Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([C:33]2[N:34]([CH3:38])[CH:35]=[N:36][CH:37]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH:13]=[C:12]3[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:22]=2)=[CH:4][CH:3]=1.N#N.C(=O)([O-])[O-].[K+].[K+].[NH:48]1[CH:52]=[N:51][CH:50]=[N:49]1>S(Cl)(Cl)=O.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:33]2[N:34]([CH3:38])[CH:35]=[N:36][CH:37]=2)([N:48]2[CH:52]=[N:51][CH:50]=[N:49]2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH:13]=[C:12]3[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[C:28][C:29]([CH3:31])([CH3:32])[CH3:30])[CH:22]=2)=[CH:6][CH:7]=1
Reactant: c1nc[nH]n1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(C#CC(C)(C)C)c1)cc(=O)n2C
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cn1cncc1C(c1ccc(Cl)cc1)(c1ccc2c(c1)c(-c1cccc(C#CC(C)(C)C)c1)cc(=O)n2C)n1cncn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3,3-dimethyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one (330 mg, 0.633 mMol) was dissolved in 4 mL of thionyl chloride and stirred at ambient temperature under a stream of dry N2 for 2 hours. The reaction mixture was then concentrated under vacuum and toluene (5 mL) was added to the reaction mixture which was subsequently concentrated under vacuum to give a yellow solid. 210 mg of the yellow solid was dissolved in 5.0 mL of anhydrous DMF under an atmosphere of dry N2. To this solution was added 800 mg of potassium carbonate and 300 mg of 1,2,4-triazole and the reaction mixture was subsequently heated to 80° C. and stirred overnight at this temperature. The reaction mixture was then concentrated under vacuum and partitioned between EtOAc and water. The EtOAc layer was washed 3 more times with water and then with brine. The EtOAc layer was then dried over Na2SO4, filtered and concentrated under vacuum to give a yellow solid. The solid was chromatographed on flash silica gel eluting with a gradient of MeOH/DCM/NH4OH (2/98/0.1) to MeOH/DCM/NH4OH (7/93/0.1) to give 150 mg of the titled product as a white solid.
Reaction SMILES: [CH3:1][C:2]1([C:12]([NH2:14])=O)[S:9](=[O:11])(=[O:10])[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH2:3]1>C1COCC1>[NH2:14][CH2:12][C:2]1([CH3:1])[S:9](=[O:11])(=[O:10])[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH2:3]1
Reactant: CC1(C(N)=O)Cc2ccsc2S1(=O)=O
Solvent: C1CCOC1
Product: CC1(CN)Cc2ccsc2S1(=O)=O
Temperature: 10 °C
Yield: 91 %

Procedure:
Borane-dimethylsulfide complex (11.12 mL, 10M) was added to a stirred solution of 2,3-dihydro-2-methylthieno[2,3-b]thiophene-2-carboxamide-1,1-dioxide (2.57 g, 11.12 mmol) in THF (75 mL) at room temperature. The reaction mixture was refluxed under a nitrogen atmosphere for 1.5 h and then cooled in an ice bath to 10° C. and slowly quenched with 6N HCl. After gas evolution ceased, the acidic solution was refluxed for 2 h. The reaction mixture was cooled to room temperature and extracted twice with ether. The aqueous phase was made alkaline with aqueous NaOH and extracted with ethyl acetate (5×300 mL). The combined ethyl acetate extracts were washed with saturated brine and then dried over MgSO4. The solution was filtered and the solvent removed in vacuo to give 2-aminomethyl-2,3-dihydro-2-methylthieno[2,3-b]thiophene-1,1-dioxide as an oil (2.2 g, 91%). 1H NMR (300 MHz,DMSO-d6) 1.40(s,3H), 2.85-3.00(m,3H), 3.30(d,1H), 7.05(s,1H), 8.05(s,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:30][CH3:31])[C:10](=[O:29])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][CH2:23]S(C)(=O)=O)[C:16](=[O:28])[C:12]3=2)[C:7]1=[O:32].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:30][CH3:31])[C:10](=[O:29])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][CH2:23][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[C:16](=[O:28])[C:12]3=2)[C:7]1=[O:32]
Reactant: C1COCCN1
Reactant: COc1c2c(c3n(c1=O)CCCCN(CCS(C)(=O)=O)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1c2c(c3n(c1=O)CCCCN(CCN1CCOCC1)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A mixture of 11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-(2-methane-sulfonylethyl)-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione (97 mg, 0.17 mmol), morpholine (30 mg, 0.35 mmol), and diisopropylethylamine (006 mL, 0.355 mmol) in THF (1.7 mL) was stirred at 40° C. overnight. The product mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with gradient mixture of methanol in dichloromethane. Collection and concentration of appropriate fractions afforded the title compound.
Reaction SMILES: [CH2:1]([N:4]1[C:17]2[C:8](=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([O:18][CH:19]([CH3:21])[CH3:20])[CH:11]=[C:10]3[C:22]([F:25])([F:24])[F:23])[O:7][CH2:6][C@H:5]1[CH2:26][CH3:27])[CH:2]=[CH2:3].CCN(CC)CC>CCOC(C)=O.[Pd]>[CH2:26]([C@@H:5]1[CH2:6][O:7][C:8]2=[C:9]3[C:14](=[CH:15][CH:16]=[C:17]2[N:4]1[CH2:1][CH2:2][CH3:3])[N:13]=[C:12]([O:18][CH:19]([CH3:20])[CH3:21])[CH:11]=[C:10]3[C:22]([F:23])([F:25])[F:24])[CH3:27]
Reactant: C=CCN1c2ccc3nc(OC(C)C)cc(C(F)(F)F)c3c2OC[C@H]1CC
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCN1c2ccc3nc(OC(C)C)cc(C(F)(F)F)c3c2OC[C@H]1CC
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solution of (3R)-4-allyl-3-ethyl-3,4-dihydro-8-isopropoxy-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (0.24 g, 0.63 mmol) and 0.1 mL Et3N in 3 mL EtOAc was added 10% Pd on carbon (0.08 g) and the mixture was vigorously stirred under H2 atmosphere for 1 h. The reaction mixture was filtered through Celite and concentrated to give 0.23 g (96% yield) of (3R)-3-ethyl-3,4-dihydro-8-isopropoxy-4-propyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline, a yellow oil. Rf0.7 (9:1 hexane:EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.41 (d, 1H, J=9.1), 7.22 (d, 1H, J=9.1), 7.17 (s, 1H), 5.47 (septet, 1H, J=6.2), 4.30 (dd, ABX, 1H, J=10.5, 1.6), 3.86 (dd, ABX, 1H, J=10.5, 2.5), 3.47–3.35 (m, 1H), 3.23–3.11 (m, 2H), 1.70–1.55 (m, 4H), 1.38 (d, 3H, J=6.2), 1.37 (d, 3H, J=6.2), 1.02–0.91 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Cl:22][C:23]1[CH:24]=[C:25]([NH:30][C:31]2[C:32]3[CH2:39][C:38](=[O:40])[NH:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH:26]=[CH:27][C:28]=1[F:29]>>[Cl:22][C:23]1[CH:24]=[C:25]([NH:30][C:31]2[C:32]3[C:39](=[CH:20][C:3]4[NH:4][C:5]5[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]6[CH2:14][CH2:15][O:16][CH2:17][CH2:18]6)[C:7](=[O:19])[C:6]=5[C:2]=4[CH3:1])[C:38](=[O:40])[NH:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Product: Cc1c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 37.9 %

Procedure:
The title compound was prepared under the same conditions as described in Example 15 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]-pyrimidin-6-one as starting materials to give 4-(3-chloro-4-fluoro-phenylamino)-5-[3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-ylmethylene]-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (33 mg, 37.9%) as a brown solid.
Reaction SMILES: [O:1]1[N:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C@@H:4]2[CH2:3][C@H:2]1[CH2:19][N:20]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[O:1]1[N:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C@@H:4]2[CH2:3][C@H:2]1[CH2:19][NH2:20]
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H]1C[C@H]2c3ccccc3Cc3ccccc3N2O1
Agent: NN
Solvent: O
Solvent: CCO
Product: NC[C@@H]1C[C@H]2c3ccccc3Cc3ccccc3N2O1
Temperature: 80 °C
Reaction time: 4 h
Yield: 22.3 %

Procedure:
A mixture of (±)-cis-2-[(2,3,3a,8-tetrahydrodibenz[c,f]isoxazolo[2,3-a]azepin-2-yl)methyl]-1H-isoindole-1,3(2H)-dione (4 g), prepared following the procedure of example 1, and hydrazine hydrate (0.5 ml) in ethanol (80 ml) was stirred at 80° C. for 4 hours. The precipitate was filtered off and purified by open column chromatography over silica gel (eluent: CH2Cl2 /2-propanone 8/2). The pure fractions were collected and evaporated. The residue (1.6 g) was convened into the oxalic acid salt (1:1) in C2H5OH at room temperature. The residue (0.8 g) was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 97.5/2.5 to 95/5). The pure fractions were collected and evaporated, yielding 0.6 g (22%) of (±)-cis-2,3,3a,8-tetrahydrodibenz[c,f]isoxazolo-[2,3-a]azepine-2-methanamine (comp. 9).
Reaction SMILES: [H-].[Na+].[CH:3]([C@@H:6]1[C:11](=[O:12])[NH:10][CH2:9][CH2:8][N:7]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:5])[CH3:4].[F:20][C:21]1[CH:30]=[C:29](F)[C:28]([N+:32]([O-:34])=[O:33])=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24].CCOC(C)=O>CN(C=O)C>[F:20][C:21]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][C:28]([N+:32]([O-:34])=[O:33])=[C:29]([N:10]2[CH2:9][CH2:8][N:7]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[C@H:6]([CH:3]([CH3:5])[CH3:4])[C:11]2=[O:12])[CH:30]=1
Reactant: CC(C)[C@@H]1C(=O)NCCN1C(=O)OC(C)(C)C
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])c(N2CCN(C(=O)OC(C)(C)C)[C@H](C(C)C)C2=O)cc1F
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
Under N2 atmosphere, NaH (8.8 g, 0.22 mol, 60% in mineral oil, 1.1 eq.) was added in portions at −10° C. to a 1 L three-neck flask containing (R)-tert-butyl 2-isopropyl-3-oxopiperazine-1-carboxylate (26.7 g, 0.11 mol) in DMF (300 mL). The mixture was stirred at −10° C. for 30 min. The mixture was added dropwise to a 1 L three-neck flask containing methyl 2,4-difluoro-5-nitrobenzoate (26.3 g, 0.121 mol, 1.1 eq.) in DMF (200 mL) at −20° C. over 10 min. After addition, the resulting mixture was stirred between −20° C. and −30° C. for another 10 min. The reaction was quenched with sat. aq. ammonium chloride (200 mL) and then water (800 mL). The aqueous layer was extracted with EtOAc (3×1 L). The combined organic layers were washed with water (3×1 L) and brine, and then dried over anhydrous Na2SO4. After the mixture was filtered and the filter was evaporated under vacuum, the residue was purified by column chromatography on silica gel eluting with PE:EtOAc 8:1-4:1 to give (R)-tert-butyl 4-(5-fluoro-4-(methoxycarbonyl)-2-nitrophenyl)-2-isopropyl-3-oxopiperazine-1-carboxylate (32 g, 66.3% yield) as a yellow solid. LC-MS MS (ESI) m/z 384.1 [M−56+H]+, 462.1 [M+Na]+. 1H NMR (CDCl3 300 MHz): δ 8.63 (d, J=6.9 Hz, 1H), 7.16 (d, J=10.2 Hz, 1H), 4.61-4.30 (m, 2H), 3.97-3.89 (m, 4H), 3.62-3.48 (m, 2H), 2.40-2.34 (m, 1H), 1.49 (s, 9H), 1.08 (d, J=6.9 Hz, 3H), 1.01 (d, J=6.9 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:10][C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]([N+:22]([O-:24])=[O:23])=[C:13](F)[C:12]=1[F:26]>>[F:26][C:12]1[C:11]([F:10])=[CH:16][C:15]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:14]([N+:22]([O-:24])=[O:23])[C:13]=1[NH:4][C:3]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=1[F:1]
Reactant: Nc1ccc(I)cc1F
Reactant: COCCOc1cc(F)c(F)c(F)c1[N+](=O)[O-]
Product: COCCOc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Yield: 32 %

Procedure:
2-Fluoro-4-iodoaniline (1.6 g, 6.8 mmol) and 1,2,3-trifluoro-5-(2-methoxyethoxy)-4-nitrobenzene (1.7 g, 6.8 mmol) were reacted using the condition described in Example 1 (Step A) to form the title compound (1.02 g, 32%); m/z=467 [M-1].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:13][C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][CH:26]=3)[N:15]=2)=[C:6]2[C:10]=1[CH2:9][N:8]([CH3:11])[C:7]2=[O:12].CC1(C)C(C)(C)OB([C:48]2[CH:49]=[N:50][N:51]([CH2:53][CH2:54][CH2:55][OH:56])[CH:52]=2)O1>>[OH:56][CH2:55][CH2:54][CH2:53][N:51]1[CH:52]=[C:48]([C:2]2[CH:3]=[CH:4][C:5]([NH:13][C:14]3[C:19]([C:20]([F:21])([F:22])[F:23])=[CH:18][N:17]=[C:16]([NH:24][C:25]4[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][CH:26]=4)[N:15]=3)=[C:6]3[C:10]=2[CH2:9][N:8]([CH3:11])[C:7]3=[O:12])[CH:49]=[N:50]1
Reactant: CC1(C)OB(c2cnn(CCCO)c2)OC1(C)C
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 97 using diethyl [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate and 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-1-ol (WO2008/001076). 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.74 (br s, 1H), 9.93 (s, 1H), 8.47 (s, 1H), 8.40-9.11 (m, 1H), 8.24 (s, 1H), 7.96 (s, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.46-7.62 (m, 2H), 7.30 (d, J=6.8 Hz, 2H), 4.64 (s, 2H), 4.22 (t, J=7.1 Hz, 2H), 3.97 (quin, J=7.2 Hz, 4H), 3.43 (q, J=6.1 Hz, 2H), 3.26 (d, J=22.0 Hz, 2H), 3.12 (s, 3H), 1.97 (qd, J=6.7, 6.6 Hz, 2H), 1.16 (t, J=6.9 Hz, 6H). MS (ES+): m/z 674.22 [MH+]. HPLC: tR=1.39 min (UPLC TOF, polar—3 min).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[C:8]([CH2:9][CH:10]([CH:19]([C:24]([O:26][CH3:27])=[O:25])[C:20]([O:22][CH3:23])=[O:21])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[C:7]([N+:28]([O-])=O)[CH:6]=[CH:5][CH:4]=1>C(OCC)(=O)C.CCCCCC>[F:1][C:2]([F:31])([F:32])[C:3]1[C:8]([CH2:9][CH:10]([CH:19]([C:24]([O:26][CH3:27])=[O:25])[C:20]([O:22][CH3:23])=[O:21])[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[C:7]([NH2:28])[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)C(C(=O)OC)C(Cc1c([N+](=O)[O-])cccc1C(F)(F)F)c1ccc(OC)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)C(C(=O)OC)C(Cc1c(N)cccc1C(F)(F)F)c1ccc(OC)cc1

Procedure:
Catalytic reduction of 40.4 g (0.088 mol) of [2-(6-trifluoromethyl-2-nitrophenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (in two portions) following the procedure of Example 28 part B gave 36.9 g of nearly colorless solid, melting point 111°-113° C. Rf 0.62 (1:1 ethyl acetate-hexane). A sample crystallized from methanol melted at 112°-114° C.
Reaction SMILES: [C:1]([O:20][CH2:21][CH:22]([CH2:31][O:32][C:33](=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[O:23][Si](C(C)(C)C)(C)C)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[C:1]([O:20][CH2:21][CH:22]([CH2:31][O:32][C:33](=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[OH:23])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)COC(=O)CCCCCCC/C=C\CCCCCCCC
Reaction time: 0.5 h

Procedure:
To 1,3-O-dioleoyl-2-O-(t-butyldimethylsilyl)glycerol was added 266 ml of 0.1 M tetra-n-butylammonium fluoride-tetrahydrofuran and the reaction was carried out at ambient temperature for 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was diluted with methylene chloride, washed with water, dried, and concentrated. The residue was subjected to column chromatography (silica gel/ethyl acetate-n-hexane) to provide 3.97 g (48.0% based on 2-O-t-butyldimethylsilylglycerol) of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:25])[CH2:20][NH:21]C(C)C)=[CH:15][CH:14]=2)=[CH:9]1.[CH:26]1([N:32]=[C:33]=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:25])[CH2:20][NH:21][C:33]([NH:32][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:34])=[CH:15][CH:14]=2)=[CH:9]1
Reactant: CC(C)NCC(C)c1ccc(-c2ccsc2)cc1
Reactant: O=C=NC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: CC(CNC(=O)NC1CCCCC1)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propyl-2-propyl amine trifluoroacetate (prepared in example 1) and cyclohexyl isocyanate in a manner analogous to the procedure described in Example 1.
Reaction SMILES: Cl.[F:2][C:3]([F:19])([F:18])[C:4]1[CH:5]=[C:6]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:7]=[CH:8][CH:9]=1.[Cl:20]C1C=C(C=CC=1)C(OO)=[O:25]>C(Cl)Cl>[F:19][C:3]([F:2])([F:18])[C:4]1[CH:5]=[C:6]([S:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:25])[CH:7]=[CH:8][CH:9]=1.[ClH:20]
Reactant: FC(F)(F)c1cccc(SCc2ccccn2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: O=S(Cc1ccccn1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred suspension of 2-(((3-trifluoromethylphenyl)thio)methylpyridine, hydrochloride (2.0 g) in methylene chloride (50 ml) at 0° C. was treated portionwise with m-chloroperoxybenzoic acid (1.5 g) over 1/2 hour. The mixture was allowed to warm to ambient temperature and the mixture was stirred a further 1/2 hour. The solution was washed with saturated Na2CO3 solution and water, dried (MgSO4) and evaporated. The residue was converted into the hydrochloride, in acetone with ethereal HCl solution, which was recrystallised from acetone-ether to give the title compound, hydrochloride (1.0 g) mp 135°-6° C. (Found: C,48.3; H,3.7; N,4.0 C13H10F3NOS.HCl requires C,48.4; H,3.45; N,4.35%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[OH:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:2].CCN(CC)CC.[O:22](S(C(F)(F)F)(=O)=O)[S:23]([C:26]([F:29])([F:28])[F:27])(=O)=[O:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:24])=[O:22])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1ccc(O)c(C#N)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
Dissolve the ethyl 3-cyano-4-hydroxy-benzoate (22.36 g, 117.1 mmoles) in anhydrous CH2Cl2 (400 mL) at 0° C. Add Et3N (24.3 mL, 175.6 mmoles), DMAP (2.14 g, 17.5 mmol), and dropwise Tf2O (49.5 g, 175.6 mmoles). Stir the mixture at room temperature for 2 hours. Concentrate the mixture under reduced pressure and subject residue to silica gel chromatography eluting hexane/EtOAc 4:1, to obtain 34.99 g of ethyl 3-cyano-4-trifluoromethanesulfonyloxy-benzoate (92% yield). MS(ES): m/z=190.0 [M-H].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.[CH3:8][NH:9][CH3:10].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:8][N:9]([CH3:10])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1nccs1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)Cc1nccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of thiazole-2-carbaldehyde (Aldrich, 2.0 g, 17.7 mmol) in DCM (20 mL) was treated with dimethylamine (Aldrich, 40% in water, 3 mL) and molecular sieves (˜1.0 g) followed by NaBH(OAc)3 (4.2 g, 20 mmol). The reaction was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give yellow solid, which was then purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as yellow solid.
Reaction SMILES: CCOC(C)=O.Cl.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([C:20]2[N:21]=[C:22]3[C:28]4[CH:29]=[CH:30][C:31]([C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=5)=[CH:32][C:27]=4[O:26][CH2:25][CH2:24][N:23]3[CH:40]=2)=[N:18][C:17]([NH:41]C(=O)O)=[N:16]1>CCOC(C)=O>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([C:20]2[N:21]=[C:22]3[C:28]4[CH:29]=[CH:30][C:31]([C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=5)=[CH:32][C:27]=4[O:26][CH2:25][CH2:24][N:23]3[CH:40]=2)=[N:18][C:17]([NH2:41])=[N:16]1
Reactant: O=C(O)Nc1nc(-c2cn3c(n2)-c2ccc(-c4ccc(Cl)cc4)cc2OCC3)n(-c2ccccc2Cl)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1nc(-c2cn3c(n2)-c2ccc(-c4ccc(Cl)cc4)cc2OCC3)n(-c2ccccc2Cl)n1
Temperature: 50 °C
Reaction time: 5 h
Yield: 34.1 %

Procedure:
A solution of EtOAc/HCl (20 mL) was added to 1-(2-chlorophenyl)-5-(9-(4-chlorophenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1H-1,2,4-triazol-3-ylcarbamic acid (270 mg, 0.6 mmol) in EtOAc (10 mL) in portions. The resulting mixture was stirred at 50° C. for 5 h. The reaction mixture was filtered and the solid was collected to give 570 (100 mg, 34%). 1H NMR (DMSO, 400 MHz) δ 7.73-7.69 (m, 5H), 7.63-7.61 (m, 2H), 7.55-7.52 (m, 1H), 7.48 (dd, J=2.0, 6.8 Hz, 2H), 7.28-7.25 (m, 2H), 4.80-4.30 (b, 2H), 4.45 (s, 4H). LCMS(ESI) m/z 489.1 (M+H+)
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][O:7]S(C)(=O)=O.[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1C(=O)CCC1>O>[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([O:7][CH2:6][C@@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CS(=O)(=O)OC[C@@H]1CCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(OC[C@@H]2CCCO2)cc1
Temperature: 75 °C

Procedure:
A mixture of methanesulfonic acid (S)-1-(tetrahydrofuran-2-yl)methyl ester (7.6 g), 4-hydroxybenzoic acid methyl ester (6.4 g), cesium carbonate (20 g) and NMP (100 ml) was heated to 75° C. for 12 hours. The cooled reaction mixture was admixed with water and extracted with ethyl acetate. The organic phase was washed three times with water, dried over magnesium sulfate and concentrated. The product was thus obtained with the molecular weight of 236.27 (C13H16O4); MS (ESI): 237 (M+H+).
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Na].[CH2:11]([O:13][P:14]([CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])([O:16][CH2:17][CH3:18])=[O:15])[CH3:12].[H-].[Na+]>O1CCOCC1>[C:5]([CH:4]=[CH:3][CH2:2][C:19]([P:14]([O:13][CH2:11][CH3:12])([O:16][CH2:17][CH3:18])=[O:15])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: CCOC(=O)/C=C/CBr
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1COCCO1
Product: CCOC(=O)C=CCC(C)(C(=O)OCC)P(=O)(OCC)OCC

Procedure:
Ethyl 4-bromocrotonate (19.3 parts) was added dropwise at 25°-30° C. to a solution of the sodium salt of ethyl 2-diethylphosphonopropionate, prepared from 23.8 parts of ethyl 2-diethylphosphonopropionate and 5.3 parts of sodium hydride (50% in oil) in dioxan. The resulting solution was heated at reflux for 18 hr., after which time the sodium bromide was removed by filtration and the solution concentrated in vacuo. The residual oil was distilled to give 12.7 parts of ethyl 5-carboethoxy-2-diethylphosphono-2-methylpent-4-enoate boiling at 158°/0.2 mm. Hydrogenation of 12 parts of this material over 5% palladium on carbon gave 7.2 parts of diethyl 2-diethylphosphono-2-methyladipate boiling at 146°-52° C./0.05 mm; subsequent hydrolysis of 5 parts of this in concentrated hydrochloric acid gave 3.7 parts of 2-methyl-2-phosphonoadipic acid as a glassy solid which had a 31P chemical shift of -24 ppm.