Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH3:17])[N:13]=[N:12]1.CC(C)([O-])C.[K+].[Si:24]([O:31][CH2:32][CH2:33][OH:34])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>C1COCC1>[Si:24]([O:31][CH2:32][CH2:33][O:34][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH3:17])[N:13]=[N:12]1)([C:27]([CH3:29])([CH3:30])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OCCO
Reactant: Cn1nnn(-c2cc([N+](=O)[O-])ccc2F)c1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1nnn(-c2cc([N+](=O)[O-])ccc2OCCO[Si](C)(C)C(C)(C)C)c1=O

Procedure:
A similar procedure as detailed below for Compound 133 was used. 1-(2-fluoro-5-nitrophenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one (prepared according to US patent application no. 2011/0130415) (250 mg, 1.1 mmol), potassium tert-butoxide (258 mg, 2.3 mmol) and 2-((tert-butyldimethylsilyl)oxy)ethan-1-ol (369 mg, 2.1 mmol) in THF (2 mL) was stirred for 1 hr at room temperature to give the product after workup (yield assumed quantitative=413 mg). The product was used in the next step without further purification.
Reaction SMILES: OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1.BrBr.Br[C:21]1[C:22](C(C2C=CC(O)=CC=2)(C)C)=[C:23]([Br:29])[C:24]([Br:28])=[C:25]([CH:27]=1)[OH:26].BrC1C(O)=C(Br)C(Br)=C(C(C2C=CC(O)=CC=2)(C)C)C=1Br>O.CO>[Br:29][C:23]1[C:24]([Br:28])=[C:25]([OH:26])[CH:27]=[CH:21][CH:22]=1
Reactant: CC(C)(c1ccc(O)cc1)c1c(Br)cc(O)c(Br)c1Br
Agent: BrBr
Agent: CC(C)(c1ccc(O)cc1)c1c(Br)c(Br)c(O)c(Br)c1Br
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: O
Solvent: CO
Product: Oc1cccc(Br)c1Br
Temperature: 30 °C
Reaction time: 1 h
Yield: 0.03 %

Procedure:
To a 2-liter 4-neck flask equipped with a -10° C. Friedrichs condenser, thermometer, mechanical stirrer, and 0.16 centimeter in diameter dip tube are added 180 grams (0.79 moles) of bisphenol-A and 880 mL of methanol containing 4 wt. % water. Bromine (513 grams, 3.2 moles) was fed with a peristaltic pump to a 1.8 meter, 0.63 centimeter outside diameter teflon tube held in hot water which was maintained at a temperature of >80° C. Bromine vapor thus generated was fed to the reaction flask over a 52 minute period and the temperature was maintained during the ({reaction at 28-32° C. by use of an ice bath. When all of the bromine had been added, additional methanol (175 mL) containing 4 wt. % water was added to the reaction flask and the mixture was stirred at 30° C. The overall methanol to bisphenol-A ratio was 32 moles of methanol per mole of bisphenol-A. A first sample of the homogenous mixture was taken 60 minutes after the bromine was added. The first sample was analyzed and indicated the presence of 0.03% yield of dibromophenol, 0.03% hydrolyzable impurities, 2.79% tribromobisphenol-A, and 97.18% tetrabromobisphenol-A. After an additional 30 minutes, a sample of liquid portion of the heterogenous mixture was analyzed and contained 2.17% tribromobisphenol-A. Water (700 mL) addition was begun immediately after taking the second sample and was complete in 20 minutes. The resulting orange mixture was filtered and the tetrabromobisphenol-A product was washed with 500 mL of deionized water. The product, thus isolated, was placed in a crystallizing dish and 1 mL of 56 wt % HBr was added. The product was then oven dried at 130° C for four hours. The dried product was analyzed as in Example 2 and indicated 99.24 wt. % tetrabromobisphenol-A, an acetone color of 10 APHA, a TOHTO color of 20 APHA, an ionic bromide content of 0 ppm, and a hydrolyzable bromide content of 21 ppm.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])(=O)=O)=CC=1.O[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1.[H-].[Na+].[OH2:39]>C(O)CCC>[CH2:21]([O:36][C:33]1[CH:34]=[CH:35][C:30]([C:27]2[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=2)=[C:31]([OH:39])[CH:32]=1)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[CH2:11]
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: C=CCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCO
Product: C=CCCCCCCCCCOc1ccc(-c2ccccc2)c(O)c1
Temperature: 110 °C
Yield: 47.6 %

Procedure:
The above-prepared 2.60 g (8.02 mM) of 10-undecenyl p-toluenesulfonate, 3.0 g (16.0 mM) of dihydroxybiphenyl and 3 ml of butanol were mixed and sufficiently stirred. To the mixture, a solution of 0.41 g (9.74 mM) of sodium hydride in 6 ml of butanol was added, followed by heat-refluxing for 7 hours at 110° C. After the reaction, the reaction mixture was subjected to distilling-off of butanol and addition of water, followed by extraction with ether to obtain an extract. The extract was dried with anhydrous sodium sulfate, followed by distilling-off of ether and purification by column chromatography (eluent: methylene chloride) to obtain 1.55 g (3.82 mM) of p-(10-undecenyl)oxyhydroxybiphenyl (Yield: 47.6%).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][CH3:20])=[O:18].Cl>O.O1CCOCC1>[CH3:20][O:19][C:17]([N:3]([CH3:2])[CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:18]
Reactant: CNCCCC(=O)O
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)N(C)CCCC(=O)O
Temperature: 25 °C
Yield: 170.4 %

Procedure:
4-(Methylamino)butyric acid hydrochloride (5 g, 32.5 mmol), and potassium carbonate (18 g, 130 mmol) were suspended in water (50 ml) and dioxane (25 ml) then cooled to 0° C. Methyl chloroformate (13 ml, 168 mmol) was added over 1 minute, then the mixture was stirred and allowed to warm slowly to room temperature for 16 hours. Conc. HCl (20 ml) was added then the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, evaporated and dried in vacuo to give 4-[(methoxycarbonyl)(methyl)amino]butyric acid as a thick clear oil (9.7 g).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[N:15][C:14]=3[C:24](O)=[O:25])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([O:29][C:30](=[O:40])[CH:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([NH2:39])[CH:34]=1)[CH3:32])C>>[C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)=[N:15][C:14]=3[C:24]([NH:39][C:35]3[CH:34]=[C:33]([CH:31]([CH3:32])[C:30]([OH:40])=[O:29])[CH:38]=[CH:37][CH:36]=3)=[O:25])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: O=C(O)c1nc(C2CCCCC2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Reactant: CCOC(=O)C(C)c1cccc(N)c1
Product: CC(C(=O)O)c1cccc(NC(=O)c2nc(C3CCCCC3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) was reacted with (±)-2-(3-amino-phenyl)-propionic acid ethyl ester (S. Mutti et al. Synth. Comm. 1997, 27, 425) according to the procedure of Example 20, step d. The ethyl ester was hydrolysed using the same procedure as in Example 247, step b to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 12.20 (2H, br s), 9.44 (1H, s), 7.64 (2H, m), 7.23 (1H, m), 6.96 (1H, d), 3.61 (1H, m), 2.86 (2H, m), 2.60 (1H, m), 1.98-1.19 (30H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 62.88; H, 8.66; N, 7.68%. C38H58N4O8.1.5 mols H2O requires: C, 62.87; H, 8.47; N, 7.72%.
Reaction SMILES: [I-].C[N+](C)(C)[CH2:4][CH:5]1[CH2:11][CH2:10][S:9][C:8]2[S:12][CH:13]=[CH:14][C:7]=2[C:6]1=[O:15].[C-:18]#[N:19].[K+]>CO.O>[O:15]=[C:6]1[CH:5]([CH2:4][C:18]#[N:19])[CH2:11][CH2:10][S:9][C:8]2[S:12][CH:13]=[CH:14][C:7]1=2
Reactant: C[N+](C)(C)CC1CCSc2sccc2C1=O
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: N#CCC1CCSc2sccc2C1=O
Temperature: 25 °C
Yield: 92.3 %

Procedure:
To a suspension of 59.5 g of N,N,N-trimethyl-N-[(4-oxo-4,5,6,7-tetrahydrothieno[2,3-b]thiepin-5-yl)methyl]ammonium iodide in 400 ml of methanol is added a solution of 25.2 g of potassium cyanide in 100 ml of water with stirring at room temperature. The mixture is stirred for 1.5 hours at the same temperature, poured into 500 ml of water and then extracted with chloroform. The extract is washed with water, dried over magnesium sulfate and the chloroform is distilled off. The resulting crystals are recrystallized from ethanol to give 32 g of 4-oxo-4,5,6,7-tetrahydrothieno[2,3-b]thiepin-5-acetonitrile as white crystals, melting at 68°-70° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([NH:8][C:9]2[O:10][C:11]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[CH:12][N:13]=2)[CH:7]=1.[F:23][C:24]1[CH:33]=[CH:32][C:27]([C:28](=[O:31])[CH2:29]Br)=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[F:23][C:24]1[CH:33]=[CH:32][C:27]([C:28](=[O:31])[CH2:29][NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([NH:8][C:9]3[O:10][C:11]([C:14]4[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=4)=[CH:12][N:13]=3)[CH:7]=2)=[CH:26][CH:25]=1
Reactant: Cc1ccc(N)cc1Nc1ncc(-c2ccc(C#N)cc2)o1
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(NCC(=O)c2ccc(F)cc2)cc1Nc1ncc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[2-(5-Amino-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile (60 mg, 0.207 mmol) in dimethylacetamide (3 mL) was added 4-fluorophenacyl bromide (45 mg, 0.207 mmol), NaHCO3 (18 mg, 0.207 mmol). The mixture was stirred at room temperature for 2 h. After removal of the solvent, the residue was treated with saturated aqueous NaHCO3 (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4 and concentrated. 4-(2-{5-[2-(4-Fluoro-phenyl)-2-oxo-ethylamino]-2-methyl-phenyl amino}-oxazol-5-yl)-benzonitrile was obtained after silica gel column chromatography (dichloromethane/ethanol: 9812) (38 mg, 43%) as beige solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([N:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15](=[O:18])[O:16][CH3:17])[CH:10]=[CH:9]2)(=[O:3])[CH3:2].CCN(CC)CC.[Si](OS(C(F)(F)F)(=O)=O)(C(C)(C)C)(C)C.O.[Br:48]Br>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:48][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([N:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15](=[O:18])[O:16][CH3:17])[CH:10]=[CH:9]2)=[O:3]
Reactant: COC(=O)N(c1ccccc1)c1ccc2cccc(C(C)=O)c2n1
Reactant: BrBr
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)N(c1ccccc1)c1ccc2cccc(C(=O)CBr)c2n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of methyl (8-acetylquinolin-2-yl)(phenyl)carbamate (46b; 790 mg) was set stirring in DCM (2 mL) at 0° C. before adding Et3N (190 μl, 1.368 mmol), and TBSOTf (266 μl, 1.158 mmol) sequentially. An additional 3.0 equivalents of Et3N and TBSOTf were then added sequentially After 5 min., the mixture was diluted with sat. aq. NaHCO3, and extracted with DCM. The organic extract was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in THF (5 mL) before adding water (303 μL, 16.84 mmol) and Br2 (67.4 μl, 1.316 mmol, Sigma Aldrich). The resulting mixture was stirred at RT for 5 min, then diluted with sat. aq. NaHCO3 and extracted with DCM. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The brominated product was used without further purification in the subsequent transformation. m/z (ESI, +ve) 399.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:7][CH:8]=[CH:9][C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH3:5].[N+:18]([C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1)([O-:20])=[O:19].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([O:11][C:10](=[O:12])[CH:9]=[CH:8][CH:7]=[C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCCC(=CC=CC(=O)O)CCCCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCC(=CC=CC(=O)Oc1ccc([N+](=O)[O-])cc1)CCCCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.6 %

Procedure:
As in Example 115, 5-pentyl-2,4-decadienoic acid (4.0 g) and 4-nitrophenol (2.8 g) in 30 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (3.48 g) and the mixture was stirred at room temperature for 18 hours. After the usual work up, the crude ester was Purified by HPLC (ether-hexane; 1:24) to furnish 2,45 g of 5-pentyl-2,4-decadienoic acid 4-nitrophenyl ester as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42][C:43](=[O:49])OC(Cl)(Cl)Cl)Cl.[CH3:51][C:52]1[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][C:53]=1[S:59][CH2:60]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:42][CH2:40][CH2:60][S:59][C:53]2[CH:54]=[C:55]([CH3:58])[CH:56]=[CH:57][C:52]=2[CH3:51])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc(C)c(SCCO)c1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCSc4cc(C)ccc4C)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 86.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (62 mg) was added to toluene/triethylamine=10/1 (61 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (85 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-[(2,5-dimethylphenyl)sulfanyl]-1-ethanol (55 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (88 mg, yield 81%).
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].O1CCCC1.[H-].[Na+].[Br:12][C:13]1[CH:14]=[CH:15][C:16](Cl)=[N:17][CH:18]=1>O>[F:1][CH2:2][CH2:3][O:4][C:16]1[CH:15]=[CH:14][C:13]([Br:12])=[CH:18][N:17]=1
Reactant: OCCF
Reactant: Clc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: FCCOc1ccc(Br)cn1
Reaction time: 0.08 h
Yield: 40.4 %

Procedure:
2-Fluoroethanol (259 mg, 3.90 mmol) was added to a solution of anhydrous tetrahydrofuran (10 mL) containing sodium hydride (NaH 60%, 94 mg, 3.90 mmol) under nitrogen, stirred for 5 minutes, and 5-bromo-2-chloropyridine (96, 500 mg, 2.59 mmol) was added thereto and stirred at room temperature for 3 hours. Water was added to the reaction mixture and organic compounds were extracted with ethyl acetate and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give the target compound 2-(2-fluoroethoxy)-5-bromopyridine (97b, 230 mg, 40%).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][C:9]([C:11]2[CH:24]=[CH:23][C:22]3[S:21][C:20]4[C:15](=[CH:16][C:17]([C:25](=[O:40])[CH2:26][CH2:27][CH2:28][N:29]5C(=O)C6=CC=CC=C6C5=O)=[CH:18][CH:19]=4)[CH2:14][C:13]=3[CH:12]=2)=[O:10])C(=O)C2=CC=CC=C12.C1(=O)N(CCCC([Cl:57])=O)C(=O)C2=CC=CC=C12.C1C2CC3C(=CC=CC=3)SC=2C=CC=1.[ClH:78]>C(O)(=O)C>[ClH:57].[ClH:78].[NH2:29][CH2:28][CH2:27][CH2:26][C:25]([C:17]1[CH:18]=[CH:19][C:20]2[S:21][C:22]3[C:13](=[CH:12][C:11]([C:9](=[O:10])[CH2:8][CH2:7][CH2:6][NH2:5])=[CH:24][CH:23]=3)[CH2:14][C:15]=2[CH:16]=1)=[O:40]
Reactant: O=C(CCCN1C(=O)c2ccccc2C1=O)c1ccc2c(c1)Cc1cc(C(=O)CCCN3C(=O)c4ccccc4C3=O)ccc1S2
Reactant: O=C(Cl)CCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: c1ccc2c(c1)Cc1ccccc1S2
Solvent: CC(=O)O
Product: NCCCC(=O)c1ccc2c(c1)Cc1cc(C(=O)CCCN)ccc1S2

Procedure:
2,7-Bis(4-phthalimidobutyryl)thioxanthene, prepared from 4-phthalimidobutyryl chloride and thioxanthene by the method of S.S. Cheng et al., J. Med. Chem. 9, 945 (1966), is treated with hot glacial acetic acid after which concentrated HCl is added gradually with stirring. The mixture is heated to reflux for 24 hours with a constant stream of HCl gas passing through the mixture. The reaction mixture is stirred and refluxed for an additional 24 hours, cooled, and the product worked up in the usual manner.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:5]=[C:4]([NH:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:10][C:9]([NH:8][C:6]1[N:5]=[C:4]([NH:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=[C:2]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:7]=1)([CH3:12])[CH3:11]
Reactant: CC(C)(C)CNc1cc(Cl)nc(NC(C)(C)C)n1
Reactant: C1CNCCN1
Product: CC(C)(C)CNc1cc(N2CCNCC2)nc(NC(C)(C)C)n1
Yield: 86 %

Procedure:
By reacting 6-chloro-2-(1,1-dimethylethylamino)-4-(2,2-dimethylpropylamino)pyrimidine with piperazine as described in Example 4, the title product is obtained in a yield of 86.0%, m.p.: 120°-124° C.
Reaction SMILES: C(OC([N:6]1[CH2:9][C:8]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][NH:19][S:20]([CH2:23][CH:24]3[CH2:26][CH2:25]3)(=[O:22])=[O:21])[CH:11]=2)[CH2:7]1)=O)C.[OH-].[Na+].CCO>[Cl-].[Na+].O>[CH2:27]([C:8]1([C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[O:16][CH2:17][CH2:18][NH:19][S:20]([CH2:23][CH:24]2[CH2:25][CH2:26]2)(=[O:22])=[O:21])[CH2:7][NH:6][CH2:9]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)N1CC(Cc2ccccc2)(c2cccc(OCCNS(=O)(=O)CC3CC3)c2)C1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=S(=O)(CC1CC1)NCCOc1cccc(C2(Cc3ccccc3)CNC2)c1

Procedure:
To 3-benzyl-3-[3-(2-cyclopropylmethanesulfonylamino-ethoxy)-phenyl]-azetidine-1-carboxylic acid ethyl ester (50 mg, 0.11 mmol) was added 4 ml 2N NaOH/EtOH. The mixture was heated for 1 hour in a microwave. After cooling to room temperature 50% brine was added and the mixture extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium bicarbonate, filtered and the solvent evaporated. The residue was purified on 4 g SiO2 using 10% methanol in dichloromethane affording the desired product as a clear oil. m=15.5 Mg
Reaction SMILES: Br.Br[CH:3]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6][CH2:5][C:4]1=O.[NH2:20][C:21]([NH2:23])=[S:22]>C(O)C>[NH2:23][C:21]1[S:22][C:4]2[CH2:5][CH2:6][N:7]([CH2:10][CH:11]=[CH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH2:9][C:3]=2[N:20]=1
Reactant: NC(N)=S
Reactant: O=C1CCN(CC#Cc2ccccc2)CCC1Br
Agent: Br
Solvent: CCO
Product: Nc1nc2c(s1)CCN(CC=Cc1ccccc1)CC2

Procedure:
Prepared from 5-bromo-1-(3-phenyl-2-propyn-1-yl)-hexahydro-4H-azepin-4-one hydrobromide by reacting with thiourea in ethanol. Yield: 4% of theory, Melting point: 145°-148° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].CN(C)C=O.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])=[CH:24][CH:23]=1>O>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:27][CH:26]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(Cc1ccc(O)cc1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc(CC(=O)OCc2ccccc2)cc1
Reaction time: 1 h
Yield: 98.3 %

Procedure:
Potassium carbonate (1.38 g) and tert-butyl bromoacetate (1.07 g) were added to a dehydrated N,N-dimethylformamide (17 mL) solution of benzyl (4-hydroxyphenyl)acetate (1.21 g) at room temperature, followed by stirring for 1 hour. Thereafter, water was added to the reaction mixture on an ice bath, and extraction was performed with hexane:ethyl acetate=2:1. The resulting organic phase was washed with an aqueous saturated sodium chloride solution and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→8:2) to obtain the title compound (1.75 g) having the following physical property values.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]([N:19]([CH:26]([CH3:28])[CH3:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]>C1COCC1.O.CCOC(C)=O>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][CH2:16][C:17]([N:19]([CH:26]([CH3:28])[CH3:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]
Reactant: Nc1ccccc1N
Reactant: CC(C)N(C(=O)CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)N(C(=O)CNc1ccccc1N)c1ccccc1
Temperature: 25 °C
Yield: 65.1 %

Procedure:
To a stirred solution of 40 g (385 mmol) of phenylenediamine is added 75 g (543 mmol, 1.4 equiv.) of potassium carbonate. The suspension is stirred at RT and a solution of 99 g (386.5 mmol, 1 equiv.) of 2-Bromo-N-isopropyl-N-phenyl acetamide in 15 mL THF is added dropwise. The resulting suspension is stirred at RT for 16 h and diluted with 1 L H2O and 1 L EtOAc. The Organics were washed with H2O (3×500 mL), brine (500 mL), dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 8/2 as eluent afforded 71 g of a yellow solid: mp. 110°-112° C.; 1H NMR (CDCl3, 300 MHz) δ7.48-7.44 (m, 4H), 7.18-7.15 (m, 2H), 6.69-6.59 (m, 3H), 6.21-6.19 (m, 1H), 5.11-4.98 (m, 1H), 3.4 (s, 2H), 1.09 (d, 6H, J=7).