Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[N+:19]([C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:22]([O-:24])=[O:23])[C:13]=1[NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])([O-:21])=[O:20]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A mixture of tert-butyl (2-aminoethyl)carbamate (5.00 g, 31.2 mmol), 2-chloro-1,3-dinitrobenzene (5.27 g, 26.0 mmol) and triethylamine (7.25 mL, 52.0 mmol) in tetrahydrofuran (260 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a yellow solid (8.44 g, 25.9 mmol, 99.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].Br[CH2:35][CH2:36][O:37][Si](C(C)(C)C)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:35][CH2:36][OH:37])[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COc1cc(-c2nnc3n2CCCC3c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(-c2nnc3n2CCCC3(CCO)c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Reaction time: 0.5 h

Procedure:
To a mixture of 8-(3,4-dichlorophenyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine (200 mg) in DMF (5 mL) was added sodium hydride (60%, 31.6 mg) under ice-cooling, and the mixture was stirred for 30 min under a nitrogen atmosphere. (2-Bromoethoxy)(tert-butyl)dimethylsilane (113 μL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a mixture of the residue in THF (2 mL) was added TBAF (1M THF solution, 439 μL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (26.9 mg).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:21][C:22]([OH:24])=[O:23].N1CCCCC1.Cl>N1C=CC=CC=1>[Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:21][C:22]([OH:24])=[O:23]
Reactant: COc1ccccc1Sc1ccc(C=O)c(Cl)c1Cl
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1ccccc1Sc1ccc(C=CC(=O)O)c(Cl)c1Cl
Yield: 75.3 %

Procedure:
A mixture of 2,3-dichloro-4-(2-methoxyphenylthio)-benzaldehyde (2.03 g), 1.44 g malonic acid, 5 mL pyridine, and 0.100 g piperidine was heated to 115 degrees for 1.5 hours. The mixture was cooled, and ice and HCl were added. The resulting solid was: filtered, washed with water and dissolved in tetrahydrofuran. This solution was dried over sodium sulfate, the solvent removed and ether added to give 1.733 g of product, m.p. 187-188 C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:18](=O)[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:4]([NH:9][C:10]([NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].F[C:28]1[C:37](F)=CC=C2[C:29]=1C(C1C=CC(F)=CC=1)(O)N(CC(F)(F)F)C(=O)N2.C(N(CC)CC)C.S(Cl)(Cl)=O.C([Mg]Br)C=C>C1COCC1>[CH2:37]([C:18]1([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:3]2[C:4](=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[NH:9][C:10](=[O:11])[N:12]1[CH2:13][C:14]([F:17])([F:16])[F:15])[CH:28]=[CH2:29]
Reactant: O=C1Nc2ccc(F)c(F)c2C(O)(c2ccc(F)cc2)N1CC(F)(F)F
Reactant: O=C(NCC(F)(F)F)Nc1ccc(F)c(F)c1C(=O)c1ccc(F)cc1
Agent: C=CC[Mg]Br
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: C=CCC1(c2ccc(F)cc2)c2c(ccc(F)c2F)NC(=O)N1CC(F)(F)F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 5.0 g (13.289 mmol) N-[3,4-difluoro-2-(4-fluorobenzoyl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (open form) and 5,6-difluoro-4-(4-fluorophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (closed form) in 25 ml THF was added 9.261 mL (66.443 mmol) triethylamine. After 1 h at 80° C., the reaction mixture was cooled to −78° C. To this solution was added 0.969 mL (13.289 mmol) thionyl chloride. After 30 mins at −78° C., 45 mL (41.195 mmol) allylmagnesium bromide (1.0M solution in dibutyl ether) was added dropwise. After 30 minutes at −78° C., the reaction mixture was quenched with saturated NH4Cl and warmed to room temperature. The reaction mixture was extracted three times with EtOAc and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Purification by flash chromatography (1×14 cm silica gel, linear gradient 0-35% EtOAc:hexane) afforded 4-allyl-5,6-difluoro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one. 1H NMR (CDCl3, 400 MHz) δ 7.46 (br s, 1H, ArNHC═O); 7.42-7.40 (m, 2H, ArH); 7.10-7.00 (m, 3H, ArH); 6.44 (m, 1H, ArH); 5.73-5.66 (m, 1H, CH2CH═CH2); 5.13-5.09 (m, 2H, CH2CH═CH2); 3.73 (m, 2H, NCH2CF3); 3.15 (m, 2H, CH2CH═CH2). HRMS (ES) exact mass calcd for C19H14F6N2O: 401.1083, Found: 401.1075.
Reaction SMILES: [CH2:1]([N:7]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:8]([C:10]1[C:11](=[O:20])[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Cl)[CH:30]=1.O>CN(C)C=O>[CH2:21]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]([C:10]1[C:11](=[O:20])[N:12]([CH2:35][C:31]2[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=2)[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: ClCc1cccnc1
Reactant: CCCCCCN(CCCCCC)C(=O)c1cc2ccccc2[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCN(CCCCCC)C(=O)c1cc2ccccc2n(Cc2cccnc2)c1=O
Temperature: 25 °C
Yield: 37.1 %

Procedure:
To a solution of 1.01 g of N,N-dihexyl-1,2-dihydro-2-oxoquinoline-3-carboxamide in 13 ml of N,N-dimethylformamide was added 136 mg of 60% sodium hydride/oil, followed by stirring at room temperature for an hour. To the reaction solution was added 434 mg of 3-picolyl chloride, followed by stirring at room temperature for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate, and the extract was washed with water, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (silica gel; Wakogel C200 (manufactured by Wako Pure Chemicals), developing solvent; hexane—ethyl acetate=7:13−1:19) and recrystallized from ethyl acetate to give 0.47 g of N,N-dihexyl-1-(3-picolyl)-1,2-dihydro-2-oxoquinoline-3-carboxamide.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:38])([CH3:37])[O:6][C@@H:7]1[C@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:9][C@H:8]1[N:29]1[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]1=[O:31])([CH3:4])[CH3:3].[CH2:39]([N:41]1[C:53]2[CH:52]=[CH:51][C:50]([CH:54]=[O:55])=[CH:49][C:48]=2[C:47]2[C:42]1=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH3:40]>>[CH2:39]([N:41]1[C:53]2[CH:52]=[CH:51][C:50]([CH:54]([OH:55])[C:35]3[C:33](=[O:34])[NH:32][C:30](=[O:31])[N:29]([CH:36]=3)[C@@H:8]3[O:9][C@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[C@@H:11]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[C@H:7]3[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:38])[CH3:37])=[CH:49][C:48]=2[C:47]2[C:42]1=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH3:40]
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Product: CCn1c2ccccc2c2cc(C(O)c3cn([C@@H]4O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]4O[Si](C)(C)C(C)(C)C)c(=O)[nH]c3=O)ccc21

Procedure:
5-((9-Ethylcarbazol-3-yl)hydroxymethyl)-2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine was prepared from 2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine according to the method of Example 1 step (i) (using 9-ethyl-3-carbazolecarboxaldehyde instead of benzophenone) as a yellow foam.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1.CN(C)C=O.[Cl:22]CCl.C(Cl)(=O)C(Cl)=O>>[O:1]=[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][Cl:22])=[O:11])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1
Reactant: O=C(O)CCCn1c(=O)[nH]c2ccccc21
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(CCCn1c(=O)[nH]c2ccccc21)OCl

Procedure:
4-(2-Oxo-2,3-dihydrobenzimidazol-1-yl)butyric acid (50 g; 0.227 mol), N,N-dimethylformamide (1.84 g; 0.025 mol; 0.11 eq), and dichloromethane (480 g; 5,652 mol; 24.89 eq) were charged to a stirred-tank reactor. Oxalyl chloride (31.12 g; 0.245 mol; 1.08 eq) was then dosed at 10-20° C. over a 1-hour period while stirring. The resulting mixture was then stirred at 10-20° C. for an additional hour. All the above steps were conducted under a N2 atmosphere.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:16][C:17]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:18]=1[C:19](O)=[O:20]>>[F:16][C:17]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:18]=1[C:19]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([C:13](=[O:15])[CH3:14])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)=[O:20]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3F)CC2)cc1

Procedure:
The title compound was prepared according to the procedure described for example K step 2 from 4′-piperazino-acetophenone and 2-fluoro-5-nitrobenzoic acid (16%, yellow solid, MS (m/e): 372.1 (M+H, 100%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2O[C:12](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[CH:18]=3)=[N:13][N:14]=2)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:35]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[NH:35][C:12](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[CH:18]=3)=[N:13][N:14]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(/C=C/c2nnc(CCc3ccc(F)cc3)o2)ccc1-n1cnc(C)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1cc(/C=C/c2nnc(CCc3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 24.3 %

Procedure:
A solution of 2-[2-(4-fluorophenyl)ethyl]-5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazole (33 mg) and ammonium acetate (126 mg) in acetic acid (1 mL) was stirred at 150° C. for 10 hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate->ethyl acetate:methanol=5:1) to obtain 8 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][C:20]([C:26]([O:28]CC)=[O:27])=[CH:19][C:18]=3[CH:31]=2)=[CH:10][CH:9]=1)[CH2:2][CH3:3].O.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCCC1.CO>[CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[S:23](=[O:24])(=[O:25])[CH2:22][CH2:21][C:20]([C:26]([OH:28])=[O:27])=[CH:19][C:18]=3[CH:31]=2)=[CH:12][CH:13]=1)[CH2:2][CH3:3]
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OCC)CCS3(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Reaction time: 1 h
Yield: 91.2 %

Procedure:
Ethyl 7-(4-propoxyethoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxlate (11 g, 24.7447 mmol) was dissolved in 110 ml of tetrahydrofuran and 55 ml of methanol, and then 93.5 ml of water was added. After adding potassium carbonate (6.84 g, 49.49 mmol), the mixture was heated under reflux for 4.5 hours. Under reflux, 39.6 ml of a 3N hydrochloric acid and 40 ml of water were dropped. After cooling, the mixture was stirred for 1 hour while cooling in ice. After filtration, the residue was washed with 88 ml of water. After vacuum drying (40° C.), 9.4 g (Yield 91.2%) of 7-(4-propoxyethoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid was obtained as pale yellowish white crystals.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5].Br[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>C1COCC1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[O:5])=[CH:15][CH:16]=1
Reactant: CON(C)C(=O)c1ccccn1
Reactant: COc1ccc(Br)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ccccn2)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of pyridine-2-carboxylic acid methoxy-methyl-amide (10.0 g, 0.060 mol) in anhydrous THF (150 mL) at −78° C. was added freshly prepared Grignard reagent of 4-bromo anisole (20.0 g, 0.106 mol). The reaction mixture was allowed to warm to room temperature. Reaction mixture was quenched with saturated ammonium chloride (100 mL) and extracted with ethyl acetate (2×200 mL). Organic layer was dried over sodium sulphate and concentrated. Purification by 100-200-mesh sized silica gel column with 0-20% EtoAc:Hexane as eluent provided the product.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]([CH2:15][CH2:16]O)[CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH2:6][N:7]=1.S(Cl)([Cl:20])=O>C(Cl)(Cl)Cl>[ClH:14].[NH2:2][C:3]1[N:4]([CH2:15][CH2:16][Cl:20])[CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH2:6][N:7]=1
Reactant: NC1=NCC(c2ccccc2Cl)N1CCO
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: NC1=NCC(c2ccccc2Cl)N1CCCl

Procedure:
A mixture of 4.15 parts of 2-amino-5-(o-chlorophenyl)-2-imidazoline-1-ethanol hydrochloride in 22.5 parts of chloroform is treated with 3.6 parts of thionyl chloride and the whole is stirred at reflux temperature for 30 minutes. The solvent is evaporated and the residue is taken up in 15 parts of chloroform. The latter is evaporated again, yielding 2-amino-1-(2-chloroethyl)-5-(o-chlorophenyl)-2-imidazoline hydrochloride as a residue.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[NH4+]>C(OCC)C.[Ti]>[CH3:4][C@@H:3]([CH:2]=[CH2:1])[C@@H:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:8]
Reactant: O=Cc1ccccc1
Agent: [Ti]
Agent: [F-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=C[C@H](C)[C@H](O)c1ccccc1
Temperature: -74 °C
Reaction time: 2 h

Procedure:
0.4 g (0.64 mmol) of the titanium compound prepared as in Example 4 are dissolved in 40 ml of diethyl ether, the solution is cooled to -74° C., 0.065 ml (0.65 mmol) of benzaldehyde are added and the mixture is stirred for 2 hours at -74° C. The reaction solution is then solution is then hydrolysed with 20 ml of aqueous ammonium fluoride solution, stirred overnight at RT, filtered through Hyflo and extracted with 3×40 ml of diethyl ether and the extract is washed with saturated NaCl solution, dried over Na2SO4 and evaporated.
Reaction SMILES: ClC1N=C(C2C=CC=CC=2)C2CCCC=2N=1.N[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1>CC(O)C>[C:22]([OH:24])(=[O:23])[C:21]1[CH:25]=[CH:26][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Clc1nc2c(c(-c3ccccc3)n1)CCC2
Solvent: CC(C)O
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Yield: 204.7 %

Procedure:
To a stirred mixture of 2-chloro-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (1.3 g, 5.4 mmol) in 2-propanol (30 mL) was added 4-aminobenzoic acid (0.82 g, 6.0 mmol) and the mixture was heated to reflux for 4 h. The mixture was cooled to rt and the precipitate was collected by filtration, washed with 2-propanol and dried to give the intermediate benzoic acid as a yellow solid (1.5 g, 84%). A portion of this intermediate (1.3 g, 3.9 mmol) was treated with 2,6-dimethylaniline (498 mg, 4.12 mmol), triethylamine (2.1 mL, 15 mmol) and HATU (1.91 g, 5.00 mmol) in dimethylformamide (10 mL). The stirred mixture was heated to 80° C. overnight, then cooled to rt. The reaction was diluted with ethyl acetate and extracted with water. The organic layer was washed with saturated sodium bicarbonate and concentrated on a rotary evaporator. The resulting residue was purified by preparative reverse phase HPLC to give N-(2,6-dimethylphenyl)-4-[(4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)amino]benzamide (1.18 g, 69%) as a light yellow solid. 1H NMR (400 MHz, CD3OD): δ 7.98 (m, 6H), 7.56 (m, 3H), 7.17 (m, 3H), 3.18 (m, 2H), 2.98 (m, 2H), 2.25 (s, 6H), 2.17 (m, 2H). MS (EI) for C28H26N4O: 435.2 (MH+).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[O:7]1[CH2:12][CH2:11]C(C(O)=O)[CH2:9][CH2:8]1>CN(C=O)C.C(Cl)Cl>[O:7]1[CH2:12][CH2:11][CH:1]([C:2]([Cl:4])=[O:3])[CH2:9][CH2:8]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1CCOCC1
Reaction time: 1.5 h

Procedure:
Oxalyl chloride (170 μL, 1.94 mmol) and DMF (2 drops) were added to a solution of tetrahydro-2H-pyran-4-carboxylic acid (84 mg, 0.64 mmol) in DCM (4 mL) and stirred for 1.5 hours. The reaction was concentrated under vacuum affording tetrahydro-pyran-4-carbonyl chloride. This was used with no further purification or analysis.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:15][CH:14]=3)[CH:8]=2)[C:3]=1[OH:28].[CH2:29](Br)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>CCOCC>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:17][CH:18]=3)[CH:8]=2)[C:3]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCOc1ccc(-c2ccc3c(O)c(F)c(F)cc3c2)cc1
Reactant: CCCCCCCCBr
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(-c2ccc3c(OCCCCCCCC)c(F)c(F)cc3c2)cc1

Procedure:
From 2,3-difluoro-6-(4-octyloxyphenyl)naphthalen-1-ol and 1-octyl bromide by means of the Williamson ether synthesis.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:6].Cl.NO>C(O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[O:6][N:2]=[CH:3][C:4]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:8][CH:9]=1
Reactant: CN(C)C=C(C(=O)c1ccc(Cl)cc1)c1ccncc1
Agent: Cl
Agent: NO
Solvent: CCO
Product: Clc1ccc(-c2oncc2-c2ccncc2)cc1
Temperature: 25 °C
Yield: 100.2 %

Procedure:
A solution of 3-dimethylamino-1-(4-chlorophenyl)-2-(pyridin-4-yl)-2-propen-1-one (22.80 g, 79.7 mmol), hydroxylamine hydrochloride (18.01 g, 0.26 mole), and 150 mL ethanol was heated to reflux for 30 minutes. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was dissolved in 1N hydrochloric acid and then treated with an aqueous saturated solution of sodium bicarbonate. The precipitates were collected by filtration, washed with water and ethanol, and dried to yield 5-(4-chlorophenyl)-4-(pyridin-4-yl)isoxazole (20.50 g, 93%). m.p. 120.8-120.9° C. 1H NMR (CDCl3/CD3OD/300 MHz) δ 8.53 (d, 2H), 8.46 (s, 1H), 7.51 (d, 2H), 7.41-7.34 (m, 4H). ESLRMS m/z 257 (M+H). ESHRMS m/z 257.0457 (M+H, C14H2N2OCl requires 257.0482).
Reaction SMILES: [CH2:1]([CH:8]1[C:13](=O)[CH2:12][CH2:11][CH2:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([CH3:27])[CH:21]=[CH:20][C:19]([S:22]([NH:25][NH2:26])(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>CO>[C:16]1([CH3:27])[CH:17]=[CH:18][C:19]([S:22]([NH:25][N:26]=[C:13]2[CH2:12][CH2:11][CH2:10][C:9](=[O:15])[CH:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:23])=[O:24])=[CH:20][CH:21]=1
Reactant: O=C1CCCC(=O)C1Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Agent: Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NN=C2CCCC(=O)C2Cc2ccccc2)cc1
Reaction time: 48 h
Yield: 15.8 %

Procedure:
1-benzyl cyclohexane-2,6-dione (17.25 g), p-toluenesulfonylhydrazine (16.52 g) in methanol (290 ml) was treated with concentrated HCl (1 ml) and left at room temperature for 48 hours. Evaporation of the solvent under reduced pressure and crystallization of the residue gave 1-benzylcyclohexane-2,6-dione mono-p-toluenesulfonylhydrazone (5 g) m.p. 172°-3° C.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH:4]([N:8]1[C:12](=[O:13])[CH:11]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[CH:19][CH:18]=2)[NH:10][C:9]1=[O:30])[CH:5]([CH3:7])[CH3:6].Cl>>[F:29][C:25]1[CH:24]=[C:23]([C:20]2[CH:19]=[CH:18][C:17]([CH2:16][O:15][CH2:14][CH:11]3[C:12](=[O:13])[N:8]([CH:4]([CH:5]([CH3:6])[CH3:7])[C:3]([OH:31])=[O:2])[C:9](=[O:30])[NH:10]3)=[CH:22][CH:21]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)C(C(C)C)N1C(=O)NC(COCc2ccc(-c3cccc(F)c3)cc2)C1=O
Agent: Cl
Product: CC(C)C(C(=O)O)N1C(=O)NC(COCc2ccc(-c3cccc(F)c3)cc2)C1=O
Yield: 46 %

Procedure:
A mixture of the compound obtained in step b above (20b) (374 mg, 0.874 mmol) and 2 N HCl (15 mL) was refluxed for 2 h. The reaction mixture was cooled down and then extracted with EtOAc. The combined organic layer was dried and concentrated; the crude product was purified by silica gel column chromatography to give the title compound as colorless oil (166 mg, 46%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([O:13][CH3:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]1[C:27](O)=[O:28])(=O)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.O>[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]1[C:27]([NH:1][C:2]1[S:3][C:4]([O:13][CH3:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1)=[O:28]
Reactant: CC(=O)n1c(C(=O)O)cc2ccccc21
Reactant: COc1sc(N)nc1-c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1sc(NC(=O)c2cc3ccccc3[nH]2)nc1-c1ccccc1
Temperature: 25 °C

Procedure:
3.15 g of 2-amino-5-methoxy-4-phenylthiazole are dissolved in 60 ml of CH2Cl2. 3.26 g of 1-acetylindole-2-carboxylic acid, 8.12 g of BOP and 1.86 g of triethylamine are added, and the reaction mixture is stirred at room temperature for one week. 50 ml of water are added and the organic phase is decanted, dried over Na2SO4, filtered and concentrated under vacuum. The residue is taken up in 100 ml of methanol, and 10 g of K2CO3 are added and the mixture is stirred overnight at room temperature. The mixture is concentrated under vacuum, and the residue is taken up in water, and the precipitate formed is separated by filtration and washed with CH2Cl2.