Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Br)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[O:26]1[CH2:31][CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:29]3[CH2:30][CH2:31][O:26][CH2:27][CH:28]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(Oc2ncccc2Br)cc1)c1nc2ccccc2s1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(Oc2ncccc2C2=CCOCC2)cc1)c1nc2ccccc2s1
Temperature: 120 °C

Procedure:
To a glass microwave vial was added benzo[d]thiazol-2-yl(4-(3-bromopyridin-2-yloxy)phenyl)methanone (1.0902 g, 2.65 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.114 g, 5.30 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (0.149 g, 0.212 mmol), and sodium carbonate (0.843 g, 7.95 mmol) in DMF (6.63 mL) and water (2.209 mL). The reaction mixture was stirred and heated in a Biotage Initiator microwave reactor at 120° C. for 20 min. Solvent was evaporated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40S), eluting with a gradient of 5% to 50% EtOAc in hexane, to provide benzo[d]thiazol-2-yl(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)methanone. MS (ESI, pos. ion) m/z: 414.8 (M+1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([OH:21])[CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:42]1[C:46](=[O:47])[C:45]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:44]2[C:43]1=[O:52]>O1CCCC1>[CH2:1]([O:8][CH2:9][C@H:10]([O:21][N:42]1[C:43](=[O:52])[C:44]2=[CH:51][CH:50]=[CH:49][CH:48]=[C:45]2[C:46]1=[O:47])[CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@@H](CCOCc1ccccc1)COCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1O[C@H](CCOCc1ccccc1)COCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60.9 %

Procedure:
To a solution of (S)-1,4-dibenzyloxy-2-hydroxybutane (5 g, 17.5 mmol) in dry tetrahydrofuran (100 ml) was added triphenylphosphine (5.1 g, 19.2 mmol) and N-hydroxyphthalimide (3.1 g, 19.2 mmol). The solution was treated dropwise with diethyl azadicarboxylate (3 ml, 19.2 mmol). A red colouration appeared, gradually fading and the solution became warm. The solution was stirred at room temperature for 48 hours and the solvent removed under vacuum. The residue was dissolved in ethylacetatehexane 1:1 (100 ml) and refrigerated. A white solid crystallised out and was filtered off. The solution was evaporated to dryness and the residue chromatographed on silica, eluting with ethylacetate-hexane 1:2 to give (R)-N-(1,4-dibenzyloxybut-2-oxy)phthalimide (4.6 g, 61%), [α]D25 +16.4° (c 1.3 in ethanol); IR: υmax (film) 3090, 3060, 3030, 2930, 2860, 1810, 1790, 1730, 1610, 1495, 1465, 1450, 1370, 1240, 1190, 1120, 1100, 1080, 1030, 1015, 980, 880, 785, 740, 700 cm-1 ; 1H NMR: δH (CDCl3) 2.1 (2H, m, CH2), 3.75 (4 H, m, 2×CH2), 4.5 (5H, m, 2×CH2 plus CH), 7.1-7.9 (14 H, m, 2×C6H5 plus C6H4); m/z (FAB) MH+ 432.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C@@H:8]([CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:9][O:10][C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:12]I)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:7]1[C@@H:8]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:9][O:10][C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12]1)=[O:35])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)COC(CI)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(c2ccccc2)(c2ccccc2)OC[C@@H]1COCc1ccccc1
Temperature: 25 °C

Procedure:
To [(S)-1-benzyloxymethyl-2-(2-iodo-1,1-diphenylethoxy)-ethyl]-carbamic acid tert-butyl ester (4.74 g, 8.07 mmol) in N,N-dimethylformamide (70 mL) at room temperature add sodium hydride (0.452 g, 11.3 mmol, 60% dispersion in mineral oil). Heat reaction mixture to 60° C. for 4 hours, cool to room temperature and dilute with ethyl acetate (˜400 mL). Wash with water and saturated aqueous sodium chloride, dry (magnesium sulfate), filter and concentrate. Purify on silica gel eluting with 0:100 to 20:80 ethyl acetate:hexanes to give the desired compound as an oil.
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]1.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25](O)=[O:26])=[CH:19][CH:18]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:25](=[O:26])/[CH:24]=[CH:23]/[C:20]2[CH:19]=[CH:18][C:17]([C:16]([F:28])([F:29])[F:15])=[CH:22][CH:21]=2)=[N:8]1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CC(F)(F)CCCCn1ccc(N)n1
Product: CC(F)(F)CCCCn1ccc(NC(=O)/C=C/c2ccc(C(F)(F)F)cc2)n1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-3-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.16 min; [M+H]+=402.11.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][CH:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]#[N:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.[BH3-]C#N.[Na+].CC(O)=O.[O:28]=[C:29]1[C:33]2[CH:34]=[CH:35][C:36]([CH2:38][CH:39]=O)=[CH:37][C:32]=2[CH2:31][O:30]1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[O:1]=[C:2]1[CH2:7][N:6]([CH2:39][CH2:38][C:36]2[CH:35]=[CH:34][C:33]3[C:29](=[O:28])[O:30][CH2:31][C:32]=3[CH:37]=2)[CH2:5][CH2:4][N:3]1[CH2:8][CH:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]#[N:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: O=CCc1ccc2c(c1)COC2=O
Reactant: N#Cc1ccc2c(c1)CCC2CN1CCNCC1=O
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CCC2CN1CCN(CCc2ccc3c(c2)COC3=O)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-[(2-Oxopiperazin-1-yl)methyl]-2,3-dihydro-1H-indene-5-carbonitrile (42 mg, 0.16 mmol), NaBH3CN (40 mg, 0.66 mmol) and HOAc (40 mg, 0.66 mmol) in 20 mL DCM was added (1-Oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (29 mg, 0.16 mmol) and the mixture was stirred at RT overnight. Then saturated Na2CO3 (50 mL) was added and stirred for 30 min and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by prep-TLC to give the title product. 1H-NMR (400 MHz, CDCl3) δ ppm 7.84 (d, J=8.6 Hz, 2H), 7.50 (s, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.32 (s, 1H), 7.27 (d, J=7.8 Hz, 1H), 5.28 (s, 2H), 3.50˜3.61 (m, 3H), 3.20˜3.32 (m, 4H), 2.99˜3.08 (m, 1H), 2.84˜2.95 (m, 3H), 2.67˜2.77 (m, 4H), 2.21˜2.30 (m, 1H), 1.87˜1.95 (m, 1H).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:5]P(=O)(OC)OC.[C:18]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][C:31](=[O:33])[CH3:32])[CH:25]=O)(=[O:20])[CH3:19]>O.C(COC)OC.CS(C)=O>[C:18]([O:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:5][C:4](=[O:3])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:27]=[CH:28][C:29]=1[O:30][C:31](=[O:33])[CH3:32])(=[O:20])[CH3:19]
Reactant: CCCCCCC(=O)CP(=O)(OC)OC
Reactant: CC(=O)Oc1ccc(C=O)cc1OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: COCCOC
Solvent: O
Product: CCCCCCC(=O)C=Cc1ccc(OC(C)=O)c(OC(C)=O)c1
Yield: 80.4 %

Procedure:
To a mixture of 400 mg of oily sodium hydride (60%) and 50 ml of 1,2-dimethoxyethane was added dropwise a mixture of 3.06 g of dimethyl 2-oxooctylphosphonate and 10 ml of dimethoxyethane with stirring under ice-cooling. After adding thereto 5 ml of dimethyl sulfoxide and stirring the mixture for one hour at room temperature, a mixture of 2.22 g of 3,4-diacetoxybenzaldehyde and 10 ml of dimethoxyethane was added dropwise to the mixture. After stirring the resultant mixture for 4 hours at room temperature, 400 ml of water was added to the reaction mixture and the product was extracted twice each time with 50 ml of ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was applied to silica gel (120 g) column chromatography and eluted with a mixture of toluene and ethyl acetate (20:1) to provide 2.67 g of 1-(3,4-diacetoxyphenyl)-1-nonen-3-one.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[CH:10]=[C:11]([N:16]2[C:20](=[O:21])[O:19][N:18]=[C:17]2[C:22]2[C:23]([NH:27][C:28](=O)[C:29]3[CH:34]=[CH:33][C:32]([CH2:35][N:36]4[CH2:41][CH2:40][S:39](=[O:43])(=[O:42])[CH2:38][CH2:37]4)=[CH:31][CH:30]=3)=[N:24][O:25][N:26]=2)[CH:12]=[CH:13][C:14]=1[F:15].P(Cl)(Cl)(Cl)(Cl)Cl>N1C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[CH:10]=[C:11]([N:16]2[C:20](=[O:21])[O:19][N:18]=[C:17]2[C:22]2[C:23]([NH:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([CH2:35][N:36]4[CH2:41][CH2:40][S:39](=[O:43])(=[O:42])[CH2:38][CH2:37]4)=[CH:33][CH:34]=3)=[N:24][O:25][N:26]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=C(Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1)c1ccc(CN2CCS(=O)(=O)CC2)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: O=c1onc(-c2nonc2NCc2ccc(CN3CCS(=O)(=O)CC3)cc2)n1-c1ccc(F)c(Br)c1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 46.4 %

Procedure:
A solution of N-{4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-4-[(1,1-dioxidothiomorpholin-4-yl)methyl]benzamide trifluoroacetate (20 mg, 28 μmol) in pyridine (0.5 mL) was treated with phosphorus pentachloride (18 mg, 85 μmol) and stirred at 0° C. for 4.5 h. The reaction mixture was concentrated, diluted with ethanol (1 mL), treated with sodium cyanoborohydride (5 mg, 85 mop, and stirred for 2 h. The reaction mixture was purified by preparative LCMS to give the desired product (9 mg, 47%). LCMS for C22H21BrFN6O5S (M+H)+: m/z=579.0, 581.0.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=O)[N:10]=2)=CC=1.[CH3:44][O:45][CH2:46][CH2:47][NH2:48]>>[CH3:44][O:45][CH2:46][CH2:47][NH:48][CH2:21][C:20]1[CH:23]=[C:16]([C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([NH2:8])[N:10]=2)[C:17]([NH:24][C:25]2[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[N:18][CH:19]=1
Reactant: COCCN
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Product: COCCNCc1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc(N)n2)c1

Procedure:
The title compound was synthesized following an analogous procedure to Example 220 using 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (0.24 g, 0.415 mmol) and 2-methoxyethanamine (Aldrich, St. Louis, Mo.) (0.054 mL, 0.623 mmol). 1H NMR (400 MHz, CDCl3) δ 11.63 (s, 1H); 8.78 (d, J=2.54 Hz, 1H); 8.35 (d, J=2.54 Hz, 1H); 8.24 (d, J=2.54 Hz, 1H); 8.12 (dd, J=8.80, 2.74 Hz, 1H); 6.77 (d, J=8.80 Hz, 1H); 5.63 (s, 2H); 3.94 (s, 3H); 3.78 (s, 2H); 3.52-3.57 (m, 2H); 3.36 (s, 3H); 2.80-2.86 (m, 2H); 2.55 (s, 3H). m/z (ESI, +ve ion) 397.0 (M+H)+.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]([O:37][CH2:38][CH3:39])(=[O:36])[C@@H:33]([CH3:35])[OH:34].[C:40]1([C:46]2[CH:51]=[CH:50][C:49](O)=[CH:48][CH:47]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCCC1>[C:40]1([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:45]=[CH:44][C:43]([O:34][C@@H:33]([CH3:35])[C:32]([O:37][CH2:38][CH3:39])=[O:36])=[CH:42][CH:41]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)[C@@H](C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)Oc1ccc(-c2ccccc2)cc1

Procedure:
Prepared according to the method described in Example 1a) from diethylazodicarboxylate (6.74 ml), triphenylphosphine (13.11 g), (R)-(+)-ethyl lactate (5.67 ml) and 4-phenylphenol (8.51 g) in dry tetrahydrofuran (125 ml). The residue obtained after work-up was purified by column chromatography over silica eluting with isohexane:dichloromethane (2:3) to give the sub-title compound as an oil (11.3 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([C:19]([O:21][CH3:22])=[O:20])=[CH:13][C:12]=1[O:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:28](I)[CH3:29]>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:25])[N:10]([CH2:28][CH3:29])[C:11]1[C:12]([O:23][CH3:24])=[CH:13][C:14]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][C:16]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: COC(=O)c1cc(OC)c(NC(=O)OCc2ccccc2)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)OCc1ccccc1)c1c(OC)cc(C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 103 g. of 2,6-dimethoxy-4-(methoxy-carbonyl)-carbanilic acid benzyl ester and 17.3 g. of sodium hydride (50% dispersion in oil) in 1 liter of absolute dimethylformamide was stirred at room temperature for 4 hours and subsequently treated with 56.2 g. of ethyl iodide with stirring and ice-cooling. After stirring at room temperature for 30 minutes, the dimethylformamide was removed at 60° C. under vacuum. Then, 1 liter of water was added to the residue and the mixture was extracted with two 1.5 liter portions of ethyl acetate. The ethyl acetate extract was washed with two 700 ml. portions of water, dried over magnesium sulfate and evaporated under vacuum. After recrystallization of the residue from alcohol, there was obtained N-ethyl-2,6-dimethoxy-4-(methoxycarbonyl)-carbanilic acid benzyl ester having a melting point of 85°-86° C.
Reaction SMILES: C1(S([CH:10]2[CH:12]([C:13]([F:16])([F:15])[F:14])O2)(=O)=O)C=CC=CC=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30](=[S:32])[NH2:31])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].N1(C(OC(C)(C)C)=O)CCNCC1.C(N1C=CN=C1)(N1C=CN=C1)=S.N>CN(C)C=O>[C:17]([O:21][C:22]([N:24]1[CH2:25][CH2:26][N:27]([C:30]2[S:32][C:12]([C:13]([F:14])([F:15])[F:16])=[CH:10][N:31]=2)[CH2:28][CH2:29]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCN(C(N)=S)CC1
Reactant: O=S(=O)(c1ccccc1)C1OC1C(F)(F)F
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: N
Agent: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C(F)(F)F)s2)CC1
Temperature: 90 °C
Yield: 26 %

Procedure:
To a solution of 17.5 mmol 2-benzenesulfonyl-3-trifluoromethyl-oxirane in 20 ml N,N-dimethylformamide was added 15.9 mmol 4-thiocarbamoyl-piperazine-1-carboxylic acid tert-butyl ester (prepared from tert-butyl 1-piperazinecarboxylate, 1,1′-thiocarbonyldiimidazole and ammonia according to the procedure of J. Med. Chem. 1998, 41, 5037–5054). The mixture was heated at 90° C. for 10 h. The reaction mixture was then concentrated in vacuo and the residue purified by chromatography (SiO2, ethyl acetate/heptane) to afford the title compound as an orange crystalline solid (yield 26%). MS (m/e): 338.1 (M+H+, 100%).
Reaction SMILES: [O:1]1[CH2:6][C:5](=S)[NH:4][C:3](=[O:8])[NH:2]1.[NH2:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[N:11]=1>>[CH3:16][C:14]1[CH:13]=[C:12]([CH3:17])[N:11]=[C:10]([NH:9][C:5]2[CH2:6][O:1][NH:2][C:3](=[O:8])[N:4]=2)[CH:15]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: O=C1NOCC(=S)N1
Product: Cc1cc(C)nc(NC2=NC(=O)NOC2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 68.6 %

Procedure:
To 0.5 g (0.0043 mole) of 6H-1,2,4-oxadiazin-3(2H)-one-5(4H)-thione dissolved in 10 ml of freshly distilled dry dioxane is added 0.56 g (0.0043 mole) of 2-amino-4,6-dimethyl pyridine. The reaction mixture is stirred at room temperature for 17 hours and the dioxane removed on a rotovap. The crystalline material is washed with chloroform, then with ether to give 0.65 g (69 percent) of 5-((4,6-dimethyl-2-pyridinyl)amino)-6H-1,2,4-oxadiazin-3(2H)-one.
Reaction SMILES: [F:1]/[C:2](/[CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH3:14])[CH2:8][CH2:7]1)=[C:3](/[F:5])\I.[F:15][C:16]1[C:21]([F:22])=[C:20]([O:23][CH2:24][CH3:25])[CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C.C1(C)C=CC=CC=1>[F:5]/[C:3](/[C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH3:25])=[C:21]([F:22])[C:16]=1[F:15])=[C:2](/[F:1])\[CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH3:14])[CH2:8][CH2:7]1
Reactant: CCOc1ccc(B(O)O)c(F)c1F
Reactant: CCCC1CCC(/C(F)=C(\F)I)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC1CCC(/C(F)=C(\F)c2ccc(OCC)c(F)c2F)CC1

Procedure:
6.30 g (20.1 mmol) of 1-((Z)-1,2-difluoro-2-iodovinyl)-4-propylcyclohexane and 4.86 g (24.1 mmol) of 2,3-difluoro-4-ethoxybenzeneboronic acid are refluxed for 19 h together with 1.16 g (1.0 mmol) of tetrakistriphenylpalladium(0) and 20 ml (20 mmol) of sodium carbonate solution (2 M) in 90 ml of ethanol/toluene (2:1). Water is added, and the batch is extracted with MTBE. The aqueous phase is extracted with MTBE, and the combined organic phases are washed with water. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:1-chlorobutane=4:1). The further purification is carried out by recrystallisation from n-heptane, giving 1-[(E)-1,2-difluoro-2-(4-propylcyclohexyl)vinyl]-4-ethoxy-2,3-difluorobenzene as a colourless solid (m.p. 60° C.).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][CH:5]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl.[NH:29]1[CH2:34][CH2:33][O:32][CH:31]([C:35]([OH:37])=[O:36])[CH2:30]1>>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH:5]1[N:6]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[NH:8][C:3]([CH2:2][N:29]2[CH2:34][CH2:33][O:32][CH:31]([C:35]([OH:37])=[O:36])[CH2:30]2)=[C:4]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncccn2)=NC1c1ccc(Cl)cc1Cl
Reactant: O=C(O)C1CNCCO1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(C(=O)O)C2)NC(c2ncccn2)=NC1c1ccc(Cl)cc1Cl
Yield: 56.5 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-1,4-dihydro-[2,2′-bipyrimidine]-5-carboxylate (0.72 g, 1.53 mmol) (The compound was synthesized according to the procedure as described in WO2010069147) was reacted with morpholine-2-carboxylic acid hydrochloride (0.26 g, 1.53 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.45 g, 56%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:4]=1.[CH3:19][O:20]C(Cl)Cl.Cl>ClCCl.O.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:10]([F:12])([F:13])[F:11])([OH:18])[C:14]([F:15])([F:16])[F:17])[CH:6]=[CH:7][C:8]=1[CH:19]=[O:20]
Reactant: COc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1C=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 48 %

Procedure:
To a solution of 31.6 g (0.12 mole) of 1-methoxy-3-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzene in 200 ml dichloromethane is added 38 g (0.2 mole) of titanium tetrachloride at 0°-5° with stirring under a nitrogen atmosphere. After the resulting solution is stirred for 15 minutes, 11.5 g (0.1 mole) of α,α-dichloromethyl methyl ether is added dropwise at 0°-5° C. Stirring is continued while the temperature of the solution is allowed to reach 20°-25° during 18 hours. The solution is then added with stirring to a solution of 100 ml 6N hydrochloric acid in 500 ml of ice and water. The resulting organic phase is separated leaving an aqueous phase which is washed with three 300 ml portions of dichloromethane. The combined dichloromethane extracts are washed with 1N hydrochloric acid and then with saturated sodium chloride solution. The dichloromethane solution is dried with anhydrous magnesium sulfate, filtered, and evaporated at reduced pressure to obtain an oily solid which is triturated with chlorobutane, filtered and recrystallized from chlorobutane to give 14.5 g of 2-methoxy-4-[2,2,2-trifluoro-1-hydroxy-(trifluoromethyl)ethyl]benzaldehyde having a melting point of 144°-146°.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][CH2:12][C:13](=[C:15]=[O:16])[CH3:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17]Br>ClCCl>[C:1]([O:9][CH2:10][CH2:11][CH:12]([Br:17])[C:13](=[C:15]=[O:16])[CH3:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: CC(=C=O)CCCOC(=O)c1ccccc1
Solvent: ClCCl
Product: CC(=C=O)C(Br)CCOC(=O)c1ccccc1

Procedure:
The intermediate, 4-carbonylpentyl benzoate (72 mmol), was dissolved in 75 ml dichloromethane. The temperature of the system was maintained below 5° C., bromine (3.7 ml, 72 mmol) was then slowly added dropwise. After the addition was completed, the stirring was maintained for half an hour, until the color of the reaction system disappears. The product was then washed with water, dried with anhydrous magnesium sulfate, and concentrated, to obtain the intermediate, i.e. 3-bromo-4-carbonylpentyl benzoate, which was directly applied in the next step without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C:22]=3[CH2:27][CH:28]=[CH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]([CH2:42][CH2:43][C:44]([F:56])([F:55])[C:45]([F:54])([F:53])[C:46]([F:52])([F:51])[C:47]([F:50])([F:49])[F:48])[C:37]([O:39][CH2:40][CH3:41])=[O:38])([CH3:20])[C@@H:18]([O:57]CC3C=CC=CC=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)C1C=CC=CC=1>CO.O1CCCC1.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C@@H:22]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]([CH2:42][CH2:43][C:44]([F:55])([F:56])[C:45]([F:53])([F:54])[C:46]([F:51])([F:52])[C:47]([F:48])([F:49])[F:50])[C:37]([O:39][CH2:40][CH3:41])=[O:38])([CH3:20])[C@@H:18]([OH:57])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: CCOC(=O)C(CCCCCCC=CCC1=C2c3ccc(OCc4ccccc4)cc3CC[C@H]2[C@@H]2CC[C@H](OCc3ccccc3)[C@@]2(C)C1)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCCCCCCC[C@H]1C[C@]2(C)[C@@H](O)CC[C@H]2[C@@H]2CCc3cc(O)ccc3[C@@H]12)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 23 h
Yield: 71.4 %

Procedure:
Ethyl 11-[3,17β-bis(benzyloxy)estra-1,3,5(10), 9(11)-tetraen-11-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-undecenoate (500 mg, 0.55 mmol) was dissolved in a mixed solvent of methanol (10 ml) and tetrahydrofuran (1 ml), followed by addition of palladium hydroxide/carbon (150 mg) at room temperature. After purging with hydrogen, the reaction mixture was stirred for 23 hours at room temperature and then filtered. The solvent was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 3/1 2/1) to give ethyl 11-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoate (287 mg, Yield 71%).