:6][N:5]([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)[C:4]=1[CH3:19].[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)([O-:22])=[O:21]>C(O)(=O)C>[Cl-:1].[CH3:17][N:16]([CH3:18])[C:13]1[CH:14]=[CH:15][C:10]([CH:9]=[N:8][N+:5]2[CH:6]=[CH:7][N:3]([N:2]=[CH:27][C:26]3[CH:29]=[CH:30][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=3)[C:4]=2[CH3:19])=[CH:11][CH:12]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: Cc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N
Agent: [Cl-]
Solvent: CC(=O)O
Product: Cc1n(N=Cc2ccc([N+](=O)[O-])cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1

Procedure:
56 mg (0.2 mmol) of 1-amino-3-[[p-(dimethylamino)-benzylidene]amino]-2-methylimidazolium chloride and 30 mg (0.2 mmol) of p-nitrobenzaldehyde are dissolved in 5 ml of glacial acetic acid. After 2 days the solution is evaporated, and the residue is chromatographed on 5 g of silica gel (particle size 0.063-0.200 mm) while eluting chloroform/methanol (87:13) and recrystallized from methylene chloride/petroleum ether. There is obtained 1-[[p-(dimethylamino)benzylidene]amino]-2-methyl-3-[[p-nitrobenzylidene]amino]-imidazolium chloride of melting point 252° (decomposition).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1.[F:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[N:15][C:16]=1[O:17][CH3:18].C(N(CC)C(C)C)(C)C>ClCCl.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:3]([NH:9][C:13]2[CH:14]=[N:15][C:16]([O:17][CH3:18])=[C:11]([F:10])[CH:12]=2)=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: COc1ncc(B(O)O)cc1F
Reactant: Nc1ncc(Cl)nc1Br
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(Nc2ncc(Cl)nc2Br)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 17.5 %

Procedure:
A mixture of 3-bromo-5-chloropyrazin-2-amine (780 mg, 3.74 mmol, Ark Phar. Inc., Libertyville, Ill.), 5-fluoro-6-methoxypyridin-3-ylboronic acid (1919 mg, 11.23 mmol, Anichem), N,N-diisopropylethylamine (1.953 mL, 11.23 mmol, Aldrich, St. Louis, Mo.) and copper (II) acetate (1.12 g, 5.61 mmol, Aldrich, St. Louis, Mo.) in dichloromethane (30 mL) was stirred at room temperature for 72 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×40 mL). The combined organic extracts were washed with saturated NaCl (20 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow solid. The crude product was purified by silica gel chromatography, eluting with 20% EtOAc/hexanes to give 3-bromo-5-chloro-N-(5-fluoro-6-methoxypyridin-3-yl)pyrazin-2-amine (218 mg, 0.654 mmol, 17.47% yield). 1H NMR (300 MHz, CDCl3) δ 4.03 (s, 3H) 7.00 (s, 1H) 7.82 (dd, J=11.25, 1.75 Hz, 1H) 8.04 (d, J=9.06 Hz, 2H). m/z (ESI, +ve ion) 331.9 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:21]([CH3:23])[CH3:22])[C:11]([O:13]CC2C=CC=CC=2)=[O:12])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O1CCOCC1.[OH-].[Na+]>O>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH:21]([CH3:23])[CH3:22])[C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1)=[N+:2]=[N-:3]
Reactant: CC(C)C(C(=O)OCc1ccccc1)c1ccc(N=[N+]=[N-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C(C(=O)O)c1ccc(N=[N+]=[N-])cc1
Yield: 60.7 %

Procedure:
A mixture of 10 g of 2-(4-azidophenyl)-3-methylbutanoic acid, benzyl ester, 25 ml of dioxane, 10 ml of water and 5.2 g of 50% sodium hydroxide was stirred and boiled under reflux for 30 hours. Most of the dioxane was evaporated in vacuum, and the oily residue diluted with water and butyl chloride, and acidified with 4 N HCl. The butyl chloride solution was washed with water (2 times) and saturated brine, dried (MgSO4), and evaporated to a residual oily solid. Stirring with hexane provided 4.3 g of 2-(4-azidophenyl)-3-methylbutanoic acid as a yellowish solid, m.p. 95°-97°. The infrared spectrum shows absorption peaks at 2120 cm-1 (azide) and 1715 cm-1 (carboxylic acid carbonyl).
Reaction SMILES: C[O-].[Na+].CO.[Na].Cl[C:8]1[N:13]=[C:12]([CH:14]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][CH:9]=1.[CH3:29][S:30](C)=O>>[CH3:29][S:30][C:8]1[N:13]=[C:12]([CH:14]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: Clc1cccc(C(Oc2ccccc2)Oc2ccccc2)n1
Reactant: CS(C)=O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CSc1cccc(C(Oc2ccccc2)Oc2ccccc2)n1
Temperature: 13 °C

Procedure:
To a mixture of sodium methoxide (made from 100 ml (2.47 m) of methanol and 1.50 g (0.652 m) of sodium metal) which had been cooled to 13° C. was added 7.0 ml (0.126 m) of methylmercaptain. The mixture was allowed to warm to room temperature and then 20.0 g of 6-chloro-2-(diphenoxymethyl)pyridine and 150 ml of dimethylsulfoxide was added thereto. The mixture was heated to 90° C. and after 4 days at this temperature, the reaction mixture was cooled to room temperature and poured into 300 ml of ice. The solution was extracted with methylene chloride and the extract was dried over magnesium sulfate and the solvent stripped off under reduced pressure. The residue was further purified using preparative high pressure liquid chromatography with a 2:98 mixture of ethylacetate and hexane. The oil thus obtained crystallized in n-hexane and was purified by recrystallization from n-hexane leaving the above named compound as a white solid in a yield of 49 g (98 percent pure). The product melted at 58°-59° C. and its structure was confirmed by its NMR spectrum. Upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 70.42, 5.19 and 4.20 percent, respectively, as compared with the theoretical contents of 70.59, 5.26 and 4.33 percent, respectively, as calculated for the above named compound (Compound 3)
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[BH4-].[Na+]>CO>[OH:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([NH2:14])(=[O:12])=[O:13])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NS(=O)(=O)c1ccc2c(c1)CCC2O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
To a stirred solution of 1-keto-5-indanesulfonamide (6.3 g, 30 mmol), in 120 ml of 50% aqueous methanol at 0° C. was added NaBH4 (1.1 g, 30 mmol) in several portions. The cooling bath was removed and the mixture allowed to stir at room temperature for 30 minutes. After removal of the methanol in vacuo, the residue was extracted with ethyl acetate (4×75 ml) and the combined organic phase dried (Na2SO4). Filtration, followed by evaporation of the solvent, gave 5.4 g (84%) of product as a white solid.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:24][CH:21]1[CH2:22][CH2:23][N:18]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:19][CH2:20]1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: Clc1nc2ccccc2[nH]1
Product: c1ccc(CN2CCC(Nc3nc4ccccc4[nH]3)CC2)cc1
Reaction time: 12 h

Procedure:
Combine 2-chloro-1H-benzimidazole (5.0 g, 33 mmol) and 1-benzyl-4-aminopiperidine (14.2 g, 75 mmol) and heat to about 150° C. After 12 hours, cool and partition between water and chloroform, warming if necessary. Separate the layers and add methanol and toluene to the organic layer. Evaporate the organic layer in vacuo to give a solid. Triturate the solid with ethyl acetate, collect by filtration, and dry to give (1H-benzimidazol-2-yl)(1-benzylpiperidin-4-yl)amine: Rf =0.30 (2% triethylamine/10% methanol/ethyl acetate).
Reaction SMILES: [NH2:1][C:2](=[S:16])[C:3]([N:6]1[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[N:7]1)([CH3:5])[CH3:4].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)=O>>[CH3:4][C:3]([N:6]1[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[N:7]1)([C:2]1[S:16][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)[N:1]=1)[CH3:5]
Reactant: CCOC(=O)c1cnn(C(C)(C)C(N)=S)c1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Product: CCOC(=O)c1cnn(C(C)(C)c2nc(-c3cccc(C(F)(F)F)c3)cs2)c1
Yield: 91.3 %

Procedure:
By a reaction in the same manner as in Example 1c and using the compound (241 mg, 1.00 mmol) obtained in Example 16b and 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (267 mg, 1.00 mmol), the title compound (374 mg, 91%) was obtained as a colorless oil.
Reaction SMILES: [O-2].[Ba+2].[N+:3]([O-:6])([O-:5])=[O:4].[Ba+2].[N+:8]([O-])([O-])=O.[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH3:19]>O>[N+:3]([O-:6])([O-:5])=[O:4].[NH2:8][N+:15]1[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([Br:12])[CH:14]=1
Reactant: Cc1ccncc1Br
Agent: O=[N+]([O-])[O-]
Agent: [Ba+2]
Agent: [O-2]
Solvent: O
Product: Cc1cc[n+](N)cc1Br
Temperature: 25 °C
Yield: 113.3 %

Procedure:
Barium oxide (950 mg, 90%, 5.56 mmol) were carefully added into 6 ml water in small portions followed by addition of barium nitrate (983 g, 3.76 mmol) and 3-bromo4-methylpyridine (1.72 g, 10 mmol). The resulting suspension was stirred at r.t. and a solution of hydroxylamine O-sulfonic acid (995 mg, 8.36 mmol) in 2 ml water was added drop-wise. The white suspension was stirred at 90° C. for 15 h before cooling down to r.t. The white precipitate was filtered off and washed with water. The aqueous phase was evaporated to dryness to give 1.065 g of 205 as off-white solid (yield: 45.7%) which were directly used for next step without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6](O)=O)[CH:3]=[N:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:21][C:22]1[C:30]([NH2:31])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([NH2:26])=[O:25]>CN(C)C=O.N1C=CC=CC=1>[NH:2]1[CH:3]=[C:4]([C:6]2[NH:21][C:22]3[C:23]([C:24]([NH2:26])=[O:25])=[CH:27][CH:28]=[CH:29][C:30]=3[N:31]=2)[CH:5]=[N:1]1
Reactant: O=C(O)c1cn[nH]c1
Reactant: NC(=O)c1cccc(N)c1N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: NC(=O)c1cccc2nc(-c3cn[nH]c3)[nH]c12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
35 0.56 g (5 mmol) of 4-pyrazolecarboxylic acid was stirred with 0.81 g (5 mmol) of carbonyldiimidazole in 20 ml of dimethylformamide at room temp. for 2 hours. 1.12 g (5 mmol) of 2,3-diaminobenzamide in 10 ml of pyridine were added. The reaction mixture was stirred at 50° C. for 2 hours. The reaction mixture was then concentrated in vacuo, and the residue was stirred with water. The precipitate was filtered off and dried in vacuo at 40° C. and then stirred in 10 ml of glacial acetic acid at 100° C. The residue after concentration in vacuo was stirred with saturated sodium bicarbonate solution. After filtration, the filtrate was concentrated with toluene in vacuo several times. The residue was stirred with tetrohydrofuran. Concentration in vacuo resulted in 150 mg of yellow powder.
Reaction SMILES: C(O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(CN(C)C)C=C2)CO)(C)(C)C.C([O:37][CH2:38][C@@H:39]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])[C:40]1[C:41]([C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=2)=[C:42]2[C:47](=[CH:48][C:49]=1[CH3:50])[N:46]=[C:45]([CH2:51][N:52]1[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1)[CH:44]=[CH:43]2)(=O)C(C)(C)C>>[C:66]([O:65][C@@H:39]([C:40]1[C:41]([C:58]2[CH:59]=[CH:60][C:61]([Cl:64])=[CH:62][CH:63]=2)=[C:42]2[C:47](=[CH:48][C:49]=1[CH3:50])[N:46]=[C:45]([CH2:51][N:52]1[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]1)[CH:44]=[CH:43]2)[CH2:38][OH:37])([CH3:69])([CH3:67])[CH3:68]
Reactant: Cc1cc2nc(CN3CCCCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: Cc1cc2nc(CN(C)C)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Product: Cc1cc2nc(CN3CCCCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C

Procedure:
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(piperidin-1-ylmethyl)quinolin-6-yl)ethanol was prepared following the procedure used to prepare compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)ethanol of Example 9, except that (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(piperidin-1-ylmethyl)quinolin-6-yl)ethyl pivalate was used instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)ethyl pivalate. LCMS-ESI+ (m/z): 467.4, 469.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=2)=[CH:12][CH:11]=1.[ClH:27]>CCOC(C)=O.CCO.[Pd]>[ClH:27].[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=2)=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])c1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1

Procedure:
A solution of 2,4,5-trifluoro-4′-(3-nitro-benzyloxy)-biphenyl (150 mg, 0.418 mmol) and 10% Pd/C (40 mg) in EtOAc (2 mL), EtOH (10 mL) and 6N HCl (100 uL) was hydrogenated at 50 psi for 1.25 hrs. The reaction mixture was filtered through Celite and evaporated to dryness to give 3-(2′,4′,5′-trifluoro-biphenyl-4-yloxymethyl)-phenylamine hydrochloride. LC-MS (ES) calculated for C19H14F3NO, 329.32; found m/z 330 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][S:18]([C:15]1[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:17][CH:16]=1)(=[O:20])=[O:19])#[N:5]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccccc1N
Product: COc1ccc(S(=O)(=O)Nc2ccccc2C#N)cc1
Yield: 63.7 %

Procedure:
Using 2-aminobenzonitrile (1.03 g, 8.55 mmol) and 4-methoxybenzenesulfonyl chloride (1.78 g, 8.55 mmol), the procedure of Reference Example 2 was repeated to obtain 1.57 g (63.7%) of the title compound in the form of colorless solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[CH2:14](N(CC)CC)[CH3:15].C=C.[OH-].[Na+].Br.C(N(CC)CC)C>Cl[Pd]Cl.C(C(CC)=O)C>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([CH:14]=[CH2:15])[CH:11]=[CH:10]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: CCN(CC)CC
Agent: Cl[Pd]Cl
Agent: Br
Agent: C=C
Solvent: CCC(=O)CC
Product: C=Cc1ccc2cc(OC)ccc2c1
Temperature: 95 °C

Procedure:
To a 5-gallon stainless steel electrically heated reactor is added 1,485 grams (6.26 mol) of 2-bromo-6-methoxynaphthalene (BMN) (produced as in Example 7 hereof, added as a dry powder through a 2" opening in the reactor head), 672 grams (6.64 mol) of triethylamine, 0.56 grams of PdCl2 (3.2 mmol) and 6.2 grams of NMDP (19 mmol). The reactor is purged three times with nitrogen (50 psig) and then three times with ethylene (50 psig). The reactor is charged with ethylene (about 300 psig) and then warmed at 95° C. Ethylene pressure in the reactor is raised to about 550 psig after reaching reaction temperature. When the reaction is completed, the reaction mixture is cooled to below 50° C. and the ethylene is vented. Diethyl ketone (3,835 g) is added to the reaction mixture. Aqueous sodium hydroxide (24.8 wt %) is then added to the reaction mixture to neutralize the triethylamine hydrobromide salt formed during the reaction. The aqueous phase is removed, as well as possible at this point, from the reactor. The reaction mixture is filtered using a medium porosity 3-liter sintered glass funnel and any further aqueous phase that separates is removed. The volatile organics (acetonitrile, diethyl ketone, triethylamine) are removed at reduced pressure (1 mm Hg, 45° C.) to give 6-methoxy-2-vinylnaphthalene as a yellow solid.