Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:34])[N:10]([CH2:19][CH2:20][CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:4][C:3]=1[CH:35]=[O:36].[CH3:37]Br.[Mg].[Cl-].[NH4+]>C1COCC1.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:34])[N:10]([CH2:19][CH2:20][CH:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:4][C:3]=1[CH:35]([OH:36])[CH3:37]
Reactant: CBr
Reactant: O=Cc1cc(NC(=O)N(CCC(c2ccccc2)c2ccccc2)CCN2CCOCC2)ccc1Cl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1cc(NC(=O)N(CCC(c2ccccc2)c2ccccc2)CCN2CCOCC2)ccc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 66.2 %

Procedure:
16 mg (0.033 mmol, 1 eq.) of 3-(4-chloro-3-formylphenyl)-1-(3,3-diphenylpropyl)-1-(2-morpholin-4-ylethyl)urea (obtained in Example 63) are dissolved in 0.7 mL of dry THF. Once the solution has been cooled to 0° C., 17 μL (0.049 mmol, 1.5 eq.) of magnesium methyl bromide in solution (3 M in diethyl ether) are added to the medium. After stirring for 20 min. at 0° C., the reaction is neutralised with a saturated ammonium chloride solution at 0° C. The aqueous phase is extracted with dichloromethane, the organic phases are washed with brine, dried over MgSO4, filtered and concentrated. The crude reaction product is subjected to chromatography over silica gel (eluent: 1/1 heptane/AcOEt). 11.4 mg of expected product are obtained (yield=67%).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]([C:23]1[C:28]([C:29]2[O:30][C:31]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][NH:41][CH3:42])=[CH:36][C:35]=3[O:43][CH3:44])=[N:32][N:33]=2)=[N:27][C:26]([C:45]2[CH:50]=[CH:49][C:48]([S:51]([CH:54]([CH3:56])[CH3:55])(=[O:53])=[O:52])=[CH:47][CH:46]=2)=[CH:25][N:24]=1)C(=O)OC(C)(C)C)=O)(C)(C)C>C(Cl)Cl>[CH:54]([S:51]([C:48]1[CH:47]=[CH:46][C:45]([C:26]2[N:27]=[C:28]([C:29]3[O:30][C:31]([C:34]4[CH:39]=[CH:38][C:37]([CH2:40][NH:41][CH3:42])=[CH:36][C:35]=4[O:43][CH3:44])=[N:32][N:33]=3)[C:23]([NH2:15])=[N:24][CH:25]=2)=[CH:50][CH:49]=1)(=[O:53])=[O:52])([CH3:56])[CH3:55]
Reactant: CNCc1ccc(-c2nnc(-c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1ccc(-c2nnc(-c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc3N)o2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
TFA (393.7 mg, 266.0 μL, 3.453 mmol) was added to a solution of tert-butyl N-tert-butoxycarbonyl-N-[5-(4-isopropylsulfonylphenyl)-3-[5-[2-methoxy-4-(methylaminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]carbamate (80 mg, 0.1151 mmol) CH2Cl2 (10 mL). The resulting mixture was stirred at room temperature for 1 h, and then concentrated in vacuo to leave an oil. The oil was re-dissolved in CH2Cl2 (10 ml), and evaporated to dryness. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as a yellow solid (27.1 mg, 39%); 1H NMR (400 MHz, DMSO) d 1.3 (d, 6H), 2.65-2.7 (m, 3H), 3.4-3.5 (m, 1H), 4.0 (s, 3H), 4.25-4.3 (m, 2H), 7.25 (d, 1H), 7.5 (s, 1H), 8.0 (d, 2H), 8.1 (d, 1H), 8.38 (d, 2H), 8.92 (br s, 2H) and 9.1 (s, 1H) ppm; MS (ES+) 495.3
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][O:39][CH2:40][CH2:41][NH:42][CH3:43]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:42]([CH2:41][CH2:40][O:39][CH3:38])[CH3:43])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CNCCOC
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: COCCN(C)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and (2-methoxy-ethyl)-methylamine according to conditions described in general procedure C. Mp: 96-98° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.90-3.15 (m, 4 H), 3.27 (t, J=4.8 Hz, 4 H), 3.20-3.40 (m, 6 H), 3.77 (t, J=4.8 Hz, 4H), 6.28 (s, 1 H), 7.05 (d, J=12.4 Hz, 1 H), 7.27 (d, J=8.7 Hz, 1 H), 7.43-7.62 (m, 5 H), 7.82 (s, 1 H), 8.00 (d, J=7.7 Hz, 1 H), 8.26 (d, J=5.1 Hz, 1 H), 10.47 (s, 1 H).
Reaction SMILES: [Na].[C:2]([C:6]1[CH:7]=[C:8]([C:17]2[N:18]=[C:19]([SH:22])[S:20][CH:21]=2)[CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:5])([CH3:4])[CH3:3].[CH3:23]I.O>CO>[C:2]([C:6]1[CH:7]=[C:8]([C:17]2[N:18]=[C:19]([S:22][CH3:23])[S:20][CH:21]=2)[CH:9]=[C:10]([C:13]([CH3:15])([CH3:16])[CH3:14])[C:11]=1[OH:12])([CH3:3])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)c1cc(-c2csc(S)n2)cc(C(C)(C)C)c1O
Agent: [Na]
Solvent: CO
Solvent: O
Product: CSc1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cs1
Yield: 73 %

Procedure:
In 30 ml of methanol was dissolved 0.18 g of metallic sodium and after adding thereto 2.1 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-mercaptothiazole, 1.15 g of methyl iodide was added dropwise to the solution at 0°-5° C. After allowing to stand the mixture for 30 minutes at room temperature, 60 ml of iced water was added to the reaction mixture. The crystals thus precipitated were recovered by filtration and recrystallized from n-hexane to provide 1.6 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthiothiazole.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[F-].[K+].[CH3:21][C@@H:22]1[NH:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1>CS(C)=O>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:6]2[C:2]([N:27]3[CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][C@@H:22]3[CH3:21])=[C:3]([N+:16]([O-:18])=[O:17])[CH:4]=[N:5]2)=[CH:9][CH:10]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: COc1ccc(Cn2ncc([N+](=O)[O-])c2Cl)cc1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(Cn2ncc([N+](=O)[O-])c2N2CCN(C(=O)OC(C)(C)C)C[C@@H]2C)cc1
Temperature: 100 °C
Yield: 88.1 %

Procedure:
To a solution of 5-chloro-1-(4-methoxybenzyl)-4-nitro-1H-pyrazole (268 mg, 1.0 mmol) and potassium fluoride (232 mg, 4.0 mmol) in dry DMSO (20 mL) was added (S)-tert-butyl 3-methylpiperazine-1-carboxylate (230 mg, 1.15 mmol) and the mixture heated in the microwave at 100° C. for 8 hr. The mixture was partitioned between water (30 mL) and EtOAc (50 mL) and the organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave (S)-tert-butyl 4-(1-(4-methoxybenzyl)-4-nitro-1H-pyrazol-5-yl)-3-methylpiperazine-1-carboxylate as a yellow gum (380 mg). To a solution of this gum (371 mg, 0.86 mmol) in ethanol/water (20 mL/2 mL) was added ammonium chloride (230 mg, 4.3 mmol) and iron powder (192 mg, 3.44 mmol.) and the mixture heated at 80° C. for 1.5 hr. The mixture was cooled, filtered through Celite® and concentrated under reduced pressure. The residue was partitioned between water (30 mL) and DCM (40 mL) and the organic layer was separated, passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-5% MeOH/DCM) gave (S)-tert-butyl 4-(4-amino-1-(4-methoxybenzyl)-1H-pyrazol-5-yl)-3-methylpiperazine-1-carboxylate as a red gum (330 mg, 84% over two steps). 1H NMR (400 MHz, CDCl3) δ 7.17-7.11 (m, 3H), 6.82 (d, J=8.6 Hz, 2H), 5.34 (d, J=14.4 Hz, 1H), 5.17 (d, J=14.4 Hz, 1H), 3.98-3.80 (m, 2H), 3.78 (s, 3H), 3.23 (ddd, J=9.9, 6.4, 3.3 Hz, 1H), 3.01 (td, J=11.4, 3.0 Hz, 1H), 2.92-2.83 (m, 1H), 2.66 (s, 1H), 2.57 (s, 1H), 1.47 (s, 9H), 0.81 (d, J=6.3 Hz, 3H).
Reaction SMILES: B(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:11]=[C:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:8][C:7]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[C:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:8][C:7]=1[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1
Reactant: COC(=O)Cc1ccc(-c2ccc(OC)cc2)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: COC(=O)Cc1ccc(-c2ccc(O)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
After boron trichloride (1.0N methylene chloride solution, 1.8 ml, 1.8 mmol) was added to a solution of methyl (2-chloro-4′-methoxy-1,1′-biphenyl-4-yl)acetate (228 mg, 0.73 mmol) obtained in Example (23-2) and tetra-n-butylammonium iodide (325 mg, 0.88 mmol) in methylene chloride (4 ml) at −78° C., the temperature of the mixture was raised to room temperature and the mixture was stirred for 2 hours. Ice was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=10/1-2/1) to give methyl (2-chloro-4′-hydroxy-1,1′-biphenyl-4-yl)acetate as a colorless solid (144 mg, yield: 71%).
Reaction SMILES: [CH2:1]([O:7][C:8](=O)[CH2:9][NH:10][C:11](=O)[C:12]([O:14][CH3:15])=[O:13])[CH2:2][CH2:3]/[CH:4]=[CH:5]/[CH3:6].N1C=CC=CC=1.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH3:6][C:5]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[N:10][CH:9]=[C:8]2[O:7][CH2:1][CH2:2][CH2:3][C:4]=12
Reactant: C/C=C/CCCOC(=O)CNC(=O)C(=O)OC
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ncc2c(c1C)CCCO2

Procedure:
(E)-Methyl 2-((2-(hex-4-en-1-yloxy)-2-oxoethyl)amino)-2-oxoacetate (0.24 g, 1 eq) and DCM (2.4 mL) were added to a vessel with stirring followed by the addition of pyridine (95 mg, 1.2 eq). Tf2O (0.42 g, 1.5 eq) was then added over 45 min at ambient temperature and the mixture was stirred at ambient temperature for 48 h. The mixture was washed with 20 wt % aqueous NaOAc (2×1.5 mL), 10 wt % aqueous citric acid (3×1.5 mL), and water (1×1.5 mL). The organic layer was then concentrated under reduced pressure to provide the title compound as a solid. 1H NMR (300 MHz, CDCl3) δ ppm 8.10 (s, 1H), 4.15-4.25 (m, 2H), 3.94 (s, 3H), 2.71 (t, J=6.56 Hz, 2H), 2.47 (s, 3H), 2.00-2.18 (m, 2H); 13C NMR (75 MHz, CDCl3) δ ppm 166.71, 153.50, 138.69, 136.72, 135.67, 130.36, 65.93, 52.35, 22.18, 21.49, 14.57; HRMS (M+H) m/z, calcd for C11H14NO3, 208.0974; found 208.0981.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12]([NH:14][C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)=[S:13])[CH2:6][CH2:5]1)(=O)C.[BrH:24].BrBr>O>[BrH:24].[BrH:24].[NH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12]2[S:13][C:23]3[CH:22]=[C:18]4[O:19][CH2:20][O:21][C:17]4=[CH:16][C:15]=3[N:14]=2)[CH2:6][CH2:5]1
Reactant: CC(=O)N1CCC(CNC(=S)Nc2ccc3c(c2)OCO3)CC1
Agent: Br
Agent: BrBr
Solvent: O
Product: c1c2c(cc3sc(NCC4CCNCC4)nc13)OCO2
Reaction time: 8 h
Yield: 58.4 %

Procedure:
A mixture of 33.3 parts of N-[(1-acetyl-4-piperidinyl)methyl]-N'-(1,3-benzodioxol-5-yl)thiourea, 112.5 parts of a hydrobromic acid solution 48% in water and 75 parts of water was stirred till all solid entered the solution. Then there were added 16 parts of bromine and stirring was continued overnight at reflux. After cooling, the product was filtered off, washed with ethanol and dried, yielding 26.5 parts (58.4%) of N-(4-piperidinylmethyl)-1,3-dioxolo[4,5-f]benzothiazol-6-amine dihydrobromide; mp.>260° C. (intermediate 44).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10]C)=[O:8])=[C:4]([NH2:12])[CH:3]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>CCO>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([N:12]=[CH:15][N:16]([CH3:18])[CH3:17])[CH:3]=1
Reactant: CCOC(=O)c1sc(Br)cc1N
Reactant: COC(OC)N(C)C
Solvent: CCO
Product: COC(=O)c1sc(Br)cc1N=CN(C)C

Procedure:
A solution of ethyl 5-bromo-3-amino-2-thiophenecarboxylate (1.0 g, 4.2 mmol) and dimethylformamide dimethylacetal (1.1 mL, 8.5 mmol) in EtOH (30 mL). was heated to reflux for 50 min. After cooling, the solvent was removed in vacuo. The residue was coevaporated with toluene (2×20 mL) to yield methyl 5-bromo-3-(((dimethylamino)methylene)amino)-2-thiophenecarboxylate. The residue and 1-((4-amino-2-methoxy)phenoxy)-2-methyl-2-propanol (0.90 mg, 4.2 mmol) (described in Part B of Example 82) were mixed with phenol (4 g) prior to heating at 130° C. for 40 min. After cooling, the mixture was chromatographed (120 g silica, CH2Cl2 to 50% EtOAc-CH2Cl2) to provide 1-(4-(6-bromo-4-oxo-thieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)-2-methyl-2-propanol as a tan solid (1.2 g, 67%).
Reaction SMILES: C(O[CH:4](OCC)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[C:16]([C@@H:21]([C@H:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[OH:24])[OH:22])([O:18][CH2:19][CH3:20])=[O:17]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1(C)C=CC=CC=1>[C:7]1([CH:6]=[CH:5][CH:4]2[O:24][C@@H:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C@H:21]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:22]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(C=Cc1ccccc1)OCC
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1OC(C=Cc2ccccc2)O[C@H]1C(=O)OCC
Temperature: 25 °C
Yield: 72.3 %

Procedure:
A mixture of cinnamaldehyde diethylacetal (223.0 g, 1.08 mol), diethyl L-tartrate (290 g, 1.41 mol), toluene (1100 g) and pyridinium p-toluenesulfonate (1.7 g) was heated at 92°-110° C. for a 6 hour period. During the heating period, volatiles (250-300 mL) were removed by distillation through an 8" Vigreaux column. The mixture was cooled (25° C.) and washed with aqueous sodium bicarbonate solution (350 mL) and brine (4×200 mL). Evaporation of solvents and crystallization of the residue gave 250 g (72.3% yield) of (4R,5R)-2-(2-phenyl-1-ethenyl)-4,5-dicarboethoxy-1-3-dioxolane, mp 55.5°-56° C., [α]D25 -5.2° (c,0.1,methanol) 1H-NMR (CDCl3)δ7.45-7.26 (5H,m), 6.86 (1H,d, J=16.1 Hz), 6.26 (1H,dd,J=6.8 Hz and 16.1 Hz), 5.82 (1H,d,J=6.8 Hz), 4.87 (1H,d,J=3.6 Hz), 4.78 (1H,d,J=3.6 Hz), 4.36-4.26 (4H,2 q, overlapping J=7.1 Hz), 1.38-1.31 (6H, 2 t, overlapping, J=7.1 Hz). IR(KBr) 2970,2890,1745,1720,1450,1410 cm.-1MS m/e (% abundance) 320(2), 247(6), 148 (38), 131(78), 115(100), 95(80), 91(8), 77(15), 55(14).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1>C1COCC1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH3:8])[CH2:20][O:21]2)=[CH:15][CH:14]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC1(c2ccc(Cl)cc2)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and the contents were stirred for 10 min. after which the solution of 1-(4-chlorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h; the reaction was monitored by LCMS. After completion, the reaction mixture was poured in ice water, extracted in diethyl ether (4×50 mL), dried over sodium sulfate and concentrated at 25° C. to get the crude product. 1H NMR (CDCl3, freebase) δ (ppm): 7.38 (m, 4H), 2.97 (d, 1H), 2.78 (d, 1H), 1.69 (s, 3H).
Reaction SMILES: [CH:1]1([CH:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH2:5][CH:6]=O)[CH2:3][CH2:2]1.[O:15]([C:22]1[CH:23]=[C:24]([CH2:28][C:29]#[N:30])[CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[O-].[Na+]>CO>[CH:1]1([CH:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH2:5][CH:6]=[C:28]([C:29]#[N:30])[C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:23]=2)[CH2:3][CH2:2]1
Reactant: O=CCC(c1ccc(Cl)cc1)C1CC1
Reactant: N#CCc1cccc(Oc2ccccc2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#CC(=CCC(c1ccc(Cl)cc1)C1CC1)c1cccc(Oc2ccccc2)c1
Yield: 67.9 %

Procedure:
A mixture of 1.5 grams (0.007 mole) of 3-cyclopropyl-3-(4-chlorophenyl)propionaldehyde and 1.5 grams (0.007 mole) of 3-phenoxyphenylacetonitrile in 50 ml of methanol was stirred, and 0.7 ml of 25% sodium methoxide in methanol was added quickly. Upon completion of addition, the reaction mixture was stirred at ambient temperature for four hours. The reaction mixture was then concentrated, and the residue was taken up in 100 ml of diethyl ether. The ether solution was washed with two 100 ml portions of water. The ether layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to centrifugally accelerated, radial thin layer chromatography. Elution was accomplished using 5% diethyl ether in hexane. The appropriate fractions were combined and concentrated under reduced pressure, yielding 1.9 grams of 1-cyclopropyl-1-(4-chlorophenyl)-4-cyano-4-(3-phenoxyphenyl)-3-butene. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:13]([O:15]C(OCC)=O)=O)[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].[CH3:21][NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[S:3]1[CH:4]=[CH:5][S:1][C:2]1=[C:6]([C:13](=[O:15])[N:22]([CH3:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]([O:9][CH:10]([CH3:11])[CH3:12])=[O:8]
Reactant: CCOC(=O)OC(=O)C(C(=O)OC(C)C)=C1SC=CS1
Reactant: CNc1ccccc1
Solvent: ClCCl
Product: CC(C)OC(=O)C(C(=O)N(C)c1ccccc1)=C1SC=CS1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.8 %

Procedure:
Isopropyl 2-(1,3-dithiol-2-ylidene)-2-(ethoxycarbonyloxy-carbonyl)acetate (15.9 g) and N-methylaniline (6.43 g) were dissolved in methylene chloride (100 ml). The solution was stirred at room temperature for 24 hrs. The resultant mixture was washed with aqueous sodium hydroxide solution, dil-HCl and water. After removal of solvent the residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate (9:1) as an eluent to give the product (13.2 g, 78.7%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([CH:9]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]2)[C:4](=[O:15])[N:3]=1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>CN(C)C=O>[F:8][C:7]1[C:2]([N:1]=[CH:18][N:19]([CH3:21])[CH3:20])=[N:3][C:4](=[O:15])[N:5]([CH:9]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]2)[CH:6]=1
Reactant: COC(OC)N(C)C
Reactant: Nc1nc(=O)n(C2CCC(O)C2)cc1F
Solvent: CN(C)C=O
Product: CN(C)C=Nc1nc(=O)n(C2CCC(O)C2)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
A solution of 4-amino-5-fluoro-1-(3-hydroxy-cyclopentyl)-1H-pyrimidin-2-one (0.346 g, 1.62 mmol) in anhydrous dimethylformamide (3 mL) was treated with dimethylformamide dimethyl acetal (3 mL). The mixture was stirred at room temperature under nitrogen for 12 hours, concentrated in vacuo, loaded on silica gel, and chromatographed on silica gel (3×7 cm SiO2, 4:1 ethyl acetate/methanol) to afford N′-[5-Fluoro-1-(3-hydroxy-cyclopentyl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-N,N-dimethyl-formamidine 30 as a milky white oil (0.361 g, 83%).
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][N:5]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[CH:6]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH:13]=[C:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[N:24][C:19]=3[CH2:18][O:17][C:16]3[CH:25]=[CH:26][C:27]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:28][C:15]2=3)[CH2:7]1.O.[OH-].[Li+]>C1COCC1.O>[Cl:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][N:5]([CH2:4][C:3]([OH:41])=[O:2])[CH:6]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH:13]=[C:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[N:24][C:19]=4[CH2:18][O:17][C:16]4[CH:25]=[CH:26][C:27]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:28][C:15]3=4)[CH2:7]2)=[CH:39][CH:38]=1
Reactant: COC(=O)CN(Cc1ccc(Cl)cc1)C1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(N(CC(=O)O)Cc3ccc(Cl)cc3)C1)c1cccnc1CO2

Procedure:
To a solution of [(4-Chloro-benzyl)-(1-{3-[7-(1-hydroxy-1-methyl-ethyl)-11H-10-oxa-1-aza-dibenzo[a,d]cyclohepten-5-ylidene]-propyl}-pyrrolidin-3-yl)-amino]-acetic acid methyl ester (116 mg, 0.2 mmol) in THF:H2O (4:1, 10 mL total volume) was added lithium hydroxide monohydrate (17 mg, 0.4 mmol). The resultant solution was stirred at rt for 3 h. The reaction solution was quenched with 1N HCl and extracted with ethyl ether, dried over MgSO4, filtered and concentrated. The final product was filtered through filter paper and re-concentrated. This product was submitted without further purification. LCMS (retention time=1.72, ES+562); 1H NMR (CD3OD): δ 8.48 (1H, d), 7.78 (1H, d), 7.48 (2H, m), 7.31 (5H, m), 6.76 (1H, d), 6.15 (1H, t), 3.85 (2H, dd), 3.60 (2H, m), 3.30 (7H, m), 3.24 (1H, s), 3.18 (1H, m), 3.06 (1H, m), 2.58 (1H, m), 2.48 (1H, t), 2.06 (2H, m), 1.50 (6H, s).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[C:12]([CH2:25][C:26]([O:28]C)=[O:27])[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl>CO.O1CCCC1.[OH-].[K+]>[CH2:1]([O:9][C:10]1[CH:11]=[C:12]([CH2:25][C:26]([OH:28])=[O:27])[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(CC(=O)OC)cc1OCCCCCCCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCOc1ccc(CC(=O)O)cc1OCCCCCCCC
Yield: 103.6 %

Procedure:
Methyl 2-[3,4-bis(octyloxy)phenyl]acetate (3.94 g, 9.69 mmol) was dissolved in a mixture of methanol (30 ml) and tetrahydrofuran (30 ml), and 1N potassium hydroxide (19 ml) was added thereto. After being refluxed for 3 hours, the mixture was acidified with 3N hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over MgSO4, and then the solvent was evaporated out, to give 2-[3,4-bis(octyloxy)phenyl]acetic acid (3.94 g, 89%).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12](OCC)=[O:13])=[CH:10][N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C=O>O>[C:1]1([N:7]2[C:11]([CH2:12][OH:13])=[CH:10][N:9]=[CH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cncn1-c1ccccc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCc1cncn1-c1ccccc1

Procedure:
To a suspension of 2.16 g (0.01 mol) of 1-phenyl-5-carbethoxyimidazole in 5 ml of water are added 0.8 g (0.02 mol) of sodium hydroxide and then 4 ml of ~37% aqueous formaldehyde. The mixture is heated at 80°-90° C. for 2 hours. The reaction mixture is concentrated in vacuo, and then the residue is extracted with ethyl acetate. The ethyl acetate extract is concentrated to give 1-phenyl-5-hydroxymethylimidazole as a solid, m.p. 81°-84° C.