Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]([CH3:30])[S:8]([CH2:11][CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=[CH:17][C:16]=2[NH2:29])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:31]#[C:32]Br>C(O)C>[CH:1]1([N:7]([CH3:30])[S:8]([CH2:11][CH2:12][N:13]2[CH2:14][C:15]3[C:16](=[CH:17][CH:18]=[C:19]([C:21](=[O:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=3)[N:29]=[C:32]2[NH2:31])(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#CBr
Reactant: CN(C1CCCCC1)S(=O)(=O)CCNCc1cc(C(=O)c2ccccc2)ccc1N
Solvent: CCO
Product: CN(C1CCCCC1)S(=O)(=O)CCN1Cc2cc(C(=O)c3ccccc3)ccc2N=C1N
Temperature: 25 °C

Procedure:
A mixture of 2-(2-amino-5-benzoyl-benzylamino)-ethanesulfonic acid cyclohexyl-methyl-amide (0.0054 mol) and cyanogen bromide (0.0080 mol) in ethanol (100 mL) was stirred and refluxed for 2 hours, and then the reaction mixture was cooled to room temperature. After filtration, the filter residue was washed with diisopropyl ether and dried under vacuum to yield the title compound as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][C:4]=1[N:13]1[CH:17]=[CH:16][CH:15]=[N:14]1)#[N:2].Cl>O1CCCC1.O.[OH-].[Li+].O>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N:13]1[CH:17]=[CH:16][CH:15]=[N:14]1)#[N:2]
Reactant: COC(=O)c1ccc(C#N)c(-n2cccn2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C(=O)O)cc1-n1cccn1
Reaction time: 2 h
Yield: 90.8 %

Procedure:
Methyl 4-cyano-3-(1H-pyrazol-1-yl)benzoate (0.27 g) was dissolved in tetrahydrofuran (10 ml). To the solution, a solution in which lithium hydroxide monohydrate (0.10 g) is dissolved in water (10 ml) was added at room temperature. The reaction mixture was stirred for 2 hours. The reaction solution was acidified with 2 N hydrochloric acid, and then extracted twice with ethyl acetate. The organic phases were combined, washed with water, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a crude product of 4-cyano-3-(1H-pyrazol-1-yl)benzoic acid (0.23 g). The crude product was used for the next step without further purification.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[ClH:14].O[CH:16]1[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]1[NH2:18]>>[ClH:14].[CH2:1]([NH:13][CH:16]1[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]1[NH2:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CCCCCCCCCCCCN
Agent: Cl
Product: CCCCCCCCCCCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N
Temperature: 25 °C

Procedure:
46 g of dodecylamine are fused at 60°, and 31 g of glucosamine hydrochloride are added with stirring. After cooling to room temperature, the product precipitates out. The solid is stirred with ether three times, filtered off with suction and then dried under high vacuum.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]1[CH2:13][CH:14]3[NH:19][CH:18]([C:7]2=1)[CH2:17][CH2:16][CH2:15]3.[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=[CH2:30]>>[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][N:9]1[C:10]2[C:6](=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:12][CH:11]=2)[C:7]2[CH:18]3[NH:19][CH:14]([CH2:13][C:8]1=2)[CH2:15][CH2:16][CH2:17]3
Reactant: C=Cc1ccccc1C
Reactant: FC(F)(F)Oc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1
Product: Cc1ccccc1CCn1c2c(c3cc(OC(F)(F)F)ccc31)C1CCCC(C2)N1

Procedure:
The coupling of 2-trifluoromethoxy-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (148 mg, 0.500 mmol; Example 140A) and 1-methyl-2-vinylbenzene (118 mg, 1.00 mmol; Aldrich) was performed according to the procedure described in Example 114B to afford the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 1.09-1.21 (m, 1H), 1.29-1.43 (m, 2H), 1.80 (d, J=13 Hz, 1H), 2.02-2.10 (m, 4H), 2.27 (tt, J=14, 5 Hz, 1H), 2.41 (tt, J=14, 4 Hz, 1H), 3.00 (dt, J=14, 5 Hz, 1H), 3.05-3.14 (m, 1H), 3.35 (dd, J=18, 7 Hz, 1H), 4.21 (ddd, J=15, 9, 6 Hz, 1H), 4.28-4.33 (m, 1H), 4.37 (ddd, J=15, 5, 5 Hz, 1H), 5.29 (s, 1H), 6.92 (d, J=7 Hz, 1H), 7.06 (t, J=7 Hz, 1H), 7.09-7.12 (m, 1H), 7.15 (t, J=7 Hz, 1H), 7.30 (d, J=10 Hz, 1H), 7.54 (d, J=9 Hz, 1H), 7.63 (s, 1H); MS (DCI/NH3) m/z 415 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH3:3].FC1C(F)=C(F)C(F)=C(F)C=1O[C:21]1[N:26]=[C:25]([C:27]2[C:35]3[C:30](=[N:31][CH:32]=[C:33]([C:36]([F:39])([F:38])[F:37])[CH:34]=3)[N:29]([S:40]([C:43]3[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=3)(=[O:42])=[O:41])[CH:28]=2)[C:24]([C:50]#[N:51])=[CH:23][N:22]=1>>[C:50]([C:24]1[C:25]([C:27]2[C:35]3[C:30](=[N:31][CH:32]=[C:33]([C:36]([F:38])([F:37])[F:39])[CH:34]=3)[N:29]([S:40]([C:43]3[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=3)(=[O:42])=[O:41])[CH:28]=2)=[N:26][C:21]([NH:1][C@@H:2]([CH:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:8][CH2:9]2)[CH3:3])=[N:22][CH:23]=1)#[N:51]
Reactant: C[C@@H](N)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(Oc4c(F)c(F)c(F)c(F)c4F)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)C4CCN(C(=O)OC(C)(C)C)CC4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
(R)-tert-butyl 4-(1-aminoethyl)piperidine-1-carboxylate (43.82 mg, 0.19 mmol) was added to a solution of 2-(perfluorophenoxy)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (100 mg, 0.16 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The crude mixture was concentrated to dryness and the resulting residue was purified on silica gel by flash column chromatography to afford the title compound (70 mg, 65% yield).
Reaction SMILES: [CH3:1][NH2:2].F[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[N+:18]([O-:20])=[O:19].O>O1CCCC1>[CH3:1][NH:2][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[N+:18]([O-:20])=[O:19]
Reactant: COc1ccnc(-c2ccc(F)c([N+](=O)[O-])c2)c1
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNc1ccc(-c2cc(OC)ccn2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methylamine in tetrahydrofuran (2M, 11 ml) was added 1-fluoro-4-(4-methoxypyridin-2-yl)-2-nitrobenzene (289 mg). The mixture was stirred at ambient temperature for 2 hours and poured into water. The precipitate was collected by filtration and dried to give 1-methylamino-4-(4-methoxypyridin-2-yl)-2-nitrobenzene (280 mg).
Reaction SMILES: [F:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][CH2:4][OH:5].[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1>[CH3:10][S:11]([O:5][CH2:4][CH2:3][C@@H:2]([F:1])[CH2:6][CH2:7][CH2:8][CH3:9])(=[O:13])=[O:12]
Reactant: CCCC[C@H](F)CCO
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCC[C@H](F)CCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 92.3 %

Procedure:
To a 100 ml flask were added 8.7 g of (S)-3-fluoroheptanol and 21.5 g of pyridine under a nitrogen atmosphere, and the solution was kept at 5° to 10° C. To the solution was added dropwise 7.5 g of methanesulfonyl chloride over 30 minutes, followed by stirring at 15° C. or less for 5 hours. The reaction mixture was poured into 200 ml of ice-water and extracted with ethyl acetate. The organic layer was washed successively with a diluted hydrochloric aqueous solution and water, dried over magnesium sulfate, and the solvent was removed by distillation at 30° C. or lower to obtain 12.7 g (yield=93.18%) of the titled compound. NMR (ppm): 0.92 (3H, t, J=7.1 Hz), 1.35-1.8 (6H, m), 2.03 (2H, m), 3.02 (3H, s), 4.37 (1H, t, J=6.2 Hz), 4.65 (2H, m)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:11]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2)=[CH:4][CH:3]=1.[Si]([N:33]=[C:34]=[O:35])(C)(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([N:11]([CH2:24][C:25]([F:26])([F:27])[F:28])[CH2:10][CH2:9][O:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:34]([NH2:33])=[O:35])=[CH:3][CH:4]=2)=[CH:13][C:14]=1[C:20]([F:21])([F:22])[F:23])#[N:17]
Reactant: N#Cc1ccc(N(CCOc2ccc(N)cc2)CC(F)(F)F)cc1C(F)(F)F
Reactant: C[Si](C)(C)N=C=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(N(CCOc2ccc(NC(N)=O)cc2)CC(F)(F)F)cc1C(F)(F)F
Reaction time: 8 h
Yield: 40.1 %

Procedure:
To a solution of 4-[{2-[(4-aminophenyl)oxy]ethyl}(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (0.105 g, 0.25 mmol; Example 28A) in dry CH2Cl2 (5 mL) at room temp, under N2, was added TMS-isocyanate (0.05 mL, 0.29 mmol) and the mixture was stirred overnight. After 12 h, an additional portion of TMS-isocyanate (0.09 mL, 0.58 mmol) and DMAP (0.003 g, 0.025 mmol) was added and stirring continued. After 2 h, the mixture was quenched with 10% v/v HCl and the whole extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), followed by preparative RP-HPLC (C18 column, MeCN/water), affording 0.0448 g of the title compound as a colorless gum: MS (ES) m/z 447 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>C(O)C>[NH:12]([C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1)[NH2:13]
Reactant: Clc1nccc2[nH]cnc12
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1nccc2[nH]cnc12

Procedure:
A mixture of 200 mg (1.3 mmol) of 4-chloro-1H-imidazo[4,5-c]pyridine [J. A. Montgomery and K. Hewson, J. Med. Chem., 8, 708 (1965)], 0.253 mL (261 mg, 5.2 mmol) of hydrazine hydrate, and 5 mL of ethanol was stirred at room temperature overnight. The precipitate was collected on a filter, washed with a little ethanol, and dried to give the title compound as a solid. LC-MS 150 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:8]=[C:7]([CH3:21])[C:3]=1[C:4]([OH:6])=O.[N:22]1([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:1][C:2]1[C:3]([C:4]([N:30]2[CH2:31][CH2:32][CH:27]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:28][CH2:29]2)=[O:6])=[C:7]([CH3:21])[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:10]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)nc(C)c1C(=O)O
Reactant: C1CCN(C2CCNCC2)C1
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)nc(C)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedures described for example 1, for intermediate 5B and for intermediate 1, the title compound has been prepared by the following reaction sequence: i) 6-chloro-2,4-dimethyl-nicotinic acid ethyl ester [Zhou, Y.; Bridger, G. J.; Skerlj, R. T.; Bogucki, D.; Yang, W.; Bourque, E.; Langille, J.; Li, T.-S.; Metz, M. U.S. Pat. Appl. Publ. (2005), US 2005277668 A1] was reacted with 3-trifluoromethyl-phenyl boronic acid to give 2,4-dimethyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid ethyl ester; ii) 2,4-dimethyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid ethyl ester has been saponified to give 2,4-dimethyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid; iii) 2,4-dimethyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid was converted into its acid chloride and reacted with 4-pyrrolidin-1-yl-piperidine to give the title compound as colorless solid. MS: 432.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.[C:30]1(=O)[CH2:34][CH2:33][C:32](=[O:35])[CH2:31]1.C([BH3-])#N.[Na+].CCN(C(C)C)C(C)C>CO>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:30]4[CH2:34][CH2:33][C:32](=[O:35])[CH:31]=4)[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)C1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C5=CC(=O)CC5)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (43 mg, 0.1 mmol), cyclopentane-1,3-dione (89 mg, 9.1 mmol), sodium cyanoborohydride (19 mg, 0.3 mmol) and DIEA (0.2 mL, 11 mmol) in MeOH (1 mL) was stirred in a sealed vial at 60° C. After 2.5 h, additional sodium cyanoborohydride (19 mg, 0.3 mmol) was added and the reaction continued to stir at 60° C. overnight. The mixture was purified by RP-HPLC to give 3-(4-(4-(5-Chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)cyclopent-2-en-one as an off white solid; 1H NMR (400 MHz, DMSO-d6) δ 9.97 (br s, 1H), 9.83 (br s, 1H), 8.90 (s, 1H), 8.32 (d, J=6.8 Hz, 1H), 7.88 (d, J=12.8 Hz, 1H), 6.97 (s, 1H), 6.04 (s, 1H), 5.30 (br s, 1H), 4.71 (d, J=12.0 Hz, 2H), 4.04 (t, J=12.4 Hz, 2H), 3.84 (m, 1H), 3.53 (m, 2H), 3.13 (m, 2H), 3.08 (s, 3H), 2.96 (s, 3H), 2.59-2.40 (m, 4H); ESMS m/z 496.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>CC(C)=O>[CH2:21]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)[CH:20]=[CH2:19]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
To a stirred solution of 66.4 g (0.4 mole) ethyl 4-hydroxybenzoate in 100 ml acetone, under a nitrogen atmosphere was added 55.3 g (0.40 mole) finely powdered potassium carbonate and 53.2 g (0.44 mole) allyl bromide and the resulting mixture was heated at reflux overnight. After cooling to room temperature the mixture was filtered, washing with ethyl ether. The filtrate and washings were washed with water, brine and dried (MgSO4). Evaporation of solvent in vacuo gave 82.3 g of product as a clear oil. 1H-NMR(CDCl3)ppm(delta): 5.0-5.5 (m), 5.8 (m), 6.8 (m), 8.0 (m).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[C@@:40]2([CH3:41])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:39]2[CH2:38][CH2:37][C@@:36]2([CH3:42])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH2:34][OH:35])[CH2:21][CH2:22][C@@H:23]([F:33])[C:24]([O:27][CH:28]([O:30][CH2:31][CH3:32])[CH3:29])([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:43][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][O:45]2)[CH2:9]1.[C:50]1([CH3:60])[CH:55]=[CH:54][C:53]([S:56](Cl)(=[O:58])=[O:57])=[CH:52][CH:51]=1>N1C=CC=CC=1>[CH3:60][C:50]1[CH:55]=[CH:54][C:53]([S:56]([O:35][CH2:34][C@@H:20]([C@@H:19]2[C@:36]3([CH3:42])[C@H:16]([C@H:15]4[C@H:39]([CH2:38][CH2:37]3)[C@:40]3([CH3:41])[C:12]([CH2:11][C@@H:10]([O:43][CH:44]5[CH2:49][CH2:48][CH2:47][CH2:46][O:45]5)[CH2:9][C@@H:8]3[O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[CH:13][CH2:14]4)[CH2:17][CH2:18]2)[CH2:21][CH2:22][C@@H:23]([F:33])[C:24]([O:27][CH:28]([O:30][CH2:31][CH3:32])[CH3:29])([CH3:26])[CH3:25])(=[O:58])=[O:57])=[CH:52][CH:51]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(C)OC(C)(C)[C@H](F)CC[C@@H](CO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Product: CCOC(C)OC(C)(C)[C@H](F)CC[C@@H](COS(=O)(=O)c1ccc(C)cc1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A mixture of 3.99 g. (0.0058 mole) of [1α,3β,24R]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-en-21-ol, 15 ml. of pyridine and 2.20 g. (0.0115 mole) of p-toluenesulfonyl chloride was stirred at 0° C. for 18 hr. The mixture was quenched with ice chips. The mixture was then poured into water and extracted with methylene chloride. The organic phase was washed with 10% aqueous sulfuric acid and saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to yield oily [1α,3β,24R]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-en-21-ol 21-(4-methylbenzenesulfonate), [α]D20 +8° (c 1, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:4]([O:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[C:19]2[CH2:24][CH2:25][CH2:26][C:18]=2[N:17]=1)[C:5]([O:7]CC1C=CC=CC=1)=[O:6].[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][C:3]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH:4]([O:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[C:19]2[CH2:24][CH2:25][CH2:26][C:18]=2[N:17]=1)[C:5]([OH:7])=[O:6]
Reactant: COc1nc(OC(C(=O)OCc2ccccc2)C(OC)(c2ccccc2)c2ccccc2)nc2c1CCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1nc(OC(C(=O)O)C(OC)(c2ccccc2)c2ccccc2)nc2c1CCC2

Procedure:
40 g (78.4 mmol) of benzyl 3-methoxy-2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3,3-diphenylpropionate were dissolved in 400 ml of ethyl acetate/methanol (4:1), about 500 mg of palladium on active carbon (10%) were added, and the mixture was exposed to a hydrogen atmosphere until no further gas was taken up. The catalyst was filtered off, the solution was evaporated, and the residue was crystallized from ether.
Reaction SMILES: [NH2:1][C:2]1[N:12]=[C:11]([NH:13]C(=O)C(C)(C)C)[C:10]([Cl:20])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[CH2:22][CH:23]=O.C>C(O)C>[NH2:13][C:11]1[N:12]2[CH:22]=[CH:23][N:1]=[C:2]2[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:9][C:10]=1[Cl:20]
Reactant: O=CCCl
Reactant: CCOC(=O)c1cc(Cl)c(NC(=O)C(C)(C)C)nc1N
Solvent: CCO
Product: CCOC(=O)c1cc(Cl)c(N)n2ccnc12
Reaction time: 8 h
Yield: 43.3 %

Procedure:
To a solution of ethyl 2-amino-5-chloro-6-[(2,2-dimethylpropanoyl)amino]nicotinate (Example 1, METHOD A, Step 2, 685 mg, 2.12 mmol) in ethanol (10 mL) was added 50% aqueous chloroacetaldehyde (430 μL, 3.4 mmol), and the mixture was refluxed with stirring overnight. The mixture was treated with charcoal and filtered. The filtrate was dry-loaded onto silica gel and chromatographed on a column of silica gel eluting with dichloromethane/methanol/25% aqueous ammonia (97:3:1 to 95:5:0.5) to give 220 mg (40%) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][Cl:13])[N:3]=1.O.[NH2:15][NH2:16]>O1CCCC1>[Cl:13][CH2:12][C:4]1[N:3]=[C:2]([NH:15][NH2:16])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: ClCc1nc(Cl)c2ccccc2n1
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: NNc1nc(CCl)nc2ccccc12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
2.1. 46.0g of 4-chloro-2-(chloromethyl)quinazoline are suspended in 600 ml of absolute tetrahydrofuran. The solution is cooled to 0° C. 23.0 ml of hydrazine hydrate are added dropwise within 5 min., whereby a solution results and the temperature rises to 15° to 20° C. The reaction mixture is stirred at room temperature for 4 h. and then evaporated in a vacuum. The residue is triturated with 0.5 l of dichloromethane and 1 l of a saturated aqueous sodium hydrogen carbonate solution and then filtered. The crystals are washed neutral with water and dried in a vacuum. 38 g of 2-(chloromethyl)-4-hydrazinoquinazoline are obtained. The dichloromethane phase of the filtrate is separated and the aqueous phase is extracted with dichloromethane. By evaporation of the organic phases, there are obtained a further 5.8 g of 2-(chloro-methyl)-4-hydrazinoquinazoline. In total there are obtained 43.8 g of 2-(chloromethyl)-4-hydrazino- quinazoline. M.p. 192° C. (dec.).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].N1CCCC1.[C:20]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:21][CH2:22][C:23]([CH3:25])=O>C1(C)C=CC=CC=1>[OH:14][C:5]1[CH:6]=[CH:7][C:8]2[C:11](=[O:12])[CH2:13][C:23]([CH2:22][CH2:21][C:20]([O:27][CH2:28][CH3:29])=[O:26])([CH3:25])[O:10][C:9]=2[C:4]=1[CH2:3][CH2:2][CH3:1]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCOC(=O)CCC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: CCCc1c(O)ccc2c1OC(C)(CCC(=O)OCC)CC2=O

Procedure:
A solution of 58.0 g (0.299 mole) of 2,4-dihydroxy-3-propylacetophenone and 29.5 ml (0.36 mole) of pyrrolidine in 250 ml of toluene was heated to reflux for three hours under a Dean-Stark trap. After cooling the mixture, 68.2 ml (0.48 mole) of ethyl levulinate was added and the mixture was refluxed for two hours. An additional 10 ml (0.12 mole) of pyrrolidine was added and the mixture was refluxed overnight under a Dean-Stark trap.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14](I)[CH:13]=2)[O:9][N:8]=1.C(N(CC)CC)C.[CH2:28]([OH:31])[C:29]#[CH:30]>CN(C)C=O.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.[Cu]I>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14]([C:30]#[C:29][CH2:28][OH:31])[CH:13]=2)[O:9][N:8]=1
Reactant: C#CCO
Reactant: N#Cc1cc(I)cc(-c2nc(-c3ccccn3)no2)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1cc(C#CCO)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 17.7 %

Procedure:
A mixture of the 3-(2-pyridyl)-5-(5-cyano-3-iodophenyl)-1,2,4-oxadiazole (140 mg, 0.374 mmol), Pd(PPh3)4 (10 mg, 0.009), and CuI (30 mg, 0.158 mmol) in N,N-dimethylformamide (3 mL) was treated with triethylamine (1 mL, 726 mg, 7 mmol). The reaction mixture was cooled to 0° C. and treated with propargyl alcohol (56 mg, 1 mmol). The mixture was stirred at ambient temperature 5 hours and then filtered through a short plug of silica gel, washing with ethyl acetate. The organic solution was concentrated in vacuo. Silica gel chromatography afforded 20 mg (18%) of 3-(2-pyridyl)-5-(5-cyano-3-[3-hydroxypropyn-1-yl]phenyl)-1,2,4-oxadiazole: 1H-NMR (MeOH-d4), δ ppm: 8.80 (d, 1H), 8.60 (s, 1H), 8.58 (s, 1H), 8.30 (d, 1H), 8.10 (m, 2H), 7.60 (m, 1H), 4.5 (s, 2H).