Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][NH:12][CH2:11][CH2:10][N:9]1[C:14](=[O:29])[C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[ClH:37].[Cl:38][CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1>CN(C)C=O>[ClH:38].[ClH:37].[CH2:1]([C@@H:8]1[CH2:13][N:12]([CH2:39][C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)[CH2:11][CH2:10][N:9]1[C:14](=[O:29])[C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1ccccc1
Reactant: ClCc1cccnc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(Cc2cccnc2)C[C@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled mixture of (2R)-2-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]piperazine (0.3 g) and triethylamine (0.39 ml) in dimethylformamide (8 ml) was added 3-(chloromethyl)pyridine hydrochloride (0.12 g). The reaction mixture was stirred at the same temperature for 30 minutes and then at room temperature for 2 hours. Additional triethylamine (0.39 ml) and 3-(chloromethyl)pyridine hydrochloride (0.12 g) were added and the resulting mixture was stirred overnight. The reaction mixture was filtered and the filtrate was concentrated and subjected to a chromatography on a silica gel eluting with a mixture of toluene and ethyl acetate (5:1). The eluent was treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-2-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(pyridin-3-yl-methyl)piperazine dihydrochloride.
Reaction SMILES: C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH3:15][S:16]([O:19][C@H:20]1[CH2:24][N:23]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[O:26])[C@H:22]([C:38]([OH:40])=O)[CH2:21]1)(=[O:18])=[O:17].[OH:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>O1CCCC1>[OH:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][N:47]([C:38]([C@@H:22]2[CH2:21][C@@H:20]([O:19][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:24][N:23]2[C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=2)=[O:26])=[O:40])[CH2:46][CH2:45]1
Reactant: OCCN1CCNCC1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCN(CCO)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.08 h
Yield: 65.2 %

Procedure:
0.21 ml of triethylamine, followed by 0.19 ml of pivaloyl chloride, were added dropwise at -20° C. to a solution of 0.5 g of trans-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-L-proline in 5 ml of dry tetrahydrofuran, and the resulting mixture was stirred at the same temperature for 5 minutes. A solution of 0.25 g of N-(2-hydroxyethyl)piperazine in 3 ml of dry tetrahydrofuran was then added, and the reaction mixture was stirred at the same temperature for 30 minutes, after which the solvent was removed by distillation under reduced pressure. The resulting residue was worked up and purified in a similar manner to that described in step 54(a)(ii), to give 0.42 g of the title compound, as a powder. The infrared absorption spectrum and nuclear magnetic resonance spectrum of the product were identical with those of the compound obtained as described in step 54(a)(ii) above.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH3:13])[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([OH:24])[CH2:21][CH2:22][CH3:23]>>[CH2:20]([O:24][C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCO
Reactant: CC(C(=O)N=C=O)(c1ccccc1)c1ccccc1
Product: CCCCOC(=O)NC(=O)C(C)(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p.=83° C. and MS: m/e=325.4 (M+H+) was prepared in accordance with the general method of example 1 from 2,2-diphenylpropionyl isocyanate and butan-1-ol.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25]Cl)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:27]#[N:28])=[C:4]([F:29])[CH:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.[I-].[Na+]>COCCOC>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:27]#[N:28])=[C:4]([F:29])[CH:3]=1
Reactant: COc1cc2c(Nc3cc(O)c(Cl)cc3F)c(C#N)cnc2cc1OCCCCl
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)c(C#N)cnc2cc1OCCCN1CCOCC1

Procedure:
A mixture of 0.8 g (1.83 mmol) of 4-(4-chloro-2-fluoro-5-hydroxy-phenylamino)-7-(3-chloro-propoxy)-6-methoxy-quinoline-3-carbonitrile, 2.4 g (27.5 mmol) of morpholine, and 0.11 g of sodium iodide in 15 ml ethylene glycol dimethyl ether refluxed for 7 hr. The solvent was removed and the residue was mixed with warm ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated and dried over magnesium sulfate. Solvent was removed and the residue was recrystallized from ethyl acetate-carbon tetrachloride giving 0.63 of the title compound as a light tan solid: mass spectrum (electrospray, m/e) M+H 487.0; (M+2H)+2 243.9.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]1[CH:29]=[CH:28][C:6]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:11][C@@H:10]2[CH3:27])=[O:8])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[C:40](Cl)(=[O:42])[CH3:41]>C(Cl)Cl>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([N:19]([C@H:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:9]([C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:30])=[CH:29][CH:28]=3)[C@@H:10]([CH3:27])[CH2:11]2)[C:40](=[O:42])[CH3:41])=[CH:25][CH:24]=1
Reactant: C[C@H]1C[C@@H](Nc2ccc(Cl)cc2)c2ccccc2N1C(=O)c1ccc(N(C)C)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N(C)C)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
To a solution of (±)-cis-1-(4-dimethylamino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-4-(N-4-chlorophenyl)aminoquinoline (120 mg, 0.29 mmol) in methylene chloride (2 mL) was added diisopropylethylamine (37 mg, 0.051 mL, 0.29 mmol) followed by acetyl chloride (2 mL). The mixture was stirred at rt 4 h. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. aqueous sodium bicarbonate, brine and dried over sodium sulfate. The drying agent was removed by filtration under reduced pressure, concentrated and purified by silica gel chromatography (100% hexanes-25/75 hexanes/ethyl acetate gradient) to afford pure (±)-cis-N-(4-chloro-phenyl)-N-[1-(4-dimethylamino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (45 mg, 34%).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[Cl:26])=[C:16]([C:27](OCC)=[O:28])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[Cl:26])=[C:16]([C:27]([N:42]3[CH2:43][CH2:44][CH:39]([C:36]4[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=4)[CH2:40][CH2:41]3)=[O:28])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NC(C)(C)C)cnn2c1Nc1cc(F)ccc1Cl
Product: CC(C)(C)NS(=O)(=O)c1cnn2c(Nc3cc(F)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 66.3 %

Procedure:
Using ethyl 3-(N-tert-butylsulfamoyl)-7-(2-chloro-5-fluorophenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (4.16 g, 8.85 mmol) obtained in step 3 and 4-(4-fluorophenyl)piperidine (2.04 g, 11.4 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (3.54 g, 77%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:23][CH2:22][CH2:21][C:18]2[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(CCCBr)cc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Product: O=C(O)c1cc(NCCCc2ccc([N+](=O)[O-])cc2)ccc1O
Yield: 50.4 %

Procedure:
According to the similar procedure to Synthesis Example 1, by using 5-aminosalicylic acid (500 mg, 3.26 mmole) and 3-(4-nitrophenyl)propyl bromide (950 mg, 3.92 mmole), 520 mg (50% yield) of 2-hydroxy-5-[3-(4-nitrophenyl)-n-propylamino]-benzoic acid was obtained as a pale yellow solid. Melting point 229-231° C.
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:22][N:23]([CH3:41])[C:24]1[CH:29]=[CH:28][C:27]([C:30]([C:32]2[CH:37]=[CH:36][C:35]([N:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=O)=[CH:26][CH:25]=1.O>C1COCC1>[CH3:22][N:23]([CH3:41])[C:24]1[CH:29]=[CH:28][C:27]([C:30]([C:32]2[CH:37]=[CH:36][C:35]([N:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=[CH:9][C:10]#[N:11])=[CH:26][CH:25]=1
Reactant: CN(C)c1ccc(C(=O)c2ccc(N(C)C)cc2)cc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1ccc(C(=CC#N)c2ccc(N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of cyanomethylphosphonic acid diethyl ester (1.4 mL, 8.9 mmol) in anhydrous THF (15 mL) was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 8.9 mL, 8.9 mmol) at 0° C. and stirred for 30 min at room temperature followed by addition of bis-(4-dimethylamino-phenyl)-methanone (1.19 g, 4.4 mmol) in THF (20 mL) and refluxed overnight. The reaction mixture was poured into water (20 mL), extracted with CH2Cl2 (2×50 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO4, and purified via flash column chromatography (EtOAc/Hexane) to give 3,3-bis-(4-dimethylamino-phenyl)-acrylonitrile as a light yellow needle-like solid (0.75 g, 58% yield): mp, 181-183° C.; 1H NMR (DMSO-d6) δ 2.96 and 2.98 (2s, 6H, 2N(CH3)2), 5.70 (s, 1H, CH), 6.67-6.80 (m, 4H, Ar), 7.15-7.23 (m, 4H, Ar); 13C NMR (DMSO-d6) δ 39.7, 39.8, 87.0, 111.3, 111.4, 120.0, 124.2, 125.6, 129.8, 130.7, 151.0, 151.5, 162.2. Anal. Calcd for C19H21N3: C, 78.32; H, 7.26; N, 14.42. Found: C, 78.33; H, 7.29; N, 14.38.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13]=1[CH:21]=O.N1CCCCC1>C(O)C>[CH3:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13]=1[CH:21]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: Cc1c(C=O)[nH]c2ccccc12
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C=C2C(=O)Nc3ccccc32)[nH]c2ccccc12
Temperature: 95 °C

Procedure:
A mixture of 2-oxindole (133 mg), 3-methyl-indole-2-carbaldehyde (190 mg) (prepared according to Synthetic Communications, 1986, 16, 1799) and piperidine (10 mg) in ethanol was heated in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in vacuum oven for overnight to give 3-(3-methyl-1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([OH:12])=[CH:5][CH:4]=1)#[N:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.[CH3:26][C:27]([CH3:29])=O>>[CH3:26][C:27]1([CH3:29])[O:12][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][C:7]=2[C:8](=[O:10])[O:9]1
Reactant: CC(C)=O
Reactant: N#Cc1ccc(O)c(C(=O)O)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC1(C)OC(=O)c2cc(C#N)ccc2O1
Reaction time: 20 h
Yield: 15 %

Procedure:
To a suspension of 5-cyano salicylic acid (60 g, 0.368 mol) in TEA (134 mL, 1.76 mol) and TFAA (45 mL, 0.32 mol) was added dry acetone (20 mL) and heated to reflux. After each 1 h interval was added 15 mL of dry acetone for 4 times and the reflux continued for 20 h. The reaction mixture was concentrated under vacuum and crude purified by flash column chromatography over silica gel (230-400 mesh) using CH2Cl2 as an eluent to give the title compound as a white solid (12 g, 15%). TLC: CH2Cl2 (100%), Rf: 0.5
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)=[O:8].Cl[C:24]1[CH:33]=[C:32]([CH3:34])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:10][CH:11]2[CH2:12][N:13]([C:24]3[CH:33]=[C:32]([CH3:34])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)[CH2:14][CH:15]2[CH2:16]1)=[O:8]
Reactant: Cc1cc(Cl)nc2ccccc12
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNCC2C1
Product: Cc1cc(N2CC3CN(C(=O)c4ccccc4-c4ccccc4)CC3C2)nc2ccccc12

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 17 and 2-chloro-4-methyl-quinoline. MS (ESI) mass calcd. for C29H27N3O, 433.56; m/z found, 434.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][C:6](=[O:15])[N:5]2[CH:16]=1.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C>C(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]([CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[NH:7][C:6]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)=[O:15])[NH:5][CH:16]=1
Reactant: CN1CCNCC1
Reactant: Cc1cn2c(n1)Cc1ccccc1NC2=O
Solvent: ClCCl
Product: Cc1c[nH]c(Cc2ccccc2NC(=O)N2CCN(C)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 16 g of 2-methyl-11H-imidazo[1,2-c][1,3]benzodiazepine-5-(6H)-one, 9.58 g of N-methylpiperazine and 160 ml of methylene chloride is stirred at room temperature overnight. The mixture is decolorized with charcoal and evaporated to dryness. The residue is crystallized from methanol-ether to give 1-[2-(4-methyl-2-imidazolylmethyl)phenylcarbamoyl]-4-methylpiperazine, m.p. 177°-179°.
Reaction SMILES: ClC(OCC)=O.[C:7]([O:11][C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])([CH3:10])([CH3:9])[CH3:8].I.[NH:20]=[C:21]1[N:25]([CH3:26])[CH2:24][CH2:23][S:22]1>C(Cl)Cl.C(N(CC)CC)C>[CH3:26][N:25]1[CH2:24][CH2:23][S:22][C:21]1=[N:20][C:16](=[O:18])[CH2:15][NH:14][C:12]([O:11][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:13]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CN1CCSC1=N
Agent: CCOC(=O)Cl
Agent: I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCSC1=NC(=O)CNC(=O)OC(C)(C)C
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
Ethyl chloroformate (0.25 ml.) at -5° C. was added to a solution of 350 mg. of t-butoxycarbonylaminoacetic acid and 0.4 ml. of triethylamine in 10 ml. of methylene chloride at -5° C. After stirring 5 minutes at -5° C. there was added a solution of 610 mg. of 2-imino-3-methylthiazolidine hydrogen iodide and 1.0 ml. of triethylamine in 10 ml. of methylene chloride also at -5° C. Stirring was continued at -5° C. for 15 minutes and one hour at room temperature. The reaction mixture was washed with 40 ml. of 20% (w/v) citric acid solution, sodium bicarbonate solution, and water, dried and concentrated to dryness. The residue was triturated with ether, petroleum ether and ether and finally collected to give pure N-(3-methylthiazolidin-2-ylidene)-t-butoxycarbonylaminoacetamide.
Reaction SMILES: ClC1C=CN=C(C(Cl)=O)C=1.CNC.Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH:16]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>>[CH3:24][N:23]([CH3:25])[C:21]([C:17]1[CH:16]=[C:15]([O:33][C:30]2[CH:31]=[CH:32][C:27]([NH2:26])=[CH:28][CH:29]=2)[CH:20]=[CH:19][N:18]=1)=[O:22]
Reactant: CN(C)C(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1
Agent: CNC
Agent: O=C(Cl)c1cc(Cl)ccn1
Product: CN(C)C(=O)c1cc(Oc2ccc(N)cc2)ccn1

Procedure:
Entry 59: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][P:15]([O-:24])[O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:10][CH:9]=1.[ClH:25]>C(Cl)Cl.CCOCC>[ClH:25].[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[P:15]([O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)(=[O:24])[O:14][C:11]1[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=1
Reactant: C1CCNCC1
Reactant: [O-]P(Oc1ccc(F)cc1)Oc1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=P(Oc1ccc(F)cc1)(Oc1ccc(F)cc1)C1CCCCN1
Yield: 54 %

Procedure:
A mixture of piperidine trimer (4.5 g, 54 mmole) and di(4-fluorophenyl)phosphite (14.8 g, 55 mmole) was heated at 90°-100° C. for 3 h under nitrogen. The resulted oil was cooled and dissolved in a mixture of 50 mL CH2Cl2 and 50 mL ether. The solution was saturated with dry HCl, the oil was separated and solidified after several hours. The solid was filtered, washed with ether and dried. The hygroscopic material was stirred in 200 mL dry ether for several hours and the yellowish solid was filtered and dried. The product was obtained in 54% yield (11.6 g) and used for subsequent reaction: mp. 155°-165° C. (dec); 1H NMR (D2O) δ7.2-6.8 (m, 8H), 3.6-2.9 (m, 3H), 2.2-1.4 (m, 6H); MS (FAB) m/e 354 (M-Cl)+. Anal. (exact mass, HRMS) calcd. for C17H19N1O3P1Cl2 m/e 354.1070, found 354.1098.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[S:7][CH2:6][CH2:5][O:4]1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[C:8]([O:1][CH2:2][C@@H:3]1[S:7][CH2:6][CH2:5][O:4]1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC[C@H]1OCCS1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OC[C@H]1OCCS1)c1ccccc1
Reaction time: 1 h
Yield: 44.6 %

Procedure:
2(S)-(Hydroxymethyl)-1,3-oxathiolane (0.25 mmol, 30 mg, 1.0 equiv.) recovered from Example 3 was treated with benzoyl chloride (0.25 mmol, 35 mg, 1.0 equiv.), triethylamine (0.25 mmol, 25 mg, 1.0 equiv.) in dichloromethane (1 mL) at ambient temperature while monitoring the reaction progress by TLC. After 1 h, the reaction was extracted with saturated ammonium chloride solution and brine. The organic phase was concentrated and chromatographed on silica gel to give 2(S)-(benzoyloxymethyl)-1,3-oxathiolane (25 mg, 44.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([S:6][C:7]3[CH:8]=[C:9]([C:16]4[NH:20][N:19]=[N:18][N:17]=4)[CH:10]=[CH:11][C:12]=3[CH2:13]2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:26]>CC(C)=O.O>[Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([S:6](=[O:26])[C:7]3[CH:8]=[C:9]([C:16]4[NH:20][N:19]=[N:18][N:17]=4)[CH:10]=[CH:11][C:12]=3[CH2:13]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(c1)Cc1ccc(-c3nnn[nH]3)cc1S2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)=O
Solvent: O
Product: O=S1c2ccc(Cl)cc2Cc2ccc(-c3nnn[nH]3)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
7-Chloro-3(5-tetrazolyl)thioxanthene (100g.) was suspended in a mixture of acetone (40 ml.) and water (10 ml.) and 85% m-chloroperoxybenzoic acid (0.61g.) was added in portions. After 1.5 hr. stirring at 25° C. the mixture was diluted with water and allowed to stand overnight. The solid product was filtered off and dried, then boiled under refulx with ether (50 ml.), filtered, washed with ether, and dried, yielding 7-chloro-3(5-tetrazolyl)thioxanthene-10-oxide which had no defined melting point.
Reaction SMILES: [F:1][C:2]1[C:14]([N:15]2[C:20](=[O:21])[C:19]([CH3:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[NH:17][C:16]2=[O:27])=[CH:13][C:5]2[N:6]([CH2:10][C:11]#[CH:12])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[CH3:28]OS(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:1][C:2]1[C:14]([N:15]2[C:20](=[O:21])[C:19]([CH3:22])=[C:18]([C:23]([F:24])([F:25])[F:26])[N:17]([CH3:28])[C:16]2=[O:27])=[CH:13][C:5]2[N:6]([CH2:10][C:11]#[CH:12])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: C#CCn1c(=O)sc2cc(F)c(-n3c(=O)[nH]c(C(F)(F)F)c(C)c3=O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C#CCn1c(=O)sc2cc(F)c(-n3c(=O)c(C)c(C(F)(F)F)n(C)c3=O)cc21

Procedure:
29,6 g of 3-[6-fluoro-2-oxo-3-(2-propinyl)-5-benzothiazolinyl]-5-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidindion in 200 ml acetonitrile is stirred with 9,25 g dimethylsulfate and 10,14 g potassium carbonate at 40° C. for 90 minutes. Thereafter, the reaction mixture is poured into 200 ml of water and extracted two times with 200 ml ethyl acetate each time. The organic phase is subsequently concentrated. The thus-obtained residue is purified by chromatography with 400 g silica gel using hexane:ethyl acetate (7:3).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:14])=[CH:5][CH:4]=1.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K]>CN(C=O)C.O>[O:20]=[C:18]1[C:17]2[C:16](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15](=[O:25])[N:19]1[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:14])=[CH:5][CH:4]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=Cc1ccc(CBr)c2ccccc12
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(CN2C(=O)c3ccccc3C2=O)c2ccccc12
Temperature: 85 °C
Yield: 99.7 %

Procedure:
To a stirred solution of 4-(bromomethyl)-1-naphthaldehyde (7 g, 28 mmol) in DMF (100 mL) was added potassium phthalimide (7.3 g, 39.5 mmol), and the mixture was heated at 85° C. for 2 h. The reaction mixture was cooled to ambient temperature and diluted with H2O (100 mL). The obtained solid was separated by filtration and dried under vacuum to afford the title compound as a white solid (8.8 g, 98%): mp 190-192° C.; 1H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 9.25 (m, 1H), 8.41 (m, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.95 (m, 4H), 7.80 (m, 4H), 7.61 (m, 4H), 5.39 (s, 2H); ESIMS m/z 316.09 ([M+H]+); IR (thin film) 1708 cm−1.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])[C:12]#[CH:13])=[CH:6][CH:5]=1)#[C:2][CH3:3].I[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:18][CH:17]=1>ClCCl.CO>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])[C:12]#[C:13][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:20][CH:21]=2)=[CH:6][CH:5]=1)#[C:2][CH3:3]
Reactant: C#CC(=O)Nc1ccc(C#CC)cc1
Reactant: Ic1ccc(CCN2CCCC2)cc1
Solvent: CO
Solvent: ClCCl
Product: CC#Cc1ccc(NC(=O)C#Cc2ccc(CCN3CCCC3)cc2)cc1

Procedure:
Prepared analogously to Example 2.1.e. from propynoic acid-(4-prop-1-ynylphenyl)amide and 1-[2-(4-iodophenyl)ethyl]pyrrolidine. Yield: 20 mg (11% of theory); melting point: 198° C.-199° C.; C24H24N2O (M=356.47); Rf value: 0.1 (silica gel, dichloromethane/methanol (10:1))