Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N+:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])([O-:29])=[O:28].C1CCN2C(=NCCC2)CC1>>[N+:27]([CH:30]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([O-:29])=[O:28]
Reactant: CCCCCC[N+](=O)[O-]
Reactant: O=C(O)CCCCCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCC(C(=O)CCCCCc1ccccc1)[N+](=O)[O-]

Procedure:
6-Phenylhexanoic acid (0.150 g, 0.78 mmol) and CDI (0.253 g, 1.56 mmol) were added together and then reacted with nitrohexane (0.153 g, 1.17 mmol) and DBU (0.297 g, 1.95 mmol) according to the general procedure. Purification by column chromatography gave 0.090 g (38%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.28 (m, 2H), 7.17 (m, 3H), 5.11 (dd, J=4.8, 10.4 Hz, 1H), 2.61 (m, 4H), 1.63 (m, 6H), 1.33 (m, 8H) 0.90 (t, J=6.8 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 199.5, 142.5, 128.6, 128.5, 126.0, 94.6, 39.5, 35.9, 31.3, 31.2, 29.9, 28.7, 25.7, 23.3, 22.4, 14.1 ppm; IR νmax (cm−1) 3027, 2930, 2858, 1731, 1559, 1454, 1363, 1030, 748, 699; HRMS (FAB) calcd for C18H27NO3 (MNa+) 328.1883, found 328.1881.
Reaction SMILES: [O-]CC.[Na+].[Na].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]([CH3:19])[O:17][CH3:18])=[O:15])=[CH:9][CH:8]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Cl>CN(C)C=O.O.C(O)C>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]([CH3:19])[O:17][CH3:18])=[O:15])=[CH:9][CH:8]=1
Reactant: CON(C)C(=O)Nc1ccc(O)cc1
Reactant: COc1ccccc1CCl
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: COc1ccccc1COc1ccc(NC(=O)N(C)OC)cc1
Temperature: 25 °C

Procedure:
To an ethanolic solution of sodium ethoxide prepared from ethanol (200 ml) and sodium (2.5 g), N-(4-hydroxyphenyl)-N'-methyl-N'-methoxyurea (20 g) is added, and a solution of 2-methoxybenzyl chloride (17 g) in N,N-dimethylformamide (50 ml) is added dropwise thereto. The reaction mixture is gradually heated, kept under reflux for 3 hours and cooled to room temperature. The reaction mixture is poured onto cold water (1 liter). The precipitated crystals are collected by filtration, washed with water, dried and recrystallized from ethanol to give N-[4-(2-methoxybenzyloxy)-phenyl]-N'-methyl-N'-methoxyurea (Compound No. 23) (12 g) as white scales. M.P., 98° C.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]3([C:37]([NH:39][NH:40]C(OC(C)(C)C)=O)=[O:38])[CH2:23][CH2:22][N:21]([C:24](=[O:36])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[C:26]=4[F:35])[CH2:20][CH2:19]3)[CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]3([C:37]([NH:39][NH2:40])=[O:38])[CH2:19][CH2:20][N:21]([C:24](=[O:36])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:34])[F:33])[C:26]=4[F:35])[CH2:22][CH2:23]3)[CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NNC(=O)C1(Cc2cccc(Nc3ccnn3C(C)(C)C)n2)CCN(C(=O)c2cccc(C(F)(F)F)c2F)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)n1nccc1Nc1cccc(CC2(C(=O)NN)CCN(C(=O)c3cccc(C(F)(F)F)c3F)CC2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 195 mg of tert-butyl 2-((4-((6-((1-tert-butyl-1H-pyrazol-5-yl)amino)pyridin-2-yl)methyl)-1-(2-fluoro-3-(trifluoromethyl)benzoyl)piperidin-4-yl)carbonyl)hydrazinecarboxylate in 4 ml of chloroform was added 2 ml of trifluoroacetic acid at 0° C. The reaction mixture was stirred at 0° C. for 2 hours and at room temperature for 2 hours, followed by concentrating in vacuo. The resulting residue was basified with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: chloroform to chloroform/methanol=10/1) to give the title compound as a colorless oil.
Reaction SMILES: [SH:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:3]=1.Cl[CH2:15][C:16]1[CH:35]=[CH:34][C:19]([O:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:27][C:26]1[O:25][C:24]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[N:23][C:22]=1[CH2:21][O:20][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][S:1][C:2]2[NH:6][N:5]=[C:4]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:3]=2)=[CH:35][CH:34]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)CCc1n[nH]c(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1n[nH]c(SCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 3-(5-mercapto-1H-1,2,4-triazol-3-yl)propionate (450 mg), 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (700 mg), potassium carbonate (370 mg) and N,N-dimethylformamide (20 ml) was stirred at room temperature for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[5-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylthio]-1H-1,2,4-triazol-3-yl]propionate was obtained as crystals (600 mg, yield 56%) from a fraction eluted with ethyl acetate-hexane (3:2, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 114–115° C.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C(N(CC)C(C)C)(C)C.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([C:53]([F:56])([F:55])[F:54])=[C:33]([C:35]2[CH:40]=[CH:39][N:38]([CH:41]([CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)[C:42](O)=[O:43])[C:37](=[O:52])[CH:36]=2)[CH:34]=1.[NH2:57][C:58]1[CH:70]=[CH:69][C:61]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])=[CH:60][CH:59]=1>C(OCC)(=O)C.O.C(OCC)(=O)C>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([C:53]([F:56])([F:54])[F:55])=[C:33]([C:35]2[CH:40]=[CH:39][N:38]([CH:41]([CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)[C:42]([NH:57][C:58]3[CH:70]=[CH:69][C:61]([C:62]([O:64][C:65]([CH3:66])([CH3:67])[CH3:68])=[O:63])=[CH:60][CH:59]=3)=[O:43])[C:37](=[O:52])[CH:36]=2)[CH:34]=1
Reactant: O=C(O)C(Cc1ccccn1)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)C(Cc2ccccn2)n2ccc(-c3cc(Cl)ccc3C(F)(F)F)cc2=O)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Under argon and at 0° C., 707 mg (50% strength in ethyl acetate, 1.11 mmol) of T3P and 0.29 ml (1.67 mmol) of N,N-diisopropylethylamine were added to a solution of 470 mg (purity 50%, 0.56 mmol) of 2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-2-yl)propanoic acid (racemate) and 129 mg (0.67 mmol) of tert-butyl 4-aminobenzoate in 45 ml of ethyl acetate. The reaction mixture was stirred at 60° C. for 1 h, another 353 mg (50% strength in ethyl acetate, 0.56 mmol) of T3P and 0.1 ml (0.56 mmol) of N,N-diisopropylethylamine were added and the mixture was stirred at 60° C. for 1 h. After addition of water/ethyl acetate and phase separation, the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 60, dichloromethane/methanol mixtures). Yield: 163 mg (purity 93%, 46% of theory)
Reaction SMILES: [CH3:1][C:2]1[S:23][C:5]2=[N:6][C:7]([CH3:22])=[C:8]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:9]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[C:4]2[C:3]=1[CH3:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:35]1[CH2:39]OC[CH2:36]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[S:23][C:5]2=[N:6][C:7]([CH3:22])=[C:8]([CH:17]([CH2:36][CH2:35][CH3:39])[C:18]([O:20][CH3:21])=[O:19])[C:9]([C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=3)=[C:4]2[C:3]=1[CH3:24]
Reactant: COC(=O)Cc1c(C)nc2sc(C)c(C)c2c1-c1ccc(C)cc1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc(C)c(C)c2c1-c1ccc(C)cc1
Yield: 58.2 %

Procedure:
This compound was prepared according to the procedure C from methyl 2-(2,3,6-trimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.113 g; 0.333 mmol), LHMDS 1N in THF (0.367 mL; 0.367 mmol), 1-iodopropane (0.049 mL; 0.502 mmol) in DMF (5 mL) for 3 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-10%) in heptane furnished 0.074 g (58%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[C:11]#[N:12])[CH3:2].Cl[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.[Ag-]=O>[CH2:14]([O:10][C:5]1[C:4]([C:11]#[N:12])=[C:3]([CH2:1][CH3:2])[CH:8]=[C:7]([CH3:9])[N:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCc1cc(C)[nH]c(=O)c1C#N
Reactant: ClCc1ccccc1
Agent: O=[Ag-]
Solvent: Cc1ccccc1
Product: CCc1cc(C)nc(OCc2ccccc2)c1C#N
Temperature: 110 °C
Yield: 82.8 %

Procedure:
A mixture of 4-ethyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (Cpd AA, 1.1 g, 6.8 mmol), (chloromethyl)benzene (1.1 mL, 9.4 mmol, 1.4 equiv) and silver(I) oxide (1.8 g, 7.7 mmol) in anhydrous toluene (22.7 mL) was heated at 110° C. for 17 hours. The reaction mixture was cooled to 23° C. then filtered through CELITE®. The filtrate was concentrated under vacuum. The residue was purified by column chromatography (heptane/EtOAc) to give 2-(benzyloxy)-4-ethyl-6-methylpyridine-3-carbonitrile (Cpd BB, 1.42 g, 83%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:43]=[CH:42][CH:41]=[CH:40][C:10]=1[CH2:11][N:12]1[C:20]2[C:19](=[O:21])[N:18]([CH3:22])[C:17](=[O:23])[N:16]([CH3:24])[C:15]=2[C:14]([OH:25])=[C:13]1[N:26]1[CH2:31][CH2:30][CH2:29][C@@H:28]([NH:32]C(=O)OC(C)(C)C)[CH2:27]1>C(Cl)(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:32][C@@H:28]1[CH2:29][CH2:30][CH2:31][N:26]([C:13]2[N:12]([CH2:11][C:10]3[CH:40]=[CH:41][CH:42]=[CH:43][C:9]=3[Cl:8])[C:20]3[C:19](=[O:21])[N:18]([CH3:22])[C:17](=[O:23])[N:16]([CH3:24])[C:15]=3[C:14]=2[OH:25])[CH2:27]1
Reactant: Cn1c(=O)c2c(c(O)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)c2c(c(O)c(N3CCC[C@@H](N)C3)n2Cc2ccccc2Cl)n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (1.5 ml) was added to a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-hydroxy-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (54 g) in chloroform (1 ml), and the resulting mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound (45 mg).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:10][CH:11]=[C:12]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:19]=2)=[O:16])[N:13]=1.[Cl-].[Be+2].[Cl-].CC[O:36]C(C)=O>C1(C)C=CC=CC=1>[OH:36][C:6]1[CH:5]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:19]=3)=[O:16])[N:13]=2)[CH:3]=[CH:8][CH:7]=1
Reactant: CCOC(C)=O
Reactant: COc1ccccc1-c1nc(NC(=O)Nc2cccc(CN3CCCCC3)n2)cs1
Agent: [Be+2]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc(CN2CCCCC2)n1)Nc1csc(-c2cccc(O)c2)n1

Procedure:
A mixture of 1-[2-(3-methoxyphenyl)thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)urea (Example 218) and beryllium chloride (5.0 eq) in dry toluene (0.2 M) and 4A molecular sieves was heated at reflux for 10 h. The starting material was not totally soluble in toluene. The mixture was brought to RT, diluted with EtOAc and washed with saturated NH4Cl. The organic phase was separated, dried over MgSO4, filtered, concentrated by rotary evaporation and purified by prep HPLC (Column Phenomenex type Prodigy 50 ODS3 100A size 250×21.20 mm 5 u, Gradient 10% to 90% CH3CN:H2O containing 1% TFA over 20 min, Detector 254 nm, 4 nm Band) to afford the title compound as an off white solid. EI-MS m/z 410 (M+H). Calc'd for C21H23N5O2S: 409.16.
Reaction SMILES: B(F)(F)F.CCOCC.C([SiH](CC)CC)C.O[CH:18]([C:30]1[CH:39]=[CH:38][C:37]2[C:36]([CH3:41])([CH3:40])[CH2:35][CH2:34][C:33]([CH3:43])([CH3:42])[C:32]=2[CH:31]=1)[C:19]#[C:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1.O>ClCCl>[CH3:40][C:36]1([CH3:41])[CH2:35][CH2:34][C:33]([CH3:42])([CH3:43])[C:32]2[CH:31]=[C:30]([CH2:18][C:19]#[C:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[CH:39]=[CH:38][C:37]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(O)C#Cc3ccc(C(=O)O)cc3)ccc21
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)c2cc(CC#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.1 ml (8.1 mmol) of BF3.Et2O (48%) and 50 ml of dichloromethane are introduced into a three-necked flask under a stream of nitrogen. 2.6 ml (16.2 mmol) of triethylsilane are added at −20° C., followed by a solution of 1 g (2.7 mmol) of 4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoic acid in 30 ml of dichloromethane and the mixture is stirred at room temperature for 30 minutes. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified on a column of silica eluted with dichloromethane. After evaporation of the solvents, 780 mg (82%) of 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoic acid are collected, with a melting point of 167-8° C.
Reaction SMILES: CCCCCCCCCCCC[NH2:13].[F:14][C:15]1[CH:16]=[C:17](NC(=O)CC(NC2C=CC=CC=2)=O)[CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[CH:28]=[C:29]([C:31]3[N:32]=[CH:33][N:34]([CH3:36])[CH:35]=3)[S:30][C:23]=12.O=C(NC1C=CC=CC=1)CC(O)=O.[F:63][C:64]1[CH:69]=[CH:68][C:67]([NH:70][C:71]([C:73]2([C:76]([OH:78])=O)[CH2:75][CH2:74]2)=[O:72])=[CH:66][CH:65]=1>>[F:14][C:15]1[CH:16]=[C:17]([N:70]([C:67]2[CH:66]=[CH:65][C:64]([F:63])=[CH:69][CH:68]=2)[C:71]([C:73]2([C:76]([NH2:13])=[O:78])[CH2:74][CH2:75]2)=[O:72])[CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[CH:28]=[C:29]([C:31]3[N:32]=[CH:33][N:34]([CH3:36])[CH:35]=3)[S:30][C:23]=12
Reactant: CCCCCCCCCCCCN
Reactant: Cn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5)cc4F)c3s2)c1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: O=C(O)CC(=O)Nc1ccccc1
Product: Cn1cnc(-c2cc3nccc(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)c3s2)c1
Yield: 24 %

Procedure:
Starting from the amine 12 (scheme 3) and following the procedure described above for the compound 5c (example 3, scheme 3), but replacing acid 1 for the acid 181, title compound 180 was obtained in 24% yield. 1H NMR (DMSO-d6) δ (ppm): 10.39 (s, 1H), 10.01 (s, 1H), 8.42 (d, J=5.5 Hz, 1H), 7.87 (dd, J=14.2 and 2.4 Hz, 1H), 7.85 (d, 1H, J=1.2 Hz), 7.70 (d, 1H, J=1.1 Hz), 7.66 (s, 1H), 7.64-7.61 (m, 2H), 7.50 (dd, J=2.0 and 8.8 Hz, 1H), 7.43 (t, 1H, J=8.8 Hz), 7.16-7.11 (m, 2H), 6.55 (d, 1H, J=5.5 Hz), 3.71 (s, 3H), 1.44 (m, 4H). MS (m/z): 546.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([F:13])([F:12])[F:11])=[CH:4][C:5]([I:9])=[C:6]([CH:8]=1)[NH2:7].[C:14](=O)(OC(Cl)(Cl)Cl)[O:15]C(Cl)(Cl)Cl>O1CCOCC1>[Cl:1][C:2]1[CH:8]=[C:6]([N:7]=[C:14]=[O:15])[C:5]([I:9])=[CH:4][C:3]=1[C:10]([F:13])([F:11])[F:12]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1I
Solvent: C1COCCO1
Product: O=C=Nc1cc(Cl)c(C(F)(F)F)cc1I
Temperature: 100 °C

Procedure:
5-Chloro-2-iodo-4-(trifluoromethyl)aniline D10 (7.7 mmol, 2.2 g), bis(trichloromethyl) carbonate (0.35 eq., 2.7 mmol, 800 mg) were dissolved in 1,4-dioxane (10 ml) and the mixture was heated to 100° C. for 15 minutes; the mixture was then cooled to room temperature and it was filtered. The filtrate was concentrated to afford 1-chloro-4-iodo-5-isocyanato-2-(trifluoromethyl)benzene which was dissolved in dichloromethane (10 ml) and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (2 eq., 11.4 mmol, 2.28 g) was added at room temperature; the mixture was stirred at room temperature for 1.5 hours. Solvent was subsequently evaporated and the crude obtained was purified by chromatography (ethyl acetate-n-hexane) to afford the title compound, 1.46 g, 46%, M+−H=546.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:18]([C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)P(OC1C=CC=CC=1)(=O)OC1C=CC=CC=1.CC(C)([O-])C.[K+]>O1CCOCC1.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:10]#[C:18][C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: O=P(Oc1ccccc1)(Oc1ccccc1)C(Cl)c1ccncc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C#Cc2ccncc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To a suspension of 3-cyclopentyloxy-4-methoxybenzaldehyde (6.07 g, 27.6 mmol) and diphenyl 1-chloro-1-(4-pyridyl)methanephosphonate (J. Org. Chem., 1992, 57, 1622) (9.03 g, 52.1 mmol) in dioxane (150 mL) there was added in portions potassium tert-butoxide (7.03 g, 62.8 mmol). The mixture was stirred at room temperature for 1 h and then refluxed. After 3.5 h, there was added another 7 g of potassium tert-butoxide and refluxing was continued for 18 h. After cooling, the mixture was diluted with water (1 L) and extracted 3 times with EtOAc. The extracts were washed 3 times with water, dried and evaporated and the residue was chromatographed on silica gel (EtOAc/hexane 1:2) to afford the title acetylene (4.72 g, 64%) as a cream-colored solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][CH:5]=[C:6]([CH2:8]Cl)[CH:7]=1.[C-:12]#[N:13].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][CH:5]=[C:6]([CH2:8][C:12]#[N:13])[CH:7]=1
Reactant: N#Cc1ncc(CCl)cc1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1cnc(C#N)c(Cl)c1
Temperature: 130 °C

Procedure:
To a solution of 3-chloro-5-(chloromethyl)picolinonitrile (from the previous step) in DMSO (0.2 M) was added sodium cyanide (1.25 eq). The reaction mixture was heated at 130° C. under microwave irradiation. The reaction mixture taken up in water and EtOAc, and extracted with EtOAc. Organic phases were dried over anhydrous Na2SO4, and concentrated. Flash chromatography (silica gel, 20-50% EtOAc in hexanes) of the crude afforded 3-chloro-5-(cyanomethyl)picolinonitrile.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:17])[CH:15]=[CH2:16]>C1(NC2C=CC3C(=CC=CC=3)C=2)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:16][CH2:15][C:14]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:17])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(=O)OCCCC
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Agent: c1ccc(Nc2ccc3ccccc3c2)cc1
Product: CCCCOC(=O)CCOc1ccc(C(C)(C)C)cc1
Yield: 45.2 %

Procedure:
A solution of 25 g (0.167 mole) p-tert-butylphenol, 0.2 g sodium hydride (as 50% dispersion in oil), 0.2 g N-phenyl-2-naphthylamine (as basic polymerization inhibitor) in 75.0 g (0.586 mole) butyl acrylate was heated at 125° C. for four hours. The temperature was then reduced to 100° C. and the excess acrylate distilled under gentle vacuum. The resulting oil was filtered through 900 g silica gel (90 to 200 mesh) using chloroform as eluant to yield 21.0 g pure butyl 3-(p-tert-butyl-phenoxy)-propionate (45%).
Reaction SMILES: [Br:1][C:2]1[C:6]([Br:7])=[C:5](Br)[N:4]([CH2:9][C:10](OCC)=[O:11])[N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>CCOCC.O>[Br:1][C:2]1[C:6]([Br:7])=[CH:5][N:4]([CH2:9][CH2:10][OH:11])[N:3]=1
Reactant: CCOC(=O)Cn1nc(Br)c(Br)c1Br
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: OCCn1cc(Br)c(Br)n1
Yield: 75 %

Procedure:
A solution of 9.7 g. (0.025 mole) ethyl 3,4,5-tribromopyrazole-1-acetate in 125 ml. dry ether was mixed with a suspension of 1.9 g. (0.05 mole) lithium aluminum hydride in 50 ml. dry ether. The reaction mixture was heated at the reflux temperature for two hrs. and then cooled. Ethyl acetate (5 ml.) and then water (30 ml.) were added and after settling the ether portion was decanted. The ether solution was washed with two 40-ml. portions of water and dried over anhydrous sodium sulfate. After removing the ether by evaporation, the oily residue was treated with decolorizing charcoal and crystallized from a mixture of ethyl ether and petroleum ether (boiling at the temperature range 30° C. to 60° C.). There was thus obtained 6.5 gms. (75% yield) of 3,4-dibromopyrazole-1-ethanol having a melting point of 64° to 66° C.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:38])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:27]([C:29]1[O:30][C:31]([O:34][C:35](=[O:37])[CH3:36])=[CH:32][CH:33]=1)=[O:28])[C:23]([OH:25])=[O:24].[CH2:39]1CCN2C(=NCCC2)CC1.S(OC)(OC)(=O)=O>C(OCC)(=O)C.Cl>[O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:38])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:27]([C:29]1[O:30][C:31]([O:34][C:35](=[O:37])[CH3:36])=[CH:32][CH:33]=1)=[O:28])[C:23]([O:25][CH3:39])=[O:24]
Reactant: CC(=O)Oc1ccc(C(=O)O[C@]2(C(=O)O)[C@H](C)CC3C4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]45O[C@H]5C[C@@]32C)o1
Reactant: C1CCC2=NCCCN2CC1
Agent: Cl
Solvent: COS(=O)(=O)OC
Solvent: CCOC(C)=O
Product: COC(=O)[C@@]1(OC(=O)c2ccc(OC(C)=O)o2)[C@H](C)CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Step 1 (721 mg) is dissolved in ethyl acetate (25 mL). DBU (242 mg) is added, followed by dimethyl sulfate (201 mg) and the reaction is stirred at room temperature for 2 hours, then diluted with 0.2 M HCl. The organic phase is washed with water and brine, then dried over magnesium sulfate and evaporated. Purification by flash chromatography on silica gel eluting with hexanes-ethyl acetate (2:1) affords 5-acetoxyfuran-2-carboxylic acid (6S,9S,10S,11S,13S,16R,17R)-9,11-epoxy-6-fluoro-17-methoxycarbonyl-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl ester. Selected NMR signals (CDCl3) δ 0.96 (3H, d), 0.98 (3H, s), 1.40 (3H, s), 2.18 (3H, s), 2.76 (3H, s).