Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[C:3]1([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@@H:12]3[CH2:19][NH:20][CH2:21][CH2:22][N:11]3[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:34])[CH2:31][CH2:32][CH3:33].Cl>C(Cl)(Cl)Cl.O1CCCC1>[C:30]([N:20]1[CH2:21][CH2:22][N:11]2[CH2:10][C@@H:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:18]3[C:13]([C@@H:12]2[CH2:19]1)=[CH:14][CH:15]=[CH:16][CH:17]=3)(=[O:34])[CH2:31][CH2:32][CH3:33]
Reactant: CCCC(=O)Cl
Reactant: c1ccc([C@@H]2CN3CCNC[C@H]3c3ccccc32)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCN2C[C@@H](c3ccccc3)c3ccccc3[C@@H]2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.9 %

Procedure:
To a stirred solution of cis-1,3,4,6,7,11b-hexahydro-7-phenyl-2H-pyrazino[2,1-a]isoquinoline dihydrochloride (7.8 g, 0.023 m) and triethylamine (9.4 g, 0.93 m) in chloroform (100 ml) maintained at 0° under nitrogen was added dropwise butyryl chloride (3.8 g, 0.0356 m). The mixture was allowed to warm to ambient temperature and stirred for 3 hours, then treated with 10% HCl (50 ml). The layers were separated and the organic phase washed with 10% HCl (2×50 ml), water (50 ml), and dried over MgSO4. Evaporation of the solvent gave an oily residue which was dissolved in tetrahydrofuran (100 ml) and a white solid crystallized which was collected by filtration to give 5.1 g of cis-1,3,4,6,7,11b-hexahydro-2-butyryl-7-phenyl-2H-pyrazino[2,1-a]isoquinoline, m.p. 212°-213°. An additional 3.5 of good purity product was recovered from the tetrahydrofuran to give a total of 8.6 g (93%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:16](Cl)(=[O:18])[CH3:17]>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:16](=[O:18])[CH3:17])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1ccc(-c2ccc(C#N)n2C)cc1

Procedure:
The title compound was prepared according to the general procedure for acylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using acetyl chloride (39 μL, 0.55 mmol) to provide N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]acetamide (0.018 g).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH:27]1([CH2:33][CH2:34][OH:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([CH2:33][CH2:34][O:35][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: OCCC1CCCCC1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCCC3CCCCC3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.197 mmol), intermediate 42.1, and 2-cyclohexylethanol (111 μl; 0.789 mmol), example 63 was prepared analogously to the procedure for the preparation of example 43.
Reaction SMILES: [C:1]([C:4]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:7][C:5]=1[NH2:6])(=[O:3])[CH3:2].[H-].[Na+].[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1.C(N1C2C(=CC=CC=2)C(=O)C=C1C1SC=CC=1)C>>[CH:20]1([C:23]([NH:6][C:5]2[CH:7]=[C:8]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:9]([O:11][CH3:12])=[CH:10][C:4]=2[C:1](=[O:3])[CH3:2])=[O:24])[CH2:22][CH2:21]1
Reactant: O=C(Cl)C1CC1
Reactant: CCCCOc1cc(N)c(C(C)=O)cc1OC
Agent: CCn1c(-c2cccs2)cc(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Product: CCCCOc1cc(NC(=O)C2CC2)c(C(C)=O)cc1OC
Yield: 87.4 %

Procedure:
2-Acetyl-5-n-butoxy-4-methoxyaniline (320 mg), 60% sodium hydride (81 mg) and cyclopropylcarbonyl chloride (296 mg) were reacted in the same manner as in the preparation of compound 97 to obtain N-cyclopropylcarbonyl-2-acetyl-5-n-butoxy-4-methoxyaniline (360 mg). This compound (250 mg) and potassium t-butoxide (460 mg) were reacted with each other in the same manner as in the preparation of compound 95 to obtain 7-n-butoxy-2-cyclopropyl-6-methoxy-4(1H)-quinolone (compound 115, 90 mg).
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].CN(C=O)C.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[S:20][C:21]([S:1]([Cl:5])(=[O:3])=[O:2])=[CH:22][CH:23]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(-c2cccs2)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(S(=O)(=O)Cl)s2)cc1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Sulfuryl chloride (0.32 g, 2.34 mmol) was added dropwise a stirred solution of dry DMF (0.18 ml, 2.34 mmol) at 0° C. under an argon atmosphere resulting in the formation of a white solid. After 15 min, 2-(4-methoxy-phenyl)-thiophene (0.38 g, 2 mmol) was added and the mixture was warmed to 100° C. and the melt was further stirred for 45 min. Crushed ice was added and the reaction mixture was extracted with ethyl acetate (2×) and the combined organic extracts were washed with water, brine, dried (MgSO4.2H2O) filtered and concentrated under reduced pressure. The crude, green solid was purified over silica gel (ethyl acetate/n-heptane 1:9): green solid, 0.13 g (18%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[N:6]1[C:11](=[O:12])[NH:10][CH:9]([NH:13][CH2:14][CH:15]([CH3:17])[CH3:16])[NH:8][C:7]1=[O:18].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[N:6]1[C:11](=[O:12])[NH:10][CH:9]([N:13]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:19](=[O:21])[CH3:20])[NH:8][C:7]1=[O:18]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)CNC1NC(=O)N(c2cccs2)C(=O)N1
Product: CC(=O)N(CC(C)C)C1NC(=O)N(c2cccs2)C(=O)N1
Temperature: 25 °C

Procedure:
A mixture of 3-(thien-2-yl)-6-isobutylamino-tetrahydro-1,3,5-triazine-2,4-dione (1.4 g.) and acetic anhydride (10 ml.) was heated under reflux for 4 hours. The mixture was then distilled to half volume at atmospheric pressure, cooled to room temperature, and diluted with water (20 ml.). The solid which formed was separated by filtration, washed with water, and then crystallised from ethanol to give 3-(thien-2-yl)-6-[N-(acetyl)isobutylamino]-tetrahydro-1,3,5-triazine-2,4-dione as a white solid (0.6 g., 37%), m.p. 138°-139° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([NH:7][C:8]([NH2:10])=[O:9])=[CH:3][CH:2]=1.C(#N)C.[C:15]1(C)[CH:20]=CC(S(O)(=O)=O)=C[CH:16]=1.[CH3:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH2:28]>CCCCCC>[C:4]1([N:7]([CH:15]([CH3:20])[CH3:16])[C:8]([NH2:10])=[O:9])[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1.[CH3:26][C:27]([NH:10][C:8]([NH:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)=[O:9])([CH3:28])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1ccc(NC(N)=O)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C=C(C)c1ccccc1
Solvent: CC#N
Solvent: CCCCCC
Product: CC(C)N(C(N)=O)c1ccccc1
Product: Cc1ccc(NC(=O)NC(C)(C)c2ccccc2)cc1
Temperature: 55 °C
Reaction time: 0.02 h

Procedure:
A phenylisopropylurea derivative was prepared in accordance with the method of Example 1, as follows: 1.5 parts of N-(p-tolyl)urea was suspended in 3.93 parts of acetonitrile at 55°, and 0.3 parts of p-toluene-sulfonic acid was added. After 1 minute, 4.7 parts of α-methylstyrene were added. The reactants were stirred at 55° C. for 18 hours. After cooling to ambient temperature, 60 parts of hexane was added and the precipitated solid collected, washed with hexane and recrystallized from methylene chloride to afford 2.2 parts of N-(α,α,-dimethylbenzyl)-N'-(p-tolyl)urea.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[N:20]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[OH:32])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: Oc1ccccc1N1CCOCC1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccccc2N2CCOCC2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 2-morpholin-4-yl-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil.
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([CH2:19][NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:15]=3)=[CH:10][CH:9]=2)[O:6]C(C)(C)[N:4]1C(OC(C)(C)C)=O.[ClH:34].O>O1CCOCC1>[Cl-:34].[F:1][CH2:2][C@@H:3]([NH3+:4])[C@H:7]([OH:6])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([CH2:19][NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:15]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(CNS(C)(=O)=O)no3)cc2)OC1(C)C
Reactant: Cl
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)NCc1cc(-c2ccc([C@@H](O)[C@H]([NH3+])CF)cc2)on1
Product: [Cl-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To (4S,5R)-tert-butyl 4-(fluoromethyl)-2,2-dimethyl-5-(4-(3-(methylsulfonamido-methyl)isoxazol-5-yl)phenyl)oxazolidine-3-carboxylate (300 mg, 0.62 mmol) is added 4N HCl in dioxane (4 ml) at room temperature. The solution is then cooled to 0° C. and water (0.5 ml) is added. The ice bath is removed after ten minutes and the reaction is stirred at room temperature for one hour. The volatiles were then removed by rotary evaporation. Several evaporation cycles were performed using acetonitrile to ensure complete removal of water and excess HCl gave the title compound (234 mg): m/z (Cl) 344 ([M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[NH:6][C:7]2=[O:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(Cl)Cl.[CH3:56][NH:57][CH2:58][CH:59]1[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1>CN(C=O)C>[CH3:56][N:57]([CH2:58][CH:59]1[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1)[C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([C:5]2[NH:6][C:7](=[O:12])[C:8]3[C:3]([CH:4]=2)=[C:2]([CH3:1])[CH:11]=[CH:10][CH:9]=3)=[CH:21][CH:20]=1
Reactant: Cc1cccc2c(=O)[nH]c(-c3ccc(C(=O)O)cc3)cc12
Reactant: CNCC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc2c(=O)[nH]c(-c3ccc(C(=O)N(C)CC4CCOCC4)cc3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
To 4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzoic acid (35 mg, 0.125 mmol), TBTU (40 mg, 0.125 mmol) was added 0.36M N,N-diisopropylethylamine/CH2Cl2 (0.35 mL, 0.125 mmol) and anhydrous DMF (0.9 mL). The reaction mixture was stirred at RT for 45 min after which time methyl-(tetrahydro-pyran-4-ylmethyl)-amine (19 mg, 0.15 mmol) in anhydrous DMF (0.45 mL) was added and the reaction mixture was stirred at RT overnight. The reaction mixture was passed through a Si—NH2 cartridge (1 g), eluting with DMF (2× column volumes), MeOH (2× column volumes) and the solvent removed in vacuo and the crude product purified by reverse phase preparative HPLC-MS to obtain N-methyl-4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-N-(tetrahydro-pyran-4-ylmethyl)-benzamide as a yellow foam (24 mg, 48%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].C(Cl)(Cl)Cl.[NH:40]1[CH2:45][CH2:44][CH:43]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)[CH2:42][CH2:41]1.C(N(CC)C(C)C)(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:40]3[CH2:45][CH2:44][CH:43]([N:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)[CH2:42][CH2:41]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: C1CC(N2CCOCC2)CCN1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(N2CCC(N3CCOCC3)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 94 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (36 mg, 0.072 mmol) in THF (2 mL)/CHCl3 (2 mL) were added 4-(4-piperidinyl)morpholine (37 mg, 0.22 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.5 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (41 mg, 94%). LC-MS m/z 607 (M+H)+; 1H-NMR (MeOD) δ 1.27 (d, 6H), 1.33 (m, 2H), 1.83 (d, 2H), 2.30 (s, 3H), 2.38 (m, 1H), 2.55 (m, 4H), 2.75 (t, 2H), 3.33 (m, 1H), 3.68 (m, 3H), 4.11 (s, 2H), 4.23 (m, 1H), 4.45 (m, 2H), 7.16 (t, 2H), 7.46 (d, 1H), 7.50 (m, 1H), 7.68 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: [C:1]1([CH3:8])[C:6](O)=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH3:20])(=[O:11])[CH3:10].C1(C=CC(O)=CC=1)[OH:22].C(O)(=O)C=C.CN(C)CC1C=CC=CC=1>>[C:8]1(=[O:22])[O:12][C:9](=[O:11])[CH:6]2[CH2:5][CH2:4][CH:3]=[CH:2][CH:1]12.[C:9]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH3:20])(=[O:11])[CH3:10]
Reactant: Oc1ccc(O)cc1
Reactant: Cc1ccccc1O
Agent: C=CC(=O)O
Agent: CCOCCOCCOC(C)=O
Agent: CN(C)Cc1ccccc1
Product: O=C1OC(=O)C2CCC=CC12
Temperature: 110 °C

Procedure:
A reflux condenser, a thermometer, a bleed tube, and a stirrer were set to a four-necked flask. In order to prepare a reaction solution, 203 parts by mass of cresol novolac epoxy resin “YDCN-700-5” (available from NIPPON STEEL CHEMICAL CO., LTD., epoxy equivalent weight: 203), 103 parts by mass of diethylene glycol monoethyl ether acetate, 0.2 parts by mass of hydroquinone, 72.7 parts by mass of acrylic acid, and 0.6 parts by mass of dimethyl benzyl amine were added to the four-necked flask. The reaction solution was heated at 110° C. for 10 hours to cause the addition reaction. Subsequently, into thus-obtained solution in the four-necked flask, 60.8 parts by mass of tetrahydrophthalic acid anhydride and 78.9 parts by mass of diethylene glycol monoethyl ether acetate were added, and then thus-obtained solution was heated at 81° C. for 3 hours to react them. Consequently, a 65 mass % solution (carboxyl group containing resin solution C-3) of resin containing a carboxyl group was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[O:8].CO[CH2:17][N:18]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19][Si](C)(C)C.FC(F)(F)C(O)=O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:24]([N:18]1[CH2:19][C@H:5]([C:4]2[CH:11]=[CH:12][C:13]([Cl:14])=[C:2]([Cl:1])[CH:3]=2)[C@@H:6]([C:7]([O:9][CH3:10])=[O:8])[CH2:17]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)C=Cc1ccc(Cl)c(Cl)c1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 103.9 %

Procedure:
To a solution of the compound (20.4 g) obtained in step 1 and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (22.0 g) in toluene (180 mL) was added a solution of trifluoroacetic acid (1.31 mL) in toluene (18 mL) at 0° C., and the mixture was stirred at room temperature for 14 hr. To the reaction mixture was added ethyl acetate (300 mL), and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution, water and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10→25% ethyl acetate/hexane) to give methyl (3R*,4S*)-1-benzyl-4-(3,4-dichlorophenyl)pyrrolidine-3-carboxylate (33.4 g, 100%) as a pale yellow oil.
Reaction SMILES: CC(C)([O-])C.[Na+].I[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[C:18]([O:22][C:23](=[O:32])[NH:24][CH2:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:21])([CH3:20])[CH3:19]>C1(C)C=CC=CC=1>[C:18]([O:22][C:23](=[O:32])[NH:24][CH2:25][CH:26]1[CH2:27][CH2:28][N:29]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH2:30][CH2:31]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 90 °C
Yield: 81 %

Procedure:
To a mixture of sodium tert-butoxide, 1-iodo-4-(trifluoromethyl)benzene (686 μl) and tert-butyl(piperidin-4-ylmethyl)carbamate (1.00 g) in toluene (10 ml) was added 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine) (286 mg) and tris-dibenzylideneacetone palladium(0) (211 mg). The mixture was heated to 90° C. for 15 h. The mixture was cooled to room temperature, concentrated in vacuo, and diluted with dichloromethane. This solution was filtered through a short plug of silica gel and concentrated. The residue was purified via flash chromatography on a Biotage Horizon, 40M column, eluting with 10 column volumes of 33% ethyl acetate in hexanes to provide 1.36 g (81%) of the title compound. Mass spectrum (ESI) 303.0 (M+1).
Reaction SMILES: [C:1]1([S:7](N)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(Cl)(Cl)(Cl)Cl.Cl>CO.C(O)(=O)C>[C:1]1([S:7]([C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:2][C:1]=3[S:7](=[O:8])[N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccncc1
Reactant: NS(=O)(=O)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: O=S1N=C(S(=O)(=O)c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
31.44 G. (0.2 mole) of benzenesulfonamide was dissolved in 80 ml. of dry pyridine to obtain a clear, straw-colored solution, which was placed in a cold water bath. To this pyridine solution was added the carbon tetrachloride solution produced in Part B above. An exothermic reaction ensued with formation of a white slurry, which was stirred at ambient temperature for 45 minutes and then poured into 600 ml. of 2N hydrochloric acid. The aqueous phase of the resultant mixture was decanted from the lower organic phase, which was cooled in ice water and filtered to remove carbon tetrachloride. The white solid thus obtained was slurried in 600 ml. of hot acetic acid, cooled and filtered to obtain a white solid, which was dried under vacuum to yield 49.7 g. of product having an infra-red spectrum consistent with the expected structure. The ultraviolet spectrum of the product in methanol showed peaks at 202 nm (ε=17,000), 232 nm. (ε=31,000) and 332 nm. (ε=4,000).
Reaction SMILES: Br[C:2]1[N:6]([Cl:7])[C:5]([Cl:8])=[C:4]([CH:9]([O:11][CH3:12])[CH3:10])[N:3]=1.[CH2:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH3:22])[C:16]=1B(O)O)[CH3:14]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH3:22])[C:16]=1[C:2]1[N:6]([Cl:7])[C:5]([Cl:8])=[C:4]([CH:9]([O:11][CH3:12])[CH3:10])[N:3]=1)[CH3:14]
Reactant: COC(C)c1nc(Br)n(Cl)c1Cl
Reactant: CCc1cccc(CC)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCc1cccc(CC)c1-c1nc(C(C)OC)c(Cl)n1Cl
Temperature: 110 °C

Procedure:
A solution containing 2-bromo-1-methoxyethyl-3,4-dichloroimidazole (2.74 g, 10 mmol), 2,6-diethylphenylboronic acid (2.14 g, 12 mmol.) and Pd(PPh3)4 (0.23 mg, 0.2 mmol) in toluene/2M Na2CO3 (30 ml/15 mL) in a sealed tube is degassed, then allowed to heat to 110° C. overnight. The organic layer is separated and concentrated in vacuo to dryness. The residue is purified by column chromatography on silica gel (hexane/ethyl acetate 100/5) to obtain the 2-(2,6-diethylphenyl)-1-methoxyethyl-3,4-dichloroimidazole. Synthesis of 2-(2,6-diethylphenyl)-1-methoxyethyl-4-chloro-imidazole-3-carboxaldehyde
Reaction SMILES: [CH3:1][O:2][CH:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:4]1[CH:16]=[CH:15][C:7]([C:8]([O:10]C(C)(C)C)=[O:9])=[CH:6][CH:5]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][CH:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:4]1[CH:16]=[CH:15][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COC(c1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(c1ccccc1)c1ccc(C(=O)O)cc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 99.8 %

Procedure:
A mixture of tert-butyl 4-(methoxy(phenyl)methyl)benzoate (200 mg, 0.67 mmol), 2,2,2-trifluoroacetic acid (1 mL) and dichloromethane (4 mL) were stirred at 20° C. for 4 hours. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give 4-(methoxy(phenyl)methyl)benzoic acid as a white solid (162 mg, 100%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[N:7]=1.N1C=CN=C1.[CH3:25][C:26]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C=O)C.CN(C1C=CN=CC=1)C>[Si:29]([O:1][CH2:2][C:3]1[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:18])([CH3:17])[CH3:19])[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[N:7]=1)([C:26]([CH3:28])([CH3:27])[CH3:25])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1cn(COCC[Si](C)(C)C)c(CO)n1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1cn(COCC[Si](C)(C)C)c(CO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Into a flask containing a solution of methyl 2-(hydroxymethyl)-1-((2-(tri-methylsilyl)-ethoxy)methyl)-1H-imidazole-4-carboxylate (1 g, 3.49 mmol) in DMF (25 ml), imidazole (0.490 g, 6.91 mmol), catalytic DMAP and TBDMSCl (0.790 g, 5.27 mmol) were added. The resulting mixture was stirred at RT for 12 h. The reaction mixture was quenched with saturated aqueous solution of NaHCO3 and extracted with EtOAc. The organic layer was concentrated and purified by flash column chromatography. Yield 800 mg. 1H-NMR (400 MHz; DMSO-d6): δ −0.04 (s, 9H), 0.05 (s, 6H), 0.80 (t, 2H), 0.86 (s, 9H), 3.49 (t, 2H), 3.74 (s, 3H), 4.71 (s, 2H), 5.41 (s, 2H), 8.02 (s, 1H). LC-MS: [M+1]=401.10.