Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[NH:21][C:20]3[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17](Cl)=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C.CN1CCCC1=O>O>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[NH:21][C:20]3[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4ccccc4)c3)[nH]c2c1=O
Reactant: C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCn1c(N2CCCC2)nc2nc(-c3cnn(Cc4ccccc4)c3)[nH]c2c1=O
Temperature: 85 °C

Procedure:
A mixture of 8-(1-benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one (prepared as given in Example 1) (1.2 g, 3.2 mmol), pyrrolidine (0.34 g, 4.8 mmol), Diisopropyl ethyl amine (0.826 g, 6.4 mmol) and N-methylpyrrolidone (12 ml) were heated at 80-90° C. for 20 hours. Reaction mixture was cooled to 20-25° C. and water (20 ml) was added, solid separated out. The solid material was filtered off and purified by column chromatography to get pure 8-(1-Benzyl-1H-pyrazol-4-yl)-1-propyl-2-pyrrolidin-1-yl-1,7-dihydro-purin-6-one as off white solid (0.83 g, 64%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][C:4]=2[N:3]=1.Br[CH2:34][CH2:35][O:36][CH2:37][CH2:38][C:39]([P:42](=[O:49])([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45])([F:41])[F:40].C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>CN(C=O)C>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:34][CH2:35][O:36][CH2:37][CH2:38][C:39]([P:42]([O:43][CH2:44][CH3:45])([O:46][CH2:47][CH3:48])=[O:49])([F:40])[F:41])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][C:4]=2[N:3]=1
Reactant: CCOP(=O)(OCC)C(F)(F)CCOCCBr
Reactant: CCOC(=O)CCc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3C)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCOCCC(F)(F)P(=O)(OCC)OCC)cc3C)cc12
Temperature: 60 °C

Procedure:
To a solution of ethyl 3-(5-amino-2-(4-hydroxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoate (6-13) (1.0 equiv.) dissolved in DMF (0.14 M) was added a solution of diethyl 3-(2-bromoethoxy)-1,1-difluoropropylphosphonate (6-14: described in Example 7—Step 1) (1.3 equiv.) in DMF (0.7 M) and cesium carbonate (4 equiv.). The reaction was stirred at 60° C. After 1.5 hours (or until reaction is complete by LCMS), DCM (2 volume equivalent) was added to the reaction. The solids (inorganic) were filtered, and the filtrate was concentration. The crude product was purified by Combiflash using 0-5% MeOH in DCM to give ethyl 3-(5-amino-2-(4-(2-(3-(diethoxyphosphoryl)-3,3-difluoropropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoate (6-15) as an oil which upon standing became a white solid.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[C:31]5[NH:35][C:34](=[O:36])[O:33][N:32]=5)=[CH:21][CH:20]=4)=[C:14]([CH2:37][CH2:38][CH3:39])[N:13]4[N:40]=[CH:41][N:42]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.O1CCCC1>C(OCC)(=O)C>[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:35][C:34](=[O:36])[O:33][N:32]=4)=[CH:23][CH:24]=3)=[C:14]([CH2:37][CH2:38][CH3:39])[N:13]3[N:40]=[CH:41][N:42]=[C:12]23)[CH2:7][CH2:6]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
A mixture of 4-(1,4-dioxaspiro[4.5]dec-8-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.27 g), 6N hydrochloric acid (2 mL) and tetrahydrofuran (10 mL) was stirred at 40° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.2 g, 81%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1>O1CCOCC1>[N:13]1([CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[CH:17]=[CH:16][CH:15]=[N:14]1
Reactant: c1cn[nH]c1
Reactant: BrCCc1c[nH]c2ccccc12
Solvent: C1COCCO1
Product: c1ccc2c(CCn3cccn3)c[nH]c2c1

Procedure:
A solution of 3-(2-bromo-ethyl)-1H-indole (2.24 g, 10 mmol) and pyrazole (1.36 g, 20 mmol) in abs. dioxane (20 ml) was stirred at 80° C. for 16 h. The solvent was then removed i. vac., CHCl3 (100 ml) was added to the residue and the mixture was washed twice with water. The organic phase was dried over Na2SO4 and concentrated i. vac. and the residue which remained was purified by flash chromatography with CHCl3/MeOH (50:1).
Reaction SMILES: [CH3:1][N+:2]#[C-:3].[C@@H:4]12[N:11](C)[C@@H:8]([CH2:9][CH2:10]1)[CH2:7][CH2:6][C:5]2=O.CC(C)([O-])C.[K+].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.C(O)C>[CH3:3][N:2]1[CH:4]2[CH2:10][CH2:9][CH:1]1[CH:7]([C:8]#[N:11])[CH2:6][CH2:5]2
Reactant: CN1[C@@H]2CCC(=O)[C@H]1CC2
Reactant: [C-]#[N+]C
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: CN1C2CCC(C#N)C1CC2
Temperature: 0 °C

Procedure:
Methyl isocyanide (5.04 g., 0.026 mol) was added to (±)-tropan-2-one (2 g., 0.0143 mol) in dimethoxyethane (80 ml) and the solution cooled to 0° C. Ethanol (2 ml) was added followed by addition of potassium tert-butoxide (5.64 g, 6.05 mol). The mixture was then heated at 50° C. for three hours, cooled and poured into a saturated potassium carbonate solution (300 ml). This was extracted with ethyl acetate (3×100 ml) and the combined extracts dried (K2CO3), filtered and evaporated to give a crude oil which was abosorbed on alumina (40 g, grade 1 neutralised by addition of 10% water) from ethereal solution. The solution was eluted with a progressively graded mixture of ether, ethyl acetate and methanol to give 8-methyl-8-azabicyclo[3.2.1]octane-2nitrile (1.1 g--46%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([NH:12][C:13](=O)[CH2:14][N:15]3[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([NH:12][C:13](=[S:34])[CH2:14][N:15]3[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)N1CC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC(C)OC(=O)N1CC(=S)Nc2ccc(-c3cccc(Cl)c3)cc21

Procedure:
Prepared according to the procedure for Example 24 from isopropyl 7-(3-chlorophenyl)-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxylate and Lawesson's reagent. A yellowish solid: m.p. 208-212° C.; 1H-NMR (DMSO-d6) δ 1.27 (d, J=6.1 Hz, 6H), 4.62 (s, 2H), 4.94 (sep, J=6.1 Hz, 1H), 7.23 (m, 4H), 7.64 (t, J=1.8 Hz, 1H), 7.90 (s, 1H), 12.80 (s, 1H), MS (ESI) m/z 359/361 (M−H)-.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)#[N:2].[CH3:9][C:10]([CH3:12])=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C1COCC1>[CH:10]([N:6]1[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]1)([CH3:12])[CH3:9]
Reactant: CC(C)=O
Reactant: N#CC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)N1CCC(C#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-cyanopiperidine (5.8 g, 53 mmol, J. Org. Chem. 21, 984-986, 1957) in methanol (30 mL) and THF (130 mL) was added with stirring acetone (7.7 mL) and glacial acetic acid (6.0 mL) followed by portion wise addition of sodium cyanoborohydride (6.6 g, 105 mmol). When addition was complete the mixture was stirred overnight at ambient temperature. The solvent was evaporated and to the residue was added 1N hydrochloric (110 mL) until pH 1. The mixture was washed with diethyl ether (100 mL) and the acidic aqueous phase was saturated with potassium carbonate. The alkaline mixture (pH 10) was extracted with ethyl acetate (2×200 mL). The combined organic extracts were dried (MgSO4) and the solvent was evaporated. This afforded 8.2 g of 1-isopropyl-4-cyanopiperidine. 1H NMR 400 MHz, DMSO-d6) δ 0.96 (d, 6H), 1.63-1.73 (m, 2H), 1.80-1.92 (m, 2H), 2.35-2.44 (m, 2H), 2.58-2.67 (m, 2H), 2.69-2.78 (m, 1H), 2.79-2.87 (m, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[CH3:25][Si:26]([CH3:32])([CH3:31])[CH2:27][CH2:28][CH:29]=O>C(Cl)Cl.CCOCC>[Br:21][C:20]([Br:24])=[CH:29][CH2:28][CH2:27][Si:26]([CH3:32])([CH3:31])[CH3:25]
Reactant: C[Si](C)(C)CCC=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: C[Si](C)(C)CCC=C(Br)Br
Reaction time: 0.5 h
Yield: 62 %

Procedure:
This known compound was prepared by a modification of the procedure in Piers, E.; Gavai, A. V. J. Org. Chem. 1990, 55, 2374. To a flame dried flask was added dry CH2Cl2 (150 mL) and triphenylphosphine (16 g, 61.2 mmol) The temperature was lowered to 0° C. and CBr4 (10.15 g, 30.6 mmol) was added portionwise. After 30 min, a solution of 3-trimethylsilylpropanal (2.0 g, 15.3 mmol) in dry CH2Cl2 (20 ml) was added. After 1 h at 0° C., the reaction was diluted with ether and filtered through celite. The celite was rinsed with ether (4×50 mL) and the combined ether solution was extracted with H2O (100 mL), saturated NaHCO3 (100 mL), saturated NH4Cl (100 mL) and brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to give a crude white solid. The solid residue was washed with pentane. The pentane solution was concentrated and the oily residue was chromatographed on silica gel (pentane 100%) to give (4,4-dibromo-but-3-enyl)trimethylsilane as a clear oil weighing 3.7 g. 1H NMR showed 27% contamination by remaining pentane which gives a corrected yield of 62%: IR (neat, cm−1) 2953, 2922, 2898, 1620, 1443, 1413, 1249, 1176, 1034, 986, 859, 837; 1H NMR (300 MHz, CDCl3) δ0.03 (s, 9 H), 0.62-0.67 (m, 2 H), 2.06-2.14 (m, 2 H), 6.41 (t, J=7 Hz 1 H); 13C NMR (75 MHz, CDCl3) δ−1.9, 15.1, 27.7, 87.5, 141.2.
Reaction SMILES: [C:1]1([CH:7]2[O:11][CH:10]([CH2:12][CH2:13][CH2:14]O)[C:9](=[C:16]=[CH2:17])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:18].[C:19]([O:22][CH2:23]C)(=[O:21])C>CO.Cl[Pd]Cl>[C:1]1([CH:7]2[O:11][CH:10]3[C:9]([C:16](=[CH2:17])[C:19]([O:22][CH3:23])=[O:21])([O:18][CH2:14][CH2:13][CH2:12]3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O
Reactant: C=C=C1CC(c2ccccc2)OC1CCCO
Reactant: CCOC(C)=O
Agent: Cl[Pd]Cl
Solvent: CO
Product: C=C(C(=O)OC)C12CC(c3ccccc3)OC1CCCO2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-(5-phenyl-3-vinylidene-tetrahydrofuran-2-yl)propan-1-ol (67 mg, 0.29 mmol) was dissolved in 2 mL of methanol, and then was filled with CO gas (1 atm), followed by addition of PdCl2 (5.2 mg, 0.029 mmol) and CuCl2 (117 mg, 0.87 mmol). The solution was stirred for 4 hours at room temperature. When the reaction was completed, H2O was added and the solution was stirred for 5 minutes. The mixture was diluted with ethyl acetate, washed with H2O and NaCl. Organic layer was separated and dried with anhydride MgSO4. Solvent was removed under reduced pressure, and the remnant was purified through silica gel tube chromatography (EtOAc:n-Hexane=1:25, v/v), thus providing products (55 mg, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([OH:30])[CH2:17][CH2:18][N:19]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:11][CH2:10]1.ClC1C(Cl)=CC=CC=1N1CCN(CC(O)CC)CC1>>[NH2:19][CH2:18][CH2:17][CH:16]([OH:30])[CH2:15][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1
Reactant: COc1ccccc1N1CCN(CC(O)CCN2C(=O)c3ccccc3C2=O)CC1
Agent: CCC(O)CN1CCN(c2cccc(Cl)c2Cl)CC1
Product: COc1ccccc1N1CCN(CC(O)CCN)CC1
Yield: 69 %

Procedure:
Prepared from 26b in a similar fashion as described above for 27a. Yield: 69%. Wax. 1H NMR (CDCl3): δ 1.59 (m, 2H), 2.41 (m, 2H), 2.57 (m, 2H), 2.79-2.81 (m, 9H), 3.86 (s, 3H), 3.91 (m, 1H), 6.86 (d, J 7.5, 1H), 6.91-6.96 (m, 2H), 6.98-7.03 (m, 1H). 13C NMR (CDCl3): δ 37.3, 39.7, 50.9, 53.6, 55.5, 64.5, 66.2, 111.2, 118.3, 121.1, 123.1, 141.3, 152.3.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3](Cl)(=[O:5])=[O:4].[CH3:9][O:10][C:11]1[CH:55]=[C:54]([O:56][CH3:57])[CH:53]=[C:52]([O:58][CH3:59])[C:12]=1/[CH:13]=[CH:14]/[CH:15]([S:25]([CH:28](/[CH:38]=[CH:39]/[C:40]1[C:45]([O:46][CH3:47])=[CH:44][C:43]([O:48][CH3:49])=[CH:42][C:41]=1[O:50][CH3:51])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([NH2:37])[CH:30]=1)(=[O:27])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([NH2:24])[CH:17]=1>>[CH3:59][O:58][C:52]1[CH:53]=[C:54]([O:56][CH3:57])[CH:55]=[C:11]([O:10][CH3:9])[C:12]=1/[CH:13]=[CH:14]/[CH:15]([S:25]([CH:28](/[CH:38]=[CH:39]/[C:40]1[C:41]([O:50][CH3:51])=[CH:42][C:43]([O:48][CH3:49])=[CH:44][C:45]=1[O:46][CH3:47])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([NH:37][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4])[CH:30]=1)(=[O:27])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([NH:24][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4])[CH:17]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(N)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NS(=O)(=O)C(F)(F)F)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NS(=O)(=O)C(F)(F)F)c2)c(OC)c1
Yield: 59.9 %

Procedure:
A solution of trifluoromethanesulfonyl chloride (10 mmol) and (E)-2,4,6-trimethoxystyryl-3-amino-4-methoxybenzylsulfone (10 mmol) was reacted according to General Method A. The product obtained was purified by column chromatography to give the desired product in 59.9% yield. (m.p. 144-46° C.)
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[C:12](=[O:13])/[C:11](=[CH:14]/[C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[C:32]([F:35])([F:34])[F:33])[N:19]=[CH:18]4)/[S:10][C:9]2=[O:36])[N:6]=1.[F:37][C:38]([F:44])([F:43])[S:39](Cl)(=[O:41])=[O:40]>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:20]2[C:21]3[C:17](=[CH:16][C:15](/[CH:14]=[C:11]4/[C:12](=[O:13])[N:8]([CH2:7][C:5]5[N:6]=[C:2]([NH:1][S:39]([C:38]([F:44])([F:43])[F:37])(=[O:41])=[O:40])[S:3][CH:4]=5)[C:9](=[O:36])[S:10]/4)=[CH:23][CH:22]=3)[CH:18]=[N:19]2)=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:27]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: Nc1nc(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)cs1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1Cc1csc(NS(=O)(=O)C(F)(F)F)n1

Procedure:
N-(4-{[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}-1,3-thiazol-2-yl)-1,1,1-trifluoromethanesulfonamide was prepared from (5Z)-3-[(2-amino-1,3-thiazol-4-yl)methyl]-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (from Example 400) and trifluoromethanesulfonyl chloride following General Procedure U.
Reaction SMILES: NC(N)=O.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([S:18]([C:21]2[C:22]([OH:29])=[C:23]([CH:25]=[CH:26][C:27]=2[Cl:28])[NH2:24])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[Cl:30][C:31]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=1[N:38]=[C:39]=[O:40]>>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([S:18]([C:21]2[C:22]([OH:29])=[C:23]([NH:24][C:39]([NH:38][C:32]3[CH:33]=[CH:34][CH:35]=[C:36]([Cl:37])[C:31]=3[Cl:30])=[O:40])[CH:25]=[CH:26][C:27]=2[Cl:28])(=[O:19])=[O:20])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c(Cl)ccc(N)c2O)CC1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Agent: NC(N)=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c(Cl)ccc(NC(=O)Nc3cccc(Cl)c3Cl)c2O)CC1
Yield: 20.9 %

Procedure:
Following the general procedure for urea formation outlined in example 15, 3-[4-(tert- butoxycarbonyl)piperazin-1-yl]sulfonyl4-chloro-2-hydroxyaniline (110 mg, 0.28 mmol) and 2,3-dichlorophenylisocyanate (64 mg, 0.34 mmol) were coupled to form the desired urea (34 mg, 25%). EI-MS (m/z) 576.65, 578.65, 580.67 (M−).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].[NH:29]1[C:33](=[O:34])[CH2:32][CH2:31][C@H:30]1[C:35]([OH:37])=[O:36]>C(OCC)(=O)C>[CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].[NH:29]1[C:33](=[O:34])[CH2:32][CH2:31][C@H:30]1[C:35]([O-:37])=[O:36]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: CCOC(C)=O
Product: O=C1CC[C@@H](C(=O)[O-])N1

Procedure:
Amlodipine (10g, 0.025 mole) was dissolved in ethyl acetate (100 ml) with stirring. The solution was adjusted to 25° C. and slowly added with (S)-(−)-pyroglutamic acid (3.61g, 0.028 mole). This reaction was stirred at 25° C. for 1 hour to produce precipitates. They were filtered off and washed with ethyl acetate (50 ml), followed by drying at 40° C. under vacuum to give 12.82 g of the title compound (Yield 95.3%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:11][O:10][C:9]1=[O:21])=[O:7].[CH3:22][CH:23]([CH3:39])[C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=1)=[O:25]>>[F:20][C:15]1[CH:14]=[C:13]([C@H:12]2[CH2:11][O:10][C:9](=[O:21])[N:8]2[C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:36]2[CH2:37][CH2:38][CH:33]([C:29]3[CH:28]=[C:27]([NH:26][C:24](=[O:25])[CH:23]([CH3:22])[CH3:39])[CH:32]=[CH:31][CH:30]=3)[CH2:34][CH2:35]2)[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: O=C(CCCCCl)N1C(=O)OC[C@@H]1c1ccc(F)c(F)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)N3C(=O)OC[C@@H]3c3ccc(F)c(F)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using (4S)-3-(5-chloropentanoyl)-4-(3,4-difluorophenyl)-1,3-oxazolidin-2-one and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 528.1 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[C:9]2[N:10]([CH3:17])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[S:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[C:25]([O:29][C:30](ON=C(C1C=CC=CC=1)C#N)=[O:31])([CH3:28])([CH3:27])[CH3:26]>O1CCCC1>[CH3:1][N:2]([CH2:3][CH:4]1[C:9]2[N:10]([CH3:17])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[S:7][CH2:6][CH2:5]1)[C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: CNCC1CCSc2c1n(C)c1ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(CC1CCSc2c1n(C)c1ccccc21)C(=O)OC(C)(C)C
Yield: 87 %

Procedure:
A solution of 4-methylaminomethyl-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole (3.2 g) in dry tetrahydrofuran (30 ml) is allowed to react with triethylamine and 2-t-butoxycarbonyloxyimino-2-phenylacetonitrile in the same manner as in Example 6(a) to give 4-(N-methyl-N-t-butoxycarbonylaminomethyl)-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole: Yield 87.0%. Mp. 111.5°-114° C. (decomp.) (b) The above product is treated in the same procedure as in Example 12 to give 4-(N-methyl-N-t-butoxycarbonylaminomethyl)-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole 1-oxide. Mp. 218°-220.5° C. (decomp.). The product is dissolved in methylene chloride (20 ml) and trifluoroacetic acid (4 ml) is added thereto. The mixture is kept at room temperature for 2 hours and then treated in the usual manner to give the title compound (1.13 g): Yield 89.7%.
Reaction SMILES: [Al:1].[C:2]1([OH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>>[O-:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al+3:1].[O-:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Al]
Reactant: Oc1ccccc1
Product: [Al+3]
Product: [O-]c1ccccc1

Procedure:
According to Ecke et al granular aluminum is reacted with phenol under anhydrous conditions to form a catalytic amount of aluminum phenoxide in the phenol. An aluminum:phenol mole ratio of 1:5 to 1:20 is useful. Cyclopentene is reacted with the phenol in an autoclave at about 200° to 300° C. for up to 24 hours. Following this the reaction mixture is washed with aqueous acid to remove aluminum. The 2,6-dicyclopentyl phenol is recovered by distillation.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1(=[O:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.[CH3:23][Si:24](Cl)([CH3:26])[CH3:25]>O1CCCC1.CCCCCC>[CH3:23][Si:24]([CH3:26])([CH3:25])[O:22][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]=1
Reactant: O=C1CCc2ccccc21
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: C[Si](C)(C)OC1=CCc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In a 2-liter flask were charged 38.2 g (0.378 mol) of diisopropylamine and 265 ml of tetrahydrofuran (THF). The mixture was cooled to 0° C. and 229 ml of a hexane solution of 1.65 M n-butyllithium was added thereto. After 15 minutes' stirring, the mixture turned dark brown. The solution was further cooled to -78° C., to which was added 50 ml of a THF solution of 50 g (378 mmol) of 1-indanone and the resulting mixture was stirred for 30 minutes. Then, 205 g (1.89 mol) of trimethylsilyl chloride was added at -78° C., and the coolant was removed to raise the temperature to room temperature followed by stirring for 2 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:17][CH2:18][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1.[CH3:27][O:28][C:29]1[C:30](=O)[C:31](=[O:35])[C:32]=1[O:33]C>CO>[CH3:27][O:28][C:29]1[C:32](=[O:33])[C:31](=[O:35])[C:30]=1[NH:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:17][CH2:18][CH:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH3:20])[CH:11]=1
Reactant: COc1ccc(C(NCC(C)c2ccccc2)c2cccc(N)c2)cc1
Reactant: COc1c(OC)c(=O)c1=O
Solvent: CO
Product: COc1ccc(C(NCC(C)c2ccccc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Yield: 70.8 %

Procedure:
In a similar manner to that described in Example (1c), a solution of 3-[(4-methoxyphenyl)-(2-phenylpropylamino)methyl]phenylamine (2.52 g) [prepared as described in step (b) above] in methanol (25 ml) and 3,4-dimethoxy-3-cyclobutene-1,2-dione (1.09 g) were reacted, to afford the title compound (2.35 g) as a pink foamy solid.