Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[O:22])=[CH:16][CH:15]=1>CCOCC>[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:22])=[CH:16][CH:15]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: C1CCNCC1
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(Cc1ccc(F)cc1)N1CCCCC1

Procedure:
A well stirred mixture of 111.8 g of piperidine, 103 g of pyridine and one liter of anhydrous ether was treated dropwise with 220 g of freshly distilled 4-fluorophenyl acetyl chloride. This mixture was stirred overnight, then filtered and the filtrate washed successively with water twice, 0.1N sodium hydroxide twice, 0.1N hydrochloric acid twice, water and saturated sodium chloride, then dried in vacuo. The residue was distilled giving a yellow liquid which crystallized on standing, giving 245 g of N-(4-fluorophenylacetyl)piperidine.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][NH:13][CH2:12][C@H:11]([OH:15])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:16][CH2:17][O:18][C:19](C)=[O:20]>O1CCOCC1.O>[Si:1]([O:8][C@@H:9]1[CH2:10][C@@H:11]([OH:15])[CH2:12][N:13]([C:19]([O:18][CH2:17][C:16]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:14]=2)=[O:20])[CH2:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CNC[C@H](O)C1
Reactant: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
To a solution of (3R,5R)-5-(tert-butyldimethylsilyloxy)piperidin-3-ol (1 eq) in 20 mL of 1,4-dioxane and 8 mL of water was added benzyl chloro formate (1.5 eq). The mixture was stirred at room temperature for 4 hours. The crude mixture was diluted with 100 mL of EtOAc, washed with brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:3) to yield (3R,5R)-benzyl 3-(tert-butyldimethylsilyloxy)-5-hydroxypiperidine-1-carboxylate (74%). LC/MS (m/z): 366.2 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH2:33][C:34]4[CH:38]=[C:37]([CH3:39])[O:36][N:35]=4)([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:40][C@@H:41]1[CH2:45][CH2:44][NH:43][CH2:42]1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([CH2:31][O:32][CH2:33][C:34]5[CH:38]=[C:37]([CH3:39])[O:36][N:35]=5)([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([N:43]3[CH2:44][CH2:45][C@@H:41]([F:40])[CH2:42]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:20][CH2:19]4)=[CH:25][CH:26]=1
Reactant: F[C@@H]1CCNC1
Reactant: Cc1cc(COC[C@]23Cc4cnn(-c5ccc(F)cc5)c4C=C2CCN(S(=O)(=O)c2ccc(Cl)nc2)C3)no1
Product: Cc1cc(COC[C@]23Cc4cnn(-c5ccc(F)cc5)c4C=C2CCN(S(=O)(=O)c2ccc(N4CC[C@@H](F)C4)nc2)C3)no1

Procedure:
The title compound was prepared by the method of Example 20 using (R)-6-(6-chloropyridine-3-sulfonyl)-1-(4-fluorophenyl)-4a-(5-methyl-isoxazol-3-ylmethoxymethyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene and (R)-3-fluoropyrrolidine. 1H NMR (400 MHz, CHCl3-d): δ 8.55 (d, 1H), 7.77 (dd, 1H), 7.49-7.37 (m, 3H), 7.14 (t, 2H), 6.41 (d, 1H), 6.35-6.20 (m, 2H), 5.40 (d, 1H), 4.62-4.48 (m, 2H), 4.19 (dd, 1H), 3.78-3.70 (m, 3H), 3.51 (d, 1H), 3.18-3.10 (m, 2H), 2.69-2.60 (m, 1H), 2.42 (d, 3H), 2.21 (d, 1H), 2.10 (d, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[CH3:18]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CC1(C(=O)OCC)CCCC1=O
Temperature: 56 °C
Yield: 37.8 %

Procedure:
To a solution of ethyl 2-oxocyclopentanecarboxylate (93.27 g, 597 mmol) and ethyl 2-bromoacetate (144.64 g, 866 mmol) in acetone (1.2 L) was added K2CO3 (165 g, 1194 mmol). The mixture was heated at 56° C. for 24 h. The solid was filtered off and the filtering cake was washed with acetone (3×100 mL). The filtrate was concentrated and the resultant liquid was purified by a silica gel plug to give the title compound as light yellow liquid (54.7 g). LCMS m/z=243.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.23 (t, J=7.14 Hz, 3H), 1.24 (t, J=7.14 Hz, 3H), 1.95-2.03 (m, 1H), 2.06-2.15 (m, 2H), 2.35-2.50 (m, 2H), 2.55-2.60 (m, 1H), 2.80 (dd, J=15.2, 2.09 Hz, 1H), 2.95 (dd, J=15.2, 2.09 Hz, 1H), 4.09 (q, J=7.14 Hz, 2H), 4.12 (q, J=7.14 Hz, 2H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:22])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][N:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.[H-].[Na+].CS(O[CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)(=O)=O.N>CN(C=O)C>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)[N:17]=[CH:16]4)[CH:7]=2)=[O:22])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2[nH]ncc2c1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2C2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 18 h
Yield: 4.4 %

Procedure:
A solution of N-cyclopropyl-3-(1H-indazol-5-yl)-4-methylbenzamide (Example 17) (0.07 g) in dry DMF (3 ml) was treated with sodium hydride (60% oil dispersion, 0.014 g) under nitrogen. After 5 min 1,1-dimethylethyl 4-[(methylsulfonyl)oxy]-1-piperidinecarboxylate (0.08 g) was added and the mixture was stirred at room temp. for 18 h. 0.88 Ammonia (1 ml) was added and the mixture was concentrated under vacuum. The residue was purified by column chromatography on silica eluting with cyclohexane:ethyl acetate (1:1) followed by reverse phase preparative Hplc to give the title compound (0.005 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[C:17]([C:19](O)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[CH2:26]([N:28]([CH2:29][CH3:30])[C:19]([C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:18]=1)=[O:20])[CH3:27]
Reactant: CCNCC
Reactant: COc1ccc(-c2cc(C(=O)O)c3ccccc3n2)cc1
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1cc(-c2ccc(OC)cc2)nc2ccccc12

Procedure:
The procedure of Example 3 is followed using 2-(4-methoxyphenyl)-quinoline-4-carboxylic acid (5 g), thionyl chloride (15 ml) and diethylamine (18.4 ml) as the starting materials.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH:32]=[CH:33][C:34](O)=[O:35]>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:34](=[O:35])[CH:33]=[CH:32][C:31]1[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:29]([O:28][CH3:27])[CH:30]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Product: COc1ccc(C=CC(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1OC
Yield: 73 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with 3,4-dimethoxycinnamic acid under the conditions described in example 86 to yield 73% of the desired product.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[CH:11]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH3:26])[CH:17]=1)[CH2:12][C:13](O)=[O:14].C(N1C=CN=C1)([N:29]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[CH:11]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH3:26])[CH:17]=1)[CH2:12][C:13]([NH2:29])=[O:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3ccccc3C2=O)ccc1OC
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(N)=O)N2Cc3ccccc3C2=O)ccc1OC
Reaction time: 0.33 h
Yield: 76.6 %

Procedure:
A mixture of 3-(1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionic acid (12.6 g, 35.4 mmol) and 1,1′-carbonyldiimidazole (5.97 g, 36.8 mmol), in tetrahydrofuran (100 mL) was stirred for 1.5 hours at room temperature. To the solution was added ammonium hydroxide (7.5 mL, 112.5 mmol, 28-30%) and stirring was continued for 20 minutes. The tetrahydrofuran was removed in vaciio and the remaining residue was slurried in 100 mL of water for 30 minutes. The mixture was filtered and the white solid was washed with water (150 mL), air dried and dried in vaczio (60° C., <1 mm). The resulting solid was recrystallized form ethyl acetate (1.1 L) and was then dried in vacuo (60° C., <1 mm) to afford 9.61 g (77%) of 3-(1-oxoisoindolin2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionamide as a white solid: mp 169-171.5; 1H NMR (DMSO-d6) δ7.75-7.40 (m, 5H), 7.05-6.80 (m, 4H), 5.75 (m, 1H), 4.56 (d, J=17.6 Hz, 1H), 4.14 (d, J=17.6 Hz, 1H), 3.98 (m, 2H), 3.72 (s, 3H), 2.93 (m, 2H), 1.30 (t, J=6.9 Hz, 3H); 13C NMR (DMSO-d6) δ171.2, 166.8, 148.3, 147.8, 141.6, 132.2, 132.1, 131.2, 127.8, 123.4, 122.7, 119.1, 112.1, 111.7, 63.6, 55.4, 51.3, 46.2, 37.8, 14.6; Anal. Calcd. for C20H22N2O5. Theoretical: C, 67.78; H, 6.26; N, 7.90. Found: C, 67.89; H, 6.31; N, 7.83.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:10][CH:9]=1.[CH2:42]([N:44]=[C:45]=[O:46])[CH3:43]>>[CH2:42]([NH:44][C:45]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:12][CH:13]=1)=[O:46])[CH3:43]
Reactant: CCN=C=O
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3N)cc2)C1=O)NC(=O)OC(C)(C)C
Product: CCNC(=O)Nc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)CCc3ccccc32)cc1

Procedure:
Prepared from N-[1-[[(2'-amino)[1,1'-biphenyl]-4-yl]-methyl]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-t-butoxycarbonylamino-3-methylbutanamide (Example 2, Step B) and ethyl isocyanate by the procedure described in Example 2, Step C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:15])(=O)=O.[OH-].[Na+]>C(O)(=O)C>[Br:1][C:2]1[C:10]2[C:6](=[C:7]([Cl:15])[N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cc2cccc(Br)c2n1
Reactant: O=S(=O)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cn1nc2c(Br)cccc2c1Cl
Reaction time: 5 h
Yield: 91.1 %

Procedure:
To a solution of 7-bromo-2-methyl-2H-indazole (6: R=Me; 0.500 g, 2.37 mmol) in 5 mL of acetic acid was added sulfuryl chloride (0.29 mL, 3.6 mmol). The mixture was stirred for 5 h, then 30 mL of a 2 M aqueous NaOH solution were added. The mixture was extracted with three 30 mL portions of ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered, and concentrated to a white solid. Column chromatography (0→15% EtOAc/hexanes) afforded slightly impure 7-bromo-3-chloro-2-methyl-2H-indazole (25: R=Me; 0.530 g; 90%) that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=1>>[Cl:21][C:22]1[N:23]=[CH:24][C:25]([C:13]2[CH:12]=[N:11][C:7]3[NH:8][CH2:9][CH2:10][N:5]([CH2:4][C:3]4[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:2]=4[Cl:1])[C:6]=3[CH:14]=2)=[CH:26][CH:27]=1
Reactant: CC1(C)OB(c2ccc(Cl)nc2)OC1(C)C
Reactant: Clc1ccc(Cl)c(CN2CCNc3ncc(I)cc32)c1
Product: Clc1ccc(Cl)c(CN2CCNc3ncc(-c4ccc(Cl)nc4)cc32)c1
Yield: 54 %

Procedure:
1-(2,5-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (115 mg) was reacted with 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as in General Procedure 4B to give the title compound as a yellow solid (54% yield). M.p.=205° C., LCMS: m/z=405.57 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.50 (2H, t, J=4.8 Hz), 3.67 (2H, m), 4.49 (2H, s), 5.10 (1H, bs), 6.52 (1H, s), 7.21 (1H, dd, J=8.3, 2.3 Hz), 7.29 (2H, m), 7.35 (1H, d, J=8.3 Hz), 7.55 (2H, m), 8.36 (1H, d, J=2.5 Hz).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[C:7]([F:13])[CH:6]=1)([F:4])[CH3:3].[CH3:14][C:15]([S@:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>ClCCCl.S([O-])([O-])(=O)=O.[Cu+2]>[F:1][C:2]([C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[N:20]/[S@@:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19])=[C:7]([F:13])[CH:6]=1)([F:4])[CH3:3]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(F)(F)c1ccc(C=O)c(F)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Product: CC(F)(F)c1ccc(/C=N/[S@](=O)C(C)(C)C)c(F)c1
Temperature: 55 °C
Yield: 46.3 %

Procedure:
To a mixture of 4-(1,1-difluoroethyl)-2-fluorobenzaldehyde (693 mg, from Step 4) and (R)-2-methylpropane-2-sulfinamide (513 mg, 4.24 mmol) in DCE (12.9 mL) was added copper(II) sulfate (882 mg, 5.52 mmol). The reaction mixture was placed in a pre-heated oil bath (55° C.) and heated for ˜2 d. The mixture was allowed to cool to room temperature, filtered through a pad of celite and rinsed with DCE. The combined filtrates were concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 24 g, heptane/ethyl acetate] providing (R,E)-N-(4-(1,1-difluoroethyl)-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (497 mg) as a yellow oil. LCMS m/z 292.1 (M+H)+, Rt 0.97 min.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:18]=[C:12]2[CH:13]=[N:14][CH:15]=[C:16](Br)[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][OH:20]>C[O-].[Na+]>[CH2:1]([S:8][C:9]1[N:18]=[C:12]2[CH:13]=[N:14][CH:15]=[C:16]([O:20][CH3:19])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cncc2nc(SCc3ccccc3)nn12
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Product: COc1cncc2nc(SCc3ccccc3)nn12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Benzylthio-5-bromo[1,2,4]triazolo[1,5-a]pyrazine (0.71 g) was dissolved in 20 mL of methanol and to this 1.20 mL of 25 percent by weight solution of sodium methoxide in methanol was added by means of a syringe with stirring at ambient temperature. The mixture turned pale yellow and the reaction was complete in 4 hours. The mixture was quenched with 0.5 mL of glacial acetic acid and the volatiles were removed by evaporation under reduced pressure. The oily residue was triturated with water and the solid that formed was recovered by filtration to obtain 0.31 g (50 percent of theory) of the title compound as a light brown solid melting at 114°-116° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[OH-].[Na+].[CH2:8]([O:14][C:15](Cl)=[O:16])[CH2:9][CH:10]=[CH:11][CH2:12][CH3:13]>C(OCC)C>[CH2:8]([O:14][C:15](=[O:16])[N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:9][CH:10]=[CH:11][CH2:12][CH3:13]
Reactant: CCC=CCCOC(=O)Cl
Reactant: CCNCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCC=CCCOC(=O)N(CC)CC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 91.3 %

Procedure:
Diethylamine (9.1 g, 125 mmol, 1.25 equiv.) was added to a 2%-aqueous NaOH-solution (200 ml) and the resulting mixture was cooled to 0° C. (icebath). At this temperature chloroformic acid hex-3-enyl ester (16.2 g, 100 mmol) in diethyl ether (200 ml) was added over a period of 35 min. After complete addition, the cooling bath was removed and stirring was continued for 1.5 h. The mixture was acidified with 2N aqueous HCl-solution, the phases separated and the organic phase was washed with brine and dried over MgSO4. The crude product was purified via fractionated distillation (74-76° C./0.05 mbar) to yield 18.2 g (92%) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Cl.[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35]Cl>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:35][CH2:34][CH2:33][N:32]([CH3:37])[CH3:31])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[C:4]([C:26]([F:29])([F:27])[F:28])[CH:3]=1
Reactant: CN(C)CCCCl
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(ccn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Agent: Cl
Product: CN(C)CCCN1C(=O)S/C(=C\c2ccc3c(ccn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-[(1-{[4-Chloro-2-(trifluoromethyl)phenyl]methyl}-1H-indol-5-yl)methylidene]-3-[3-(dimethylamino)propyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 243) and 3-(dimethylamino)propyl chloride hydrochloride following General Procedure H.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Cl[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[CH2:22][N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19]
Reactant: ClCc1ccc2ccccc2n1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2ccc3ccccc3n2)c(=O)[nH]c1=O
Yield: 38.5 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 2-chloromethyl quinoline were reacted by the same way with the example 1 to obtain the titled compound (159 mg, yield: 38.5%).
Reaction SMILES: [Cl:1][CH:2]1[CH:12]=[CH:11][CH:5]2[C:6]([O:8][C:9](=[O:10])[CH:4]2[CH2:3]1)=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:13]1[C:9](=[O:10])[CH:4]2[CH2:3][CH:2]([Cl:1])[CH:12]=[CH:11][CH:5]2[C:6]1=[O:8]
Reactant: Nc1ccccn1
Reactant: O=C1OC(=O)C2CC(Cl)C=CC12
Product: O=C1C2C=CC(Cl)CC2C(=O)N1c1ccccn1
Temperature: 130 °C
Yield: 97 %

Procedure:
119.5 grams (0.64 moles) of 4-chlorotetrahydrophthalic anhydride and 94.1 grams (0.64 moles) of 2-aminopyridine were added to a 500-mL, 3-necked, round-bottomed flask equipped with a Dean-Stark trap topped with a condenser, a nitrogen outlet, means for maintaining a mild sweep of nitrogen over the reaction mixture, and a magnetic stir. The material was heated to 130° C. with an externally heated oil bath to provide an easily stirred melt. The reaction was heated to 175° C. for a 45 minute period. The water of imidization collected in the Dean-Stark trap. The reaction was then heated to 220 to 225° C. for 2.5 hours and the resulting amber material was transferred into a clean glass jar. The crude material was recovered in 97% yield. HPLC analysis of the crude material indicated >98% purity of the desired compound.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[C:13](=[O:14])[CH2:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[S:9][C:8]=2[CH:19]=1)=[O:3].[Na].[OH:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]>O1CCCC1>[O:14]=[C:13]1[CH2:12][C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[S:9][C:8]2[CH:19]=[C:4]([C:2]([O:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:3])[CH:5]=[CH:6][C:7]1=2
Reactant: O=C(Cl)c1ccc2c(c1)Sc1ccccc1CC2=O
Reactant: O=C(O)CCO
Agent: [Na]
Solvent: C1CCOC1
Product: O=C(O)CCOC(=O)c1ccc2c(c1)Sc1ccccc1CC2=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve 1.0 gm. of 3-chlorocarbonyl-10,11-dihydro-11-oxodibenzo[b,f]thiepin in 20 cc. of tetrahydrofuran and add 1.0 gm. of the sodium salt of β-hydroxypropionic acid. Stir the mixture at room temperature for 18 hours. Filter and evaporate the filtrate to dryness. Recrystallize the solid residue from ethanol to obtain the title product.
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].[N:7]1([CH2:12][C:13]([C:15]2([CH2:20][CH3:21])[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[CH:11]=[N:10][CH:9]=[N:8]1.C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1>[Cl:4][C:3]([Cl:6])([Cl:5])[CH:2]([OH:1])[CH:12]([N:7]1[CH:11]=[N:10][CH:9]=[N:8]1)[C:13]([C:15]1([CH2:20][CH3:21])[CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:14]
Reactant: CCC1(C(=O)Cn2cncn2)CCCC1
Reactant: O=CC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCC1(C(=O)C(C(O)C(Cl)(Cl)Cl)n2cncn2)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
9.3 g (0.064 mol) of chloral were added dropwise to 10.4 g (0.05 mol) of 1-ethylcyclopentyl (1,2,4-triazol-1-yl)methyl ketone (prepared as described in Example 1) and 13.8 g (0.1 mol) of ground potassium carbonate in 100 ml of tetrahydrofuran. The reaction mixture was stirred overnight at room temperature and was then stirred with water. The solid formed was filtered off under suction and recrystallized from ethyl acetate. 7 g (39.5% of theory) of 1,1,1-trichloro-2-hydroxy-3-(1,2,4-triazol-1-yl)-4-(1-ethylcyclopentan-1-yl)-butan-4-one of melting point 194° to 196° C. were obtained.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[CH:9]([O:11][CH2:12][CH3:13])=[CH2:10].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH2:9]([O:11][CH:12]([O:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1)[CH3:13])[CH3:10]
Reactant: C=COCC
Reactant: O=C1CC[C@H](CO)N1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(C)OC[C@H]1CCC(=O)N1
Reaction time: 3 h
Yield: 102 %

Procedure:
To a solution of (5R)-5-(hydroxymethyl)pyrrolidin-2-one (Aldrich, 8.86 g, 77 mmol) in 70 mL of chloroform at room temperature under an argon atmosphere was added ethyl vinyl ether (10.4 mL, 108 mmol) and catalytic anhydrous trifluoroacetic acid (0.2 mL). After stirring for 3 hours, the reaction was partitioned between methylene chloride (150 mL) and aqueous sodium bicarbonate solution (150 mL) and the phases were separated. The organic phase was dried (K2CO3) and filtered. The filtrate was evaporated under reduced pressure to give 14.7 g of the (5R)-5-(1-ethoxyethoxymethyl)pyrrolidin-2-one.