Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:17](Cl)(=[O:19])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O.NN>CO>[CH2:1]([S:17]([OH:19])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Cl
Agent: NN
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCCCCS(=O)O

Procedure:
200 g of cetyl sulphonic acid chloride are introduced at room temperature into 87 ml of hydrazine hydrate in 600 ml of methanol. The sulphonic acid hydrazide precipitates and may be separated by suction filtration. The residue is then introduced into a solution of 48 g of NaOH in 1,500 ml of water and 1,000 ml of methanol and slowly heated to boiling with stirring. The solvent is slowly distilled off and the temperature is maintained at 90° to 95° C. for about 4 hours. The sodium salt of cetyl sulphinic acid is separated by suction filtration after cooling. The compound is dried.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21]I>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]([CH3:21])[C:12]1[CH:13]=[CH:14][C:15]([I:18])=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(I)cc1)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OCc1ccccc1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
A stirred solution of N-benzyloxycarbonyl-4-iodoaniline (11.5 g, Reference Example 27) in dimethylformamide (70 ml) was treated portionwise with sodium hydride (⅙ g of a 60% dispersion in oil), under nitrogen and at room temperature. When effervescence had ceased methyl iodide (6.3 g) was added and the mixture was stirred at room temperature for 2 hours, after which it was partitioned between ethyl acetate and water. The organic phase was separated, then dried over magnesium sulphate and then evaporated to give the title compound (11.5 g) as a pink oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](SC)[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:16]([CH2:18][NH2:19])[OH:17]>C(OCC)(=O)C>[OH:17][CH2:16][CH2:18][NH:19][C:4]1[N:5]=[N:6][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:2]([CH3:1])[N:3]=1
Reactant: CSc1nnc(-c2ccccc2)c(C)n1
Reactant: NCCO
Solvent: CCOC(C)=O
Product: Cc1nc(NCCO)nnc1-c1ccccc1
Yield: 88.7 %

Procedure:
A mixture of 5-methyl-3-methylthio-6-phenyl-1,2,4-triazine (3 g) and ethanolamine (3 g) was heated at 150° to 160° C. for 5.25 hours. The reaction mixture was dissolved in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was crystallized from a small amount of diethyl ether and then diisopropyl ether was added thereto. The crystals were collected by filtration, washed with diisopropyl ether and dried to give 3-(2-hydroxyethylamino)-5-methyl-6-phenyl-1,2,4-triazine (2.82 g).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[OH-].[Na+].[CH3:13]OS(OC)(=O)=O>O>[CH3:13][S:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(S)nc1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1ccc([N+](=O)[O-])cn1

Procedure:
4.68 gm (0.03 mol) of 2-mercapto-5-nitro-pyridine were dissolved, while gently heating, in a sodium hydroxide solution prepared by dissolving 1.32 gm (0.033 mol) of sodium hydroxide in 60 ml of water. 4.17 gm (0.033 mol) of dimethylsulfate were added to this solution, and the mixture was shaken well. The resulting precipitate was filtered off with suction, and the still moist product was recrystallized from ethanol. 2-Methylthio-5-nitro-pyridine was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.Cl.[CH3:11][NH:12][O:13][CH3:14].O>C(Cl)Cl>[CH3:14][O:13][N:12]([CH3:11])[C:7](=[O:9])[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: CNOC
Reactant: O=C(O)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1ccncc1
Reaction time: 0.67 h

Procedure:
A suspension of 4-picolinic acid (3.00 g, 24.4 mmol) and 1,1-carbonyldiimidazole (4.74 g, 29.2 mmol) in CH2Cl2 (35 mL) was stirred for ˜40 min and became a clear solution. After the addition of N,O-dimethylhydroxylamine hydrochloride (2.85 g, 29.2 mmol), the mixture was stirred at room temperature for 22 hours. Water was added, the organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water once, and the aqueous layer was back extracted with CH2Cl2. The organic phase was dried (Na2SO4), filtered, concentrated, and purified by flash column chromatography (80 g silica gel column, 100% EtOAc) to give the title compound as a clear oil.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[NH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[CH:28]2>C1(C)C=CC=CC=1>[NH:30]1[C:31]2[C:27](=[CH:26][C:25]([NH:24]/[C:13](=[C:6]3\[C:5](=[O:23])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[CH:10][CH:11]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:33][CH:32]=2)[CH:28]=[CH:29]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: Cc1ccccc1
Product: O=C1Nc2ccccc2/C1=C(/Nc1ccc2[nH]ccc2c1)c1ccccc1

Procedure:
0.307 g (1 mmol) of 1-acetyl-3-{1-ethoxy-1-phenylmethylidene}-2-indolinone and 0.400 mg (3 mmol) of 5-amino-indole are refluxed in 10 ml toluene for 1 hour. The mixture is evaporated down in vacuo and the evaporation residue is distributed between EtOac and water. A viscous oil is obtained from the organic phase after drying, filtering and evaporation in vacuo, and this oil is purified by column chromatography on silica gel with the eluant EtOac/petroleum ether (1:1).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[O:6]([CH2:13][C:14](Cl)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>O.CCOCC>[O:6]([CH2:13][C:14]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCC(=O)O
Reactant: O=C(Cl)COc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=C(O)CNC(=O)COc1ccccc1

Procedure:
Glycine (20 mmol) was reacted with distilled phenoxyacetyl chloride (22 mmol) in the presence of NaOH (40 mmol) in a mixture of water and ether as described in Example 5 Part A. The crude product was recrystallized from EtOAc (15 ml) to give title acid (2.38 gm, 57%).
Reaction SMILES: [CH2:1]([NH:4][CH:5]([CH3:11])[CH:6]([O:9][CH3:10])[O:7][CH3:8])[CH:2]=[CH2:3].C1(C)C=CC=CC=1.[OH-].[Na+].Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>O>[CH2:1]([N:4]([CH:5]([CH3:11])[CH:6]([O:9][CH3:10])[O:7][CH3:8])[C:22](=[O:23])[O:24][CH2:25][CH3:26])[CH:2]=[CH2:3]
Reactant: CCOC(=O)Cl
Reactant: C=CCNC(C)C(OC)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCN(C(=O)OCC)C(C)C(OC)OC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
125 g (0.785 mol) of allyl-(1,1-dimethoxyprop-2-yl)amine are initially introduced into 400 ml of toluene, a solution of 40 g of sodium hydroxide in 200 ml of water is added, the mixture is cooled in an ice-bath to 0° C. and 95 g (0.876 mol) of ethyl chloroformate are added dropwise. The mixture is then stirred for 3 hours at room temperature, and the aqueous phase is separated off and extracted twice using 100 ml of toluene each time. The extracts are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)OC)#[N:2].[C:12]1([CH2:18][CH2:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[C:1]([NH:3][C:4]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=[N:20][CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:2]
Reactant: NCCc1ccccc1
Reactant: COC(=NC#N)c1ccco1
Solvent: CO
Product: N#CNC(=NCCc1ccccc1)c1ccco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
Methyl N-cyano-2-furancarboximidate (0.30 g, 2.0 mmol) was dissolved in methanol (2 ml), and 2-phenylethylamine (0.27 g, 2.2 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was crystallized from diethyl ether-hexane to give the title compound (0.46 g, 1.93 mmol, yield: 97%) as colorless crystals.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[CH:3]([NH2:37])[CH:4]1[CH:9]([O:10]CC2C=CC=CC=2)[CH:8]([O:18]CC2C=CC=CC=2)[CH:7]([O:26]CC2C=CC=CC=2)[CH:6]([CH2:34][CH:35]=[CH2:36])[O:5]1.Cl>C1COCC1.[Pd]>[NH2:37][CH:3]([CH:4]1[CH:9]([OH:10])[CH:8]([OH:18])[CH:7]([OH:26])[CH:6]([CH2:34][CH2:35][CH3:36])[O:5]1)[CH:2]([CH3:38])[CH3:1]
Reactant: C=CCC1OC(C(N)C(C)C)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Product: CCCC1OC(C(N)C(C)C)C(O)C(O)C1O
Yield: 89 %

Procedure:
2-Methyl-1-(6-allyl-3,4,5-tris-benzyloxy-tetrahydro-pyran-2-yl)-propylamine, 15c 160 mg and 100 mg degussa 50% w/w wet 10% palladium/carbon under N2 was suspended in THF (5 mL) and 1M aq. HCl (1 mL) the reaction mixture was stirred 24 h under 1 atm pressure H2. The reaction mixture was filtered through Celite evaporated to dryness to provide the product 2-(1-Amino-2-methyl-propyl)-6-propyl-tetrahydro-pyran-3,4,5-triol (60.8 mg 89%) as the HCl salt. TLC (CHCl3: MeOH: 32% aq. AcOH) Rf=0.35. MS (ESPOS): 248 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[C:4]([C:12]([F:13])([F:14])[F:15])[C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:6]([N+:16]([O-:18])=[O:17])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(F)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1c([N+](=O)[O-])cc(F)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
8.80 g (39.7 mmol) N-(4-fluoro-2-trifluoromethyl-phenyl)-acetamide were added to 60 mL 97% sulphuric acid while cooling with ice. 6.60 mL (95.3 mmol) nitric acid were slowly added dropwise to this mixture at 0° C. and with constant stirring. After the addition had ended the mixture was stirred for 30 min at 0° C. Then the cooling was removed and the reaction mixture was stirred for a further 1.5 h to complete the reaction. The reaction mixture was carefully poured onto 500 g ice and stirred for 30 min. The precipitate formed was filtered off, washed with 150 mL water and dried i. vac.
Reaction SMILES: [CH:1]1([C:7]2([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:12][CH2:11][N:10]([C:13](=[O:27])[C@H:14]([N:24]=[C:25]=[S:26])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:33][CH2:34][CH2:35][C:36]1[N:40]=[CH:39][NH:38][CH:37]=1.N12CCCN=C1CCCCC2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH:1]1([C:7]2([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:12][CH2:11][N:10]([C:13](=[O:27])[C@H:14]([NH:24][C:25]([NH:33][CH2:34][CH2:35][C:36]3[N:40]=[CH:39][NH:38][CH:37]=3)=[S:26])[CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(OC)cc2)N=C=S)CC1
Reactant: NCCc1c[nH]cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=S)NCCc2c[nH]cn2)CC1
Reaction time: 2 h
Yield: 53.5 %

Procedure:
To 400 mg (0.87 mmol) of ethyl 4-cyclohexyl-1-[(R)-2-isothiocyanato-3-(4-methoxy-phenyl)propionyl]piperidine-4-carboxylate in 5 mL of DMF are added 97 mg (0.87 mmol) of histamine and then 0.130 mL (0.87 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction medium is stirred for 2 hours and then hydrolysed by adding aqueous 5% citric acid solution. The organic compounds are extracted with dichloromethane. The organic phase is dried over MgSO4, filtered and concentrated. The crude product obtained is chromatographed on silica gel (eluent: 80/20 CH2Cl2/MeOH). 265 mg of ethyl 4-cyclohexyl-1-[(R)-2-{3-[2-(1H-imidazol-4-yl)ethyl]thioureido}-3-(4-methoxyphenyl)propionyl]piperidine-4-carboxylate in the form of a pale yellow powder are obtained in a yield of 53%.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:15]2=[CH:16][CH:17]=[N:18][CH:19]=[C:14]2[C:5]2[C:6]([OH:13])=[CH:7][C:8]([CH:10]([CH3:12])[CH3:11])=[CH:9][C:4]=2[O:3]1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([O:13][C:6]1[C:5]2[C:14]3[C:15]([C:2]([CH3:1])([CH3:20])[O:3][C:4]=2[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=1)=[CH:16][CH:17]=[N:18][CH:19]=3)(=[O:23])[CH3:22]
Reactant: CC(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(C(C)C)cc2c1-c1cnccc1C(C)(C)O2

Procedure:
10-Acetoxy-5,5-dimethyl-8-iso-propyl-5H-[1]benzopyrano[3,4-d]pyridine is prepared by reacting 5,5-dimethyl-10-hydroxy-8-iso-propyl-5H-[1]benzopyrano[3,4-d]pyridine and acetic anhydride in the presence of pyridine according to the method of Example 12.
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.C[Si](Cl)(C)C.[CH2:15]([O:17][C:18](=[O:50])[CH2:19][CH2:20][N:21]([C:39]1([C:47](Cl)=[O:48])[CH2:45][CH:44]2[O:46][CH:41]([CH2:42][CH2:43]2)[CH2:40]1)[S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH3:16].Cl>ClCCl>[CH2:15]([O:17][C:18](=[O:50])[CH2:19][CH2:20][N:21]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:39]1([C:47](=[O:48])[NH:2][OH:3])[CH2:45][CH:44]2[O:46][CH:41]([CH2:42][CH2:43]2)[CH2:40]1)[CH3:16]
Reactant: NO
Reactant: CCOC(=O)CCN(C1(C(=O)Cl)CC2CCC(C1)O2)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CCN(C1(C(=O)NO)CC2CCC(C1)O2)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (19.7 mmol, 1.3 equivalents) of hydroxylamine hydrochloride in 9.2 mL (114 mmol, 7.5 equivalents) of dry pyridine at 0° C. is treated with 5.8 mL (45 mmol, 3.0 equivalents) of trimethylsilyl chloride, causing white solids to precipitate. The mixture is allowed to warm to ambient temperature overnight. This mixture is then cooled to 0° C. and treated with a solution of (15.1 mmol) of the product from Step F in 73 mL of dichloromethane causing an exotherm to about 8° C. This mixture is stirred at 0° C. for 30 minutes and at ambient temperature for about one hour. The reaction is then treated with 50 mL of 2N aqueous hydrochloric acid and was stirred at ambient temperature for one hour. The aqueous phase is extracted with dichloromethane and the combined organic phases are washed with 2N aqueous hydrochloric acid (2×50 mL) and water (50 mL). This solution of the title compound in dichloromethane is used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([C:13](=O)[CH3:14])=[CH:9][C:8]=2[CH3:16])=[CH:4][CH:3]=1.[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>>[F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([CH:13]([NH:25][S@@:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24])[CH3:14])=[CH:9][C:8]=2[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(Oc2ccc(F)cc2)c(C)c1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1Oc1ccc(F)cc1
Yield: 76 %

Procedure:
The title compound is prepared in 76% yield (2.67 g, white solid) from 1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethanone (2.47 g, 10.1 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.83 g, 15.1 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]#[N:17].[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:23]([OH:25])=O>>[C:16]([CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:8]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:2]([CH3:1])[C:23](=[O:25])[C:22]1[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=[C:20]([C:19]([F:18])([F:34])[F:33])[CH:21]=1)#[N:17]
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1CC#N
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1CC#N

Procedure:
The title compound was prepared in analogy to example 90, from [2-(3-methylamino-pyridin-4-yl)-phenyl]-acetonitrile and 3,5-bis(trifluoromethyl)benzoic acid (CAS RN 725-89-3) after a reaction time of 5 days. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50) followed by a second chromatography, using preparative HPLC (Phenomenex Gemini® column, gradient of methanol:water (10:90 to 95:5)). Colorless solid (3%). MS (ESI): m/z=464.118 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br[CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: BrC1CCCC1
Product: Cc1cc(C#Cc2cn(C3CCCC3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=266.3 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and bromocyclopentane.
Reaction SMILES: [OH:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[C:5]([C:12](=O)[CH3:13])=[CH:4][CH:3]=1.Cl.[NH2:16][OH:17]>N1C=CC=CC=1.C(O)C>[OH:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[C:5]([C:12](=[N:16][OH:17])[CH3:13])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(=O)c1ccc(O)c2c1OCCO2
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NO)c1ccc(O)c2c1OCCO2
Yield: 57.4 %

Procedure:
A solution of 19.4 g (0.1 mole) of 5-hydroxyl 8-acetyl-1,4-benzodioxane (VIIi) and 10.4 g (0.15 mole) of hydroxylamine hydrochloride in 50 ml of pyridine and 50 ml of ethanol was brought to reflux for 7 hours. Then, the solvents were evaporated and the residue crystallized in water. 12 g of product were obtained.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Br)=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:23]=[N+:24]=[N-:25].[Li+]>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:23]=[N+:24]=[N-:25])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [Li+]
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CN=[N+]=[N-])cc1
Yield: 74 %

Procedure:
Reaction of [2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl bromide (from Step D) with lithium azide was carried out according to the procedure of Example 9, Step A. The crude product was purified by flash chromatography on silica gel (elution with 10% EtOAc in hexane) to give a 74% yield of the title compound as a white solid; satisfactory purity (by TLC in 9:1 hexane-EtOAc) for use in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:18][CH:19]=2)[N:14]=1.C(O)C>O>[NH:23]([C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: Nc1ccc2ccc(Nc3ccccc3)nc2n1
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc3ccc(Nc4ccccc4)nc3n2)cc1
Temperature: 4 °C
Yield: 41 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with 4-methoxybenzoic acid (6.1 g), N,N'-carbonyldiimidazole (6.5 g) and 2-amino-7-anilino-1,8-naphthyridine (7 g). The product obtained by precipitation in water (12 g) is dissolved in boiling ethanol (140 cc). After cooling for 1 hour at 4° C., the crystallized solid is separated by filtration, washed with ethanol (10 cc), and dried at 45° C. under reduced pressure (0.07 kPa). N-(7-Anilino-1,8-naphthyridin-2-yl)-4-methoxybenzamide (4.5 g), m.p. 245° C., is obtained.
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.C[O-].[Na+]>C(OCC)(=O)C>[OH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=Cc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 54 %

Procedure:
First, 100.00 parts by mass of p-acetoxystyrene was dissolved in 400 parts by mass of ethyl acetate, and cooled to 0° C. Subsequently, 47.60 parts by mass of sodium methoxide (28% methanol solution) was dropped into the cooled solution over a period of 30 minutes, and agitated at room temperature for five hours. Ethyl acetate was added, and the resultant organic phase was washed with distilled water thrice. The washed organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off. Thus, 131.70 parts by mass of p-hydroxystyrene (54% ethyl acetate solution) was obtained.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[C:15]1([CH2:21]O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[CH2:21]([O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccnc(-n2nccc2OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
To a solution of 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile (186 mg, 1 mmol), phenylmethan-1-ol (216 mg, 2 mmol), and PPh3 (523 mg, 2 mmol) in THF (10 mL) was added dropwise DIAD (402 mg, 2 mmoL) at 0° C. under N2. Then the mixture was stirred at rt overnight. Water was added, and the reaction mixture was extracted with EtOAc, then washed with water and brine. The organic phase was dried, concentrated, and purified by prep-HPLC to afford the title compound (60 mg). 1H NMR (400 MHz, CDCl3): δ 5.25 (2H, s), 5.75 (1H, d, J=2.0 Hz), 7.36-7.44 (5H, m), 7.57 (1H, d, J=2.0 Hz), 8.04 (1H, s), 8.71 (1H, d, J=5.2 Hz). [M+H] Calc'd for C16H12N4O, 277. Found, 277.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[S:23][C:22]3[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:20][C:19](Cl)=[N:18][C:17]=3[C:16]=2[CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:40]2[C:41]([C:47]([F:50])([F:49])[F:48])=[N:42][C:43]([NH2:46])=[N:44][CH:45]=2)O1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[S:23][C:22]3[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:20][C:19]([C:40]4[C:41]([C:47]([F:50])([F:49])[F:48])=[N:42][C:43]([NH2:46])=[N:44][CH:45]=4)=[N:18][C:17]=3[C:16]=2[CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(CN2CCN(C(=O)OC(C)(C)C)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CC1(C)OB(c2cnc(N)nc2C(F)(F)F)OC1(C)C
Product: Cc1c(CN2CCN(C(=O)OC(C)(C)C)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3C(F)(F)F)nc12

Procedure:
4-(2-Chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (200 mg), prepared as in Example 118, was coupled to 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4-trifluoromethyl-pyrimidin-2-ylamine via General Procedure A to yield 30 mg of 4-[2-(2-Amino-4-trifluoromethyl-pyrimidin-5-yl)-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester.