Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9](O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]1(C)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[NH3:39]>C1C=CC=CC=1>[C:12]1([C:8]2[S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[C:9]=2[NH:39][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N
Reactant: Cc1ccccc1
Reactant: O=C(O)C(Sc1ccccc1)c1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: c1ccccc1
Product: c1ccc(Nc2c(-c3ccccc3)sc3ccccc23)cc1
Reaction time: 8 h

Procedure:
A mixture of 9.6 g (30 mmol) of anilide of α-phenylthio-phenylacetic acid (colourless needles in a mixture of benzene and petroleum ether, mp 142°-143°), 70 milliliters of absolute toluene and 30.0 g (211 mmol) of phosphoric anhydride is stirred at 100° for 8 hours. The cooled reaction mixture is poured onto ice, made alkaline by concentrated ammonia and extracted with methylene chloride. By drying over sodium sulphate and evaporating the organic phase, 8.9 g (98.4% of theory) of crude product are obtained which are recrystallised in ethanol: 5.7 g (64% of theory) of yellow crystals, mp 150°-151° (ethanol).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[C:18](=[O:19])[N:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:23][CH:22]=4)[C:16]([CH2:35][CH2:36][CH3:37])=[N:15][C:14]=3[CH3:38])[CH:11]=2)[O:6][C:5]([CH3:40])([CH3:39])[CH2:4]1.Cl.[NH2:42]O.[C:44](=[O:47])([O-])[OH:45].[Na+]>CS(C)=O.C(OCC)(=O)C>[CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[C:18](=[O:19])[N:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:33]5[NH:42][C:44](=[O:47])[O:45][N:34]=5)=[CH:23][CH:22]=4)[C:16]([CH2:35][CH2:36][CH3:37])=[N:15][C:14]=3[CH3:38])[CH:11]=2)[O:6][C:5]([CH3:39])([CH3:40])[CH2:4]1
Reactant: CCCc1nc(C)c(-c2ccc3c(c2)C(OC)CC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)c(-c2ccc3c(c2)C(OC)CC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
4′-{[5-(4-Methoxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.38 g) was dissolved in dimethyl sulfoxide (5 mL), and hydroxylamine hydrochloride (0.49 g) and sodium hydrogen carbonate (0.72 g) were added. The mixture was stirred overnight at 90° C. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The residue was dissolved in tetrahydrofuran (5 mL), and N,N′-carbonyldiimidazole (0.17 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 mL) were added. After stirring for 30 min, the reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.27 g, 64%).
Reaction SMILES: P(Cl)(Cl)[Cl:2].[CH2:5]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH3:8]>CCCCCC.C(OCC)C>[ClH:2].[CH2:5]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH3:8]
Reactant: ClP(Cl)Cl
Solvent: CCCCCC
Solvent: CCCCNCCCC
Solvent: CCOCC
Product: Cl

Procedure:
A solution of 68.7 g (0.5 mole) of phosphorus trichloride in dry hexane or diethyl ether is added slowly to a stirred solution of 363.6 g (3.0 moles) of dibutylamine in the same solvent. A voluminous precipitate of dibutylamine hydrochloride is formed, the temperature remaining between 10° and 40° C. After all the phosphorus trichloride has been added, the mixture is boiled and refluxed for between 30 minutes and 2 hours. The mixture is then cooled to room temperature and filtered to separate it from 280 g (1.7 moles) of dibutylamine hydrochloride. The solvent is then stripped off at reduced pressure in a rotary evaporator.
Reaction SMILES: C(C1C=CC(N[C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH2:19][CH3:20])[C:14]([C:21]([NH:23]CCCNC(=O)OC(C)(C)C)=[O:22])=[CH:13][N:12]=2)=CC=1)(=O)N>C(Cl)(Cl)Cl.CO.FC(F)(F)C(O)=O>[CH2:18]([NH:17][C:15]1[C:14]([C:21]([NH2:23])=[O:22])=[CH:13][N:12]=[CH:11][N:16]=1)[CH2:19][CH3:20]
Reactant: CCCNc1nc(Nc2ccc(C(N)=O)cc2)ncc1C(=O)NCCCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCNc1ncncc1C(N)=O
Reaction time: 0.5 h
Yield: 385.6 %

Procedure:
To a suspension of tert-butyl (3-(2-((4-carbamoylphenyl)amino)-4-(propylamino)pyrimidine-5-carboxamido)propyl)carbamate (D2, 190 mg) in chloroform (8 mL) and methanol (2 mL), trifluoroacetic acid (1 mL) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The solvent was evaporated under reduced pressure to obtain N-(3-aminopropyl)-2-(4-carbamoylphenyl)amino)-4-(propylamino)pyrimidine-5-carboxamide (D3) trifluoroacetate (280 mg).
Reaction SMILES: [C:1]([C:5]1[CH:38]=[CH:37][C:8]([C:9]([NH:11][C:12]2[CH:36]=[CH:35][CH:34]=[CH:33][C:13]=2[C:14]([NH:16][C:17]2[CH:25]=[C:24]3[C:20]([CH:21]=[N:22][N:23]3C(OC(C)(C)C)=O)=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C1(OC)C=CC=CC=1.ClCCl>[C:1]([C:5]1[CH:38]=[CH:37][C:8]([C:9]([NH:11][C:12]2[CH:36]=[CH:35][CH:34]=[CH:33][C:13]=2[C:14]([NH:16][C:17]2[CH:25]=[C:24]3[C:20]([CH:21]=[N:22][NH:23]3)=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ncc2ccc(NC(=O)c3ccccc3NC(=O)c3ccc(C(C)(C)C)cc3)cc21
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc3cn[nH]c3c2)cc1
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
To a stirring solution of 2-[(4-t-butylbenzoyl)amino]-N-(1-Boc-6-indazolyl)benzamide (200 mg, 0.39 mmol) in anisole (1 mL) and dichloromethane (10 mL) was added TFA (10 mL). After stirring for 30 min, the solvents were removed by rotary evaporation and the residue was partitioned between ethyl acetate and satd aq NaHCO3. The aqueous phase was removed and the organic phase was washed again with NaHCO3, followed by brine. The organic phase was then dried with MgSO4, filtered and concentrated in vacuo to a very small volume, then diluted with ether and sonicated. The white precipitate was then filtered and dried in vacuo to give 124 mg (77%) of white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:27]=[C:26]([CH3:28])[O:25][N:24]=3)=[O:22])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:35].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:35])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:21]([C:23]3[CH:27]=[C:26]([CH3:28])[O:25][N:24]=3)=[O:22])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2cc(C)on2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1cc(C(=O)N2CCN(c3c(C(C)N)cc(Cl)c4cccnc34)CC2)no1
Temperature: 65 °C

Procedure:
A mixture of 1-(5-chloro-8-{4-[(5-methylisoxazol-3-yl)carbonyl]piperazin-1-yl}quinolin-7-yl)ethanone (0.032 g, 0.080 mmol) and ammonium acetate (0.0618 g, 0.802 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.20 mL, 0.20 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C20H23ClN5O2 (M+H)+: m/z=400.2; Found: 400.2.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][CH2:5][OH:6].N1C=CC=CC=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl>O>[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([O:6][CH2:5][CH2:4][CH:3]([C:2]([F:11])([F:12])[F:1])[CH2:7][CH2:8][CH2:9][CH3:10])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCC(CCO)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Yield: 87.8 %

Procedure:
In a round-bottomed flask, 3.3 g of (-)-3-trifluoromethyl-1-heptanol and 5.7 g of pyridine were placed and stirred, and 3.4 g of p-toluenesulfonyl chloride was added, followed by 4 hours of reaction at 15°-20° C. The reaction mixture was poured into water, acidified with hydrochloric acid and extracted with diethyl ether, followed further by drying with sodium sulfate, and distilling-off of the solvent to obtain 5.3 g of (+)-3-trifluoromethylheptyl p-toluenesulfonate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:15]([OH:17])=O)=[C:12]([CH3:14])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(NC(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH2:47]([NH2:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>ClCCl.C(OCC)(=O)C>[CH2:47]([NH:54][C:15]([C:11]1[S:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[N:13][C:12]=1[CH3:14])=[O:17])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: Cc1nc(NC(=O)OC(C)(C)C)sc1C(=O)NCc1ccccc1
Yield: 50.1 %

Procedure:
To a stirred solution of 2-(tert-butoxycarbonylamino)-4-methylthiazole-5-carboxylic acid (2.97 g, 11.50 mmol) and diisopropylamine (8.5 mL, 48.70 mmol) in dichloromethane (40 mL) was added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.25 g, 11.50 mmol) and 1-hydroxybenzotriazole (2.02 g, 14.80 mmol). After 30 min benzylamine (1.7 mL, 15.60 mmol) was added. The resultant mixture was stirred at ambient temperature over 8 h, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with ethyl acetate/hexanes (5/95 to 100/0) to afford 2-(tert-butoxycarbonylamino)-4-methylthiazole-5-carboxylic acid benzylamide (2.00 g, 50% yield).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[CH:6]=[C:7]([CH:10]=O)[CH:8]=[CH:9][C:2]=12.[NH2:12][CH:13]1[CH2:18][CH2:17][C:16]([CH2:20][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)([OH:19])[CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.ClC(Cl)C>[N:1]1[S:5][N:4]=[C:3]2[CH:6]=[C:7]([CH2:10][NH:12][CH:13]3[CH2:18][CH2:17][C:16]([CH2:20][CH2:21][C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=5)[N:25]=[CH:24][N:23]=4)([OH:19])[CH2:15][CH2:14]3)[CH:8]=[CH:9][C:2]=12
Reactant: COc1ccc2ncnc(CCC3(O)CCC(N)CC3)c2c1
Reactant: O=Cc1ccc2nsnc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(Cl)Cl
Product: COc1ccc2ncnc(CCC3(O)CCC(NCc4ccc5nsnc5c4)CC3)c2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Molecular sieve, type 3A, (1 g) and benzo[1,2,5]thiadiazol-5-carbaldehyde (0.066 g, 0.4 mmol) were added to a solution of 4-amino-1-[2-(6-methoxy-quinazolin-4-yl)-ethyl]-cyclohexanol (0.116 g, 0.38 mmol) in methanol (1 ml) and dichloroethane (3 ml). The reaction mixture was stirred at room temperature for 20 hours and sodium triacetoxyborohydride (0.22 g, 1.04 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and then filtered over Hydromatrix (wetted with an NaHCO3 solution, 2 ml) and subsequently washed with dichloromethane. The filtrate was concentrated to dryness by rotary evaporation. The residue was purified by column chromatography on silica gel (dichloromethane/MeOH 9/1 1% NH4OH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].IC1C=CC=CC=1C(NCCN1C(=O)CC(=O)NC2C3C(C=CC1=2)=CC=CC=3)=O>>[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:29]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C(Cl)c1ccccc1F
Agent: O=C1CC(=O)N(CCNC(=O)c2ccccc2I)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3F)cc2)c2ccc3ccccc3c2N1
Yield: 67.6 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.101 mmol) obtained in Example 1, (3), and 2-fluorobenzoyl chloride (32 mg, 0.202 mmol), the title compound (30 mg, yield 67%) was obtained as white crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)=[CH:4][CH:3]=1.[C:23](O)(=[O:25])[CH3:24].C(OC(=O)C)(=O)C>O>[C:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:15])([CH3:16])[CH3:17])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)=[CH:4][CH:3]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)O
Reactant: CC(C)(C)c1cc(-c2ccc(N)cc2)cc(C(C)(C)C)c1O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1

Procedure:
A solution of 15 g. (0.050 mole) of 4-(4'-aminophenyl)-2,6-di(t-butyl)phenol in 100 ml. of glacial acetic acid is treated with 5.2 g. (0.050 mole) of acetic anhydride. The resulting solution is heated gently for 10 minutes, diluted with water, cooled, and the solid product is separated by filtration. Recrystallization from a benzene-hexane mixture provides 4-(4'-acetamidophenyl)-2,6-di(t-butyl)phenol, m.p. 173°-174.5° C.
Reaction SMILES: I[C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24].C(N(C(C)C)CC)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[CH:17]([C:5]1[CH:4]=[C:3]([O:20][CH3:21])[C:2]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[CH:16][C:6]=1[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)([CH3:19])[CH3:18]
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C#C[Si](C)(C)C
Temperature: 50 °C
Reaction time: 17 h
Yield: 91.8 %

Procedure:
5-(5-Iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (2.0 g, 5 mmol), bis(triphenylphosphine)-Palladium dichloride (700 mg, 1 mmol) and CuI (100 mg, 0.5 mmol) were added to 14 mL dry THF under nitrogen. Trimethylsilyl acetylene (1.4 mL, 10 mmol) was added, followed by 7 mL diisopropylethylamine. The reaction mixture was stirred at 50° C. under nitrogen for 17 hours, then was allowed to cool for two hours with stirring. The reaction mixture was poured into 15% aqueous NHCl and extracted into EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed on 150 g of flash silica (2%-4% MeOH/CH2Cl2) to give 1.70 g of 5-(2-Isopropyl-4-methoxy-5-trimethylsilanylethynyl-phenoxy)-pyrimidine-2,4-diamine, MS (M+H)=371.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2](OCC)=O.[NH:11]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[NH2:12]>>[C:2]1([C:1]([O:8][CH2:9][CH3:10])=[O:7])[N:14]2[C:15]3[C:20]([CH:21]=[CH:22][C:13]2=[N:11][N:12]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: NNc1ccc2ccccc2n1
Reactant: CCOC(=O)C(=O)OCC
Product: CCOC(=O)c1nnc2ccc3ccccc3n12

Procedure:
Ethyl s-triazolo(4,3-a)quinoline-1-carboxylate was prepared by reacting diethyl oxalate with 2-hydrazinoquinoline, in the manner described in Examples 1 and 2.
Reaction SMILES: Br[C:2]1[N:3]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH:13]1[CH2:16][CH2:15][CH2:14]1)[N:5]=2.C[O-].[Na+].[C:26](OCC)(=[O:28])C.O>CO>[CH:13]1([O:12][C:6]2[N:5]=[C:4]3[C:9]([N:10]=[C:2]([O:28][CH3:26])[N:3]3[CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[C:8]([NH2:11])[N:7]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: Nc1nc(OC2CCC2)nc2c1nc(Br)n2C1CCCCO1
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc2c(N)nc(OC3CCC3)nc2n1C1CCCCO1
Temperature: 67 °C

Procedure:
8-Bromo-2-(cyclobutyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.79 g, 4.86 mmol) was dissolved in anhydrous methanol (25 ml) and 25% sodium methoxide in methanol (2.274 ml, 9.72 mmol) was added under nitrogen. The mixture was heated at 67° C. for 24 hours and then cooled to room temperature. Ethyl acetate and water were added and the layers separated. The aqueous layer was extracted twice more with ethyl acetate, and the organic extracts were combined, washed with brine, dried over anhydrous magnesium sulfate, and evaporated to give the title compound as a cream foam (1.27 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([Br:10])[S:8][CH:9]=1)=O.[NH3:11]>CO>[Br:10][C:7]1[S:8][CH:9]=[C:5]([C:3]([NH2:11])=[O:2])[N:6]=1
Reactant: COC(=O)c1csc(Br)n1
Reactant: N
Solvent: CO
Product: NC(=O)c1csc(Br)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
2-Bromothiazole-4-carboxylic acid methyl ester (50 mg) was dissolved in a solution of saturated ammonia in methanol (4 ml). The reaction solution was stirred overnight at room temperature. The solvent was removed under reduced pressure to give 2-bromothiazole-4-carboxylic acid amide (46 mg, yield 100%) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 8.11 (s, 1H). LC-MS calcd for C4H3BrN2OS (m/e) 205.91, obsd 207 and 209 [M+1]+.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH3:23])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)#[CH:2].[Li][CH2:25]CCC.CI.Cl>C1COCC1.O>[CH2:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:12]2[CH2:13][CH2:14][CH:9]([CH:6]3[CH2:5][CH2:4][CH:3]([C:1]#[C:2][CH3:25])[CH2:8][CH2:7]3)[CH2:10][CH2:11]2)=[CH:16][CH:17]=1)[CH2:22][CH3:23]
Reactant: C#CC1CCC(C2CCC(c3ccc(CCC)cc3)CC2)CC1
Reactant: [Li]CCCC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CC#CC1CCC(C2CCC(c3ccc(CCC)cc3)CC2)CC1
Reaction time: 3 h

Procedure:
3.5 g (11.3 mmol) of 4-ethynyl-4′-(4-propylphenyl)bicyclohexyl are initially introduced in 30 ml of THF at −20° C., and 8.6 ml (13.6 mmol) of n-BuLi (15% soln. in hexane) are added dropwise. After 1 h at this temperature, 0.85 ml (13.6 mmol) of methyl iodide is metered in, and the batch is left in the cooling bath to thaw for 3 h. Water and dil. hydrochloric acid are added, and the mixture is extracted a number of times with MTBE. The combined organic phases are washed with water and sat. sodium chloride soln., and the solution is dried using sodium sulfate. The crude product obtained after removal of the solvents is purified by column chromatography (SiO2, n-heptane:1-chlorobutane=4:1). The further purification is carried out by recrystallisation from n-heptane. This gives 4′-(4-propylphenyl)-4-prop-1-ynylbicyclohexyl as a colourless solid having an m.p. of 70° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:36][N:37]([CH3:41])[C:38](Cl)=[O:39]>>[CH3:36][N:37]([CH3:41])[C:38]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]3)=[O:15])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)=[O:39]
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCNCC4)cc3)cc(=O)c2c1
Reactant: CN(C)C(=O)Cl
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCN(C(=O)N(C)C)CC4)cc3)cc(=O)c2c1

Procedure:
This compound was prepared from 6 methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially available dimethylcarbamyl chloride (Aldrich) via the parallel synthesis described above. MS-base peak at m/z=549 by positive ion CI.
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([N:3]2[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.9 %

Procedure:
To a solution of 4-piperidone monohydrate hydrochloride (7.68 g, 50 mmol) in methylene chloride (50 ml) were added sequentially p-toluenesulfonyl chloride (10.50 g, 55.07 mmol) and triethylamine (21 ml). The mixture was stirred at room temperature for 16 h before being quenched with water (100 ml). The organic layer was washed with 1 M HCl (100 ml) and brine (100 ml), and dried over sodium sulfate. Evaporation of the solvent gave the desired ketone (8.60 g, 68%) as a colorless solid. mp 130-132° C.; 1H NMR (500 MHz, CDCl3) δ2.40 (s, 3H), 2.58 (t, J=6.4 Hz, 4H), 3.38 (t, J=6.4 Hz, 4H), 7.35 (d, J=7.8 Hz, 2H), 7.68 (d, J=8.3 Hz, 2H).
Reaction SMILES: C1(O)C=CC=CC=1.C(O)/C=C/CCCCCCC.CCOC(/N=N/C(OCC)=O)=O.[CH3:31][O:32][C:33](=[O:59])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]CCCCCCCC)=[CH:36][CH:35]=1>CCOCC>[CH3:31][O:32][C:33](=[O:59])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41]/[CH:42]=[CH:43]/[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:36][CH:35]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: CCCCCCC/C=C/CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CCOCC
Solvent: Oc1ccccc1
Product: CCCCCCC/C=C/COc1ccc(C(=O)OC)cc1
Yield: 65 %

Procedure:
Phenol 34 (486 mg, 3.2 mmol), 2-decenol 26g (500 mg, 3.2 mmol), TPP (965 mg, 3.68 mmol), and DEAD (641 mg, 3.68 mmol) in 32 ml ether were reacted according to the procedure for compound 35a. The crude product was purified via flash chromatography over silica gel with gradual elutions from 95/5-90/10 (v/v, Hex/EtOAc). Evaporation of solvent yielded 603 mg (65%) of colorless needles.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH2:23][OH:24])=[C:9]2[CH3:25])=[CH:4][CH:3]=1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:57]([O:64][C:65]1[CH:70]=[CH:69][C:68](O)=[CH:67][CH:66]=1)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH2:23][O:24][C:68]3[CH:69]=[CH:70][C:65]([O:64][CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)=[CH:66][CH:67]=3)=[C:9]2[CH3:25])=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: Cc1c(CO)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(COc2ccc(OCc3ccccc3)cc2)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1

Procedure:
Compound 6 (from Example A) (1 mmol) is added to a solution of diethylazodicarboxylate (1 mmol) and triphenylphosphine (1 mmol) in dry THF (10 mL). 4-Benzyloxyphenol (7) (1 mmol) is then added, and the progress of the reaction is monitored by tlc. When the reaction is complete, water is added and the product is extracted with ethyl acetate. The extract is dried and evaporated and the title compound 8 is then purified by HPLC.