Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C1C=CC2C3(C4C(OC=2C=1)=CC(C)=C(NC1C=CC=CC=1)C=4)OC(=[O:20])C1C3=CC=CC=1)CC.P([O-])([O-])([O-])=O.[CH3:42][C@@H:43]([C@@H:50]1[C@@:54]2([CH3:69])[CH2:55][CH2:56][CH2:57]/[C:58](=[CH:59]\[CH:60]=[C:61]3\[CH2:62][C@@H:63]([OH:68])[CH2:64][CH2:65][C:66]\3=[CH2:67])/[C@@H:53]2[CH2:52][CH2:51]1)[CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48].C(Cl)Cl>C(O)C>[CH3:42][C@@H:43]([C@@H:50]1[C@@:54]2([CH3:69])[CH2:55][CH2:56][CH2:57]/[C:58](=[CH:59]\[CH:60]=[C:61]3\[CH2:62][C@@H:63]([OH:68])[CH2:64][CH2:65][C:66]\3=[CH2:67])/[C@@H:53]2[CH2:52][CH2:51]1)[CH2:44][CH2:45][CH2:46][C:47]([OH:20])([CH3:48])[CH3:49]
Reactant: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]12
Reactant: CCN(CC)c1ccc2c(c1)Oc1cc(C)c(Nc3ccccc3)cc1C21OC(=O)c2ccccc21
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)(C)O)CC[C@@H]12
Reaction time: 48 h

Procedure:
Nocardia autotrophica N-102 in the same BG medium (100 ml/500 ml-Erlenmeyer flask) as used in Example 1 was cultured at 28° C. under the aerobic conditions for 48 hours. To the culture solution were added 10 ml of a 5% PMCD (made by Mercian Co.) solution (0.01 M phosphate buffer, pH 7.0) and a solution of 2% vitamin D3 in 1 ml of ethanol (in the amount of 7 mol of PMCD relative to 1 mol of vitamin D3), and cultivation was continued for a further 96 hours. After completion of the cultivation, 200 ml of methylene chloride was added to the flask, and the mixture was extracted. The methylene chloride layer was concentrated to dryness under reduced pressure, and immediately after the residue was dissolved in 3 ml of 2-propanol:n-hexane (1:9) and allowed to stand at -20° C. for 2 hours. The resulting insolubles were removed by centrifugation. The supernatant was concentrated under reduced pressure and applied to HPLC on Zorbax SIL column (4.6 mm×25 cm) with n-hexane-2-propanol (86:14) as a mobile phase at a flow rate of 1.5 ml/min. The peak fraction at 3.8 minutes was collected, and concentrated to dryness at 40° C. or below under reduced pressure with a nitrogen gas replacement to give 25-hydroxyvitamin D3, which was strictly identical to the authentic sample of the commercially available 25-hydroxyvitamin D3 (made by Duphar Co., Holland) in terms of the retention time of HPLC, the UV absorption spectrum and mass spectrum cleavage pattern.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N)[C:34]1[O:38][CH:37]=[CH:36][CH:35]=1.F[P-](F)(F)(F)(F)F.[CH3:47][N:48](C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:48][CH2:47][C:36]5[CH:35]=[CH:34][O:38][CH:37]=5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NCc1ccco1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCc2ccoc2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 18 h
Yield: 42.7 %

Procedure:
A mixture of 0.070 g (0.16 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.031 g (0.32 mmole) of furfurylamine, 0.071 g (0.19 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.136 mL (0.78 mmole) of diisopropylethyl amine and 2.0 mL of dimethylformamide was stirred for 18 hours. The mixture was diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes-ethyl acetate (gradient, 80:20-0:100) to give 0.036 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-furan-3-ylmethyl-3-methoxy-benzamide (I-34) as a white solid.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)=[CH:8][N:9]=1)(=O)C.O1CCCC1.Cl>C(O)C>[NH2:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)=[CH:8][N:9]=1
Reactant: CC(=O)Nc1ncc(Sc2ccc(C(F)(F)F)cn2)s1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ncc(Sc2ccc(C(F)(F)F)cn2)s1
Yield: 75.6 %

Procedure:
A mixture of 2-acetylamino-5-(5-trifluoromethylpyridin-2-ylthio)thiazole (3.2 g) in a mixture of ethanol (60 ml), tetrahydrofuran (30 ml) and aqueous 6N-hydrochloric acid (10 ml) was refluxed for 3 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The solution was adjusted to pH 8.5 using aqueous sodium bicarbonate and extracted with mixture of tetrahydrofuran and ethyl acetate (1:1) and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 150 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-5-(5-trifluoromethylpyridin-2-ylthio)thiazole (2.1 g, yield: 75.8%). mp: 135°-138° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][N:10]2[CH:12]=[C:13]([CH2:14][C:15]([O-:17])=O)[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.[Na+].[NH2:19][C:20]1[CH:21]=[C:22]2[C:35](=[CH:36][CH:37]=1)[CH2:34][C:24]1([C:32]3[C:27](=[N:28][CH:29]=[CH:30][CH:31]=3)[NH:26][C:25]1=[O:33])[CH2:23]2.C(Cl)CCl.C1C=CC2N([OH:51])N=NC=2C=1>CN(C=O)C.C(O)(C(F)(F)F)=O>[O:1]=[C:2]1[C:11](=[O:51])[N:10]2[CH:12]=[C:13]([CH2:14][C:15]([NH:19][C:20]3[CH:21]=[C:22]4[C:35](=[CH:36][CH:37]=3)[CH2:34][C:24]3([C:32]5[C:27](=[N:28][CH:29]=[CH:30][CH:31]=5)[NH:26][C:25]3=[O:33])[CH2:23]4)=[O:17])[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: On1nnc2ccccc21
Reactant: O=C([O-])Cc1cn2c3c(cccc13)NC(=O)C2
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Cc1cn2c(=O)c(=O)[nH]c3cccc1c32)Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21

Procedure:
A solution of sodium (2-oxo-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-6-yl)acetate (45 mg, 0.195 mmol, described in Intermediate 26), (−)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1 H)-one (59 mg, 0.235 mmol, described in Intermediate 3), EDC (75 mg, 0.391 mmol), and HOBT (60 mg, 0.391 mmol) in DMF (12 mL) and TFA (0.1 mL) was stirred for 18 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were combined and lyophilized to give the title compound. MS: m/z=478 (M+1). HRMS: m/z=478.1524; calculated m/z=478.1510 for C27H20N5O4.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([CH2:7][CH3:8])[CH3:6].O>C(O)(=O)C>[N+:1]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH:5]([CH2:7][CH3:8])[CH3:6])[C:10]=1[OH:15])([O-:4])=[O:2]
Reactant: CCC(C)c1ccccc1O
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CCC(C)c1cccc([N+](=O)[O-])c1O
Temperature: 0 °C
Yield: 48.1 %

Procedure:
A mixture comprising 290.6 g of 65% nitric acid and 800 g of glacial acetic acid is cooled to 0° C., and at 0° to 4° C. there is added in the course of 11/2 hours, with thorough stirring and with cooling, a solution of 375.6 g of sec-butylphenol in 375 g of glacial acetic acid. There results a dark solution which is stirred at 0° to 4° C. for a further one hour. The reaction mixture is subsequently stirred into 5000 ml of water and ice. The nitrating mixture is obtained as a dark oil which is extracted with 1500 ml of chloroform. The chloroform is distilled off, and steam is passed into the dark oil obtained. As distillate is obtained 235 g of 2-nitro-6-sec-butylphenol in the form of light-yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:15]1[N:16]=[CH:17][N:18]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=1)CCC>>[C:33]1([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:18]2[CH:19]=[C:15]([C:2]3[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=3)[N:16]=[CH:17]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: N#Cc1ccnc(Cl)c1
Product: N#Cc1ccnc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Yield: 77 %

Procedure:
The title compound was prepared in 77% yield from 2-chloro-4-pyridinenitrile and 4-(tributylstannyl)-1-tritylimidazole according to the procedure for Example 1, part A. 1H NMR (400 MHz, DMSO-d6): δ 7.17 (5H, m), 7.40-7.47 (10H, m), 7.49 (1H, d, J=1.2 Hz), 7.62 (1H, d, J=1.3 Hz), 7.65 (1H, dd, J=1.5 Hz and 5.0 Hz), 8.13 (1H, s), 8.67 (1H, d, 5.0 Hz).
Reaction SMILES: [Li+].CCC[CH2-].[F:6][C:7]([F:21])([F:20])[S:8]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)(=[O:10])=[O:9].[Br:22][C:23]1[CH:24]=[CH:25][C:26]2[N:27]([CH2:37][CH:38]3[CH2:40][O:39]3)[C:28]3[C:33]([C:34]=2[CH:35]=1)=[CH:32][C:31]([Br:36])=[CH:30][CH:29]=3>O1CCOCC1.C(OCC)(=O)C.N.CO>[Br:22][C:23]1[CH:24]=[CH:25][C:26]2[N:27]([CH2:37][CH:38]([OH:39])[CH2:40][N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[S:8]([C:7]([F:20])([F:6])[F:21])(=[O:9])=[O:10])[C:28]3[C:33]([C:34]=2[CH:35]=1)=[CH:32][C:31]([Br:36])=[CH:30][CH:29]=3
Reactant: COc1cccc(NS(=O)(=O)C(F)(F)F)c1
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2CC1CO1
Agent: N
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cccc(N(CC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)S(=O)(=O)C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 23.2 %

Procedure:
N-butyllithium (2.5 M in hexanes, 48 ml) was added dropwise to an ice-cooled solution of 1,1,1-trifluoro-N-(3-methoxyphenyl)methanesulfonamide (22.07 g, 86.5 mmol) in dry dioxane (145 ml) over a 40 minute period. The solution was then stirred at rt for 15 minutes before addition of 3,6-dibromo-9-(oxiran-2-ylmethyl)-9H-carbazole (25.05 g, 65.7 mmol), followed by heating at 90° C. for an hour. These conditions were optimized to maximize conversion while minimizing formation of an aziridene by-product. The reaction was allowed to cool to rt then diluted with 1.2 L ethyl acetate and washed several times with water and finally brine. The organic layer was dried over MgSO4, filtered and condensed to give an orange viscous mixture. To this mixture was added 150 ml of 60% methylene chloride/hexanes, and the solution was then concentrated to generate a yellow foam (presumably this procedure helps remove residual ethyl acetate and/or dioxane). A further 150 ml of 60% methylene chloride/hexanes was added and stirred overnight. The mixture was filtered and washed several times with 60% methylene chloride/hexanes until the solid was white giving 20.1 g of 99% purity. A second crop gave 2.98 g in 91% purity. Filtrates and washings were combined and found to contain a 2:2.6:1 mixture of SM:product:aziridene by-product. This mixture was subjected to amination conditions by heating the mixture (24 g in approximately 2 equal portions) in ammonia in methanol (7N, 11 and 8 ml, respectively) at 100° C. in sealed pressure tubes overnight. Epoxide SM is converted to β-hydroxy amine (MacMillan et al., J. Am. Chem. Soc. 2011, 133, 1428), which aids chromatographic purification. Column chromatography in 80% DCM/hexanes gave a further 9.7 g of product with an overall yield of 32.78 g and 78%.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[CH:48]=[C:47]([CH3:49])[O:46][N:45]=1>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:32]([NH:43][C:44]1[CH:48]=[C:47]([CH3:49])[O:46][N:45]=1)=[O:34]
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(N)no1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)on4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.7 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (100 mg) was dissolved in chloroform (5 ml) and triethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 3-amino-5-methylisoxazole (38 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 78 mg of the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:10]([C:11]2[NH:15][CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:12]=2[F:26])=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4].C1OCCOCCOCCOCCOC1.[N:42]1[CH:47]=[CH:46][CH:45]=[C:44]([S:48](Cl)(=[O:50])=[O:49])[CH:43]=1>O1CCCC1.O>[C:3]([C:5]1[C:10]([C:11]2[N:15]([S:48]([C:44]3[CH:43]=[N:42][CH:47]=[CH:46][CH:45]=3)(=[O:50])=[O:49])[CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[C:12]=2[F:26])=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CN(Cc1c[nH]c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2cccnc2)c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (4 mL) were added dropwise a solution (2 mL) of tert-butyl {[5-(2-cyanopyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (330 mg) in tetrahydrofuran, 15-crown-5 (330 mg) and pyridine-3-sulfonyl chloride (266 mg) under ice-cooling and the mixture was stirred for 1 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:2) to give the title compound as a pale-yellow oil (yield 421 mg, 89%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=2)[CH:6]=1)[CH3:2].I[Si](C)(C)C>C(#N)C.O>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:13]=[N:14][C:15]([OH:18])=[CH:16][CH:17]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Oc2ccc(OC)nc2)c1
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cccc(Oc2ccc(O)nc2)c1
Yield: 68.9 %

Procedure:
A solution of 3-(6-methoxy-pyridin-3-yloxy)-benzoic acid ethyl ester (0.5 g, 1.83 mmol) in acetonitrile (8 ml) and iodotrimethylsilane (0.439 g, 2.2 mmol) was refluxed for 1 h, the mixture was diluted with water (8 ml) and extracted with chloroform. The extract was washed with 10% of aqueous Na2S2O3, water, dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to afford 0.327 g (69%) of 3-(6-hydroxy-pyridin-3-yloxy)-benzoic acid ethyl ester as colorless powder.
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:12]=1[CH:13]=O.C(O)(=O)C>N1CCCCC1.C1(C)C=CC=CC=1>[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:12]=1[CH:13]=[C:4]([C:3](=[O:9])[CH2:2][CH3:1])[C:5](=[O:8])[CH2:6][CH3:7]
Reactant: CCC(=O)CC(=O)CC
Reactant: O=Cc1c(F)cccc1F
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCC(=O)C(=Cc1c(F)cccc1F)C(=O)CC
Temperature: 70 °C
Reaction time: 7 h
Yield: 30.7 %

Procedure:
A mixture of 3,5-heptanedione (1.36 ml, 10 mmol), 2,6-difluorobenzaldehyde (1.08 ml, 10 mmol), piperidine (20 μL, 0.2 mmol), glacial acetic acid (149 μL, 2.6 mmol), molecular sieves and toluene (7 ml) was heated at 70° C., under a nitrogen atmosphere for 3 hours. Further 2,6-difluorobenzaldehyde (540 μL, 5 mmol) was added and the resulting mixture was stirred at 70° C. for a further 7 hours. After cooling, the molecular sieves were filtered off. The filtrate was concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic phase was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with pentane:dichloromethane (4:1, by volume) and then with a solvent gradient of pentane:diethylether (20:1, by volume) gradually changing to pentane:diethylether (10:1, by volume) to afford the title compound (775 mg) as a colourless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].C(OCC)C.[BH4-].[Na+].Cl>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(-c2ccc(C3CCC(=O)CC3)cc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: N#Cc1ccc(-c2ccc([C@H]3CC[C@H](O)CC3)cc2)cc1
Reaction time: 3 h

Procedure:
A suspension of 10 g of 4-(4'-cyano-4-biphenylyl)cyclohexanone, 30 ml of diethyl ether and 270 ml of methanol was treated portionwise at 0° C. with 1.8 g of sodium borohydride. After 3 hours the reaction mixture was made acid (pH 1-2) with 25% hydrochloric acid. The reaction mixture was extracted three times with 50 ml of dichloromethane each time. The combined organic phases were washed twice with 500 ml of water each time and subsequently dried over magnesium sulfate, filtered and concentrated. Recrystallization from methanol gave 3.5 g of trans-4-(4'-cyano-4-biphenylyl)cyclohexanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][N:8]=[C:9]=[S:10])=[CH:5][CH:4]=1.[C:13]([NH:18][NH2:19])(=O)[C:14]([OH:16])=[O:15].[CH2:20](O)[CH3:21]>>[CH2:20]([O:16][C:14]([C:13]1[N:8]([CH2:7][C:6]2[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]([SH:10])=[N:19][N:18]=1)=[O:15])[CH3:21]
Reactant: COc1ccc(CN=C=S)cc1
Reactant: NNC(=O)C(=O)O
Reactant: CCO
Product: CCOC(=O)c1nnc(S)n1Cc1ccc(OC)cc1

Procedure:
A solution of p-methoxybenzyl isothiocyanate (8.95 g.) and the ethyl ester of oxalic acid monohydrazide (6.8 g.) in ethanol (50 ml.) was refluxed for a period of approximately 16 hours (overnight). The hot solution was then filtered, the filtrate evaporated in vacuo and the resulting oil triturated with dry diethyl ester. The solid product so obtained, viz., 3-ethoxycarbonyl-4-(p-methoxybenzyl)-1,2,4-triazole-5-thiol (yield, 7.2 g.) was then recrystallized from ethanol-water to yield 4.0 g. of pure material. The analytical sample melted at 142°-144° C. after a further recrystallization from ethyl acetate/petroleum ether (b.p. 60°-80° C.).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)=[N:9][C:10](=[O:17])[N:11]2[CH:14]([CH3:16])[CH3:15])=[CH:6][CH:5]=1)([OH:3])=[O:2].Cl.[CH3:27]O>>[C:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)=[N:9][C:10](=[O:17])[N:11]2[CH:14]([CH3:16])[CH3:15])=[CH:6][CH:5]=1)([O:3][CH3:27])=[O:2]
Reactant: CO
Reactant: COc1cccc(-c2nc(=O)n(C(C)C)c3cc(C(=O)O)ccc23)c1
Agent: Cl
Product: COC(=O)c1ccc2c(-c3cccc(OC)c3)nc(=O)n(C(C)C)c2c1
Reaction time: 7 h

Procedure:
Into a flask containing 7.0 g. of 7-carboxy-1-isopropyl-4-(m-methoxyphenyl)-2(1H)-quinazolinone dissolved in anhydrous methanol is introduced hydrogen chloride gas until the temperature reaches 50° C. The flask is then equipped with a stopper and the reaction mixture allowed to stand under ambient conditions for 7 hours. The resulting mixture is evaporated to dryness, the residue taken up in benzene, washed with water, followed by evaporation to dryness and crystallization of the residue from methanol to obtain 7-carbomethoxy-1-isopropyl-4-(m-methoxyphenyl)-2(1H)-quinazolinone, m.p. 164°-167° C.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:3]=1[C:4]#[N:5].[ClH:23].[F:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[O:28][CH2:29][CH2:30][NH2:31].C(=O)([O-])O.[Na+].CS(C)=O>O>[ClH:1].[ClH:23].[F:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[O:28][CH2:29][CH2:30][NH:31][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(Nc2cc(-c3cccnc3)c(C#N)c(Cl)n2)n[nH]1
Reactant: NCCOc1cccc(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(-c3cccnc3)c(C#N)c(NCCOc3cccc(F)c3)n2)n[nH]1
Temperature: 130 °C
Reaction time: 24 h
Yield: 6.7 %

Procedure:
Compound D (202 mg, 650 μmol), 2-(3-fluorophenoxy)ethylamine hydrochloride (357 mg) and sodium hydrogencarbonate (540 mg) were added to DMSO (3 ml), and the mixture was stirred at 130° C. for 24 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was purified by silica gel chromatography (90 mg). This was converted to hydrochloride to give the object compound of 2-(2-(3-fluorophenoxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-(pyridin-3-yl)nicotinonitrile dihydrochloride (22 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]#[C:12][CH:13]=[O:14].[CH2:15]([Mg]Br)[CH:16]=[CH2:17]>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]#[C:12][CH:13]([OH:14])[CH2:17][CH:16]=[CH2:15]
Reactant: O=CC#Cc1ccc2ccccc2c1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCC(O)C#Cc1ccc2ccccc2c1
Reaction time: 8 h
Yield: 47 %

Procedure:
A solution of 3-(naphthalen-2-yl)propiolaldehyde (3.97 g, 22.0 mmol) in tetrahydrofuran (250 mL) was added to a solution of allyl magnesium bromide (33.1 mL, 33.0 mmol, 1.5 eq.) at 0° C. over 25 min. Stirring was continued overnight and the reaction was carefully quenched with water (50 mL) at 0° C. tert-butyl methyl ether (100 mL) was added, and the layers were stirred and allowed to separate. The aqueous phase was re-extracted with tert-butyl methyl ether (50 mL) and the combined organic layers were dried over sodium sulphate and filtered. The filtrate was concentrated in vacuo. Purification by silica gel chromatography using 1:6 ethyl acetate/petrol as the eluting solvent to afford the desired compound (2.30 g, 47%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 2.58-2.65 (2H, m, CH2), 4.71 (1H, t, J=6.3 Hz, CH), 5.24-5.31 (2H, m, CH2), 5.95-6.06 (1H, m, CH), 7.46-7.51 (3H, m, ArH), 7.76-7.83 (3H, m, ArH), 7.96 (1H, s, ArH).