Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][C:18](OCC)=[O:19].B>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][OH:19]
Reactant: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2c(Br)cccc12
Agent: B
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of EXAMPLE 1A (1.85 g) in THF (50 mL) was added 1M borane.THF (30 mL). The mixture was stirred at room temperature for 16 hours, quenched with methanol (10 mL) and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5-25% ethyl acetate/hexanes.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1)([CH3:3])[CH3:2].[Cl:10][C:11]1[C:12]([CH3:21])=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1>>[Cl:10][C:11]1[C:12]([CH3:21])=[C:13]([S:17]([NH:9][C:6]2[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=2)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)c1csc(N)n1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(C(C)C)cs1
Yield: 48 %

Procedure:
The title compound was prepared from 4-isopropyl-1,3-thiazol-2-ylamine (METHOD I) and 3-chloro-2-methylbenzenesulfonyl chloride according to METHOD A, white foam, 80 mg (48% yield): HRMS Calcd (found) for C13H15ClN2O2S2 m/z 330.0263 (330.0257).
Reaction SMILES: Cl[CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH2:4]1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[N:16]1([CH2:2][CH:3]2[O:8][CH2:7][CH2:6][NH:5][CH2:4]2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C1CCNC1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Product: C1CCN(CC2CNCCO2)C1

Procedure:
By the use of 2-chloromethyl-4-benzylmorpholine and pyrrolidine, the reaction is similarly carried out as Reference example 2 to give 2-(1-pyrrolidinylmethyl)morpholine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH2:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][B-:19]([F:22])([F:21])[F:20].[CH2:23]([O+](CC)CC)[CH3:24].C(Cl)Cl.CO>C(Cl)Cl>[F:18][B-:19]([F:22])([F:21])[F:20].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](=[NH:14])[O:13][CH2:23][CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cccc(OCc2ccccc2)c1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CCOC(=N)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Under an atmosphere of argon 11.36 g of 3-benzyloxybenzamide were suspended in CH2Cl2 (200 ml) and 9.5 g triethyloxonium fluoroborate in CH2Cl2 (100 ml) were added dropwise on ice cooling. The reaction mixture was then stirred further 20 h at RT until completion of reaction according to TLC analysis (CH2Cl2/MeOH: 15/1). The solid which had formed was filtered off, washed with ether to give the desired ethyl m-benzyloxybenzimidate tetrafluoroborate as white crystals, mp 152°-154° C., which was used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23](=[O:37])[C:24]4[C:29]([C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:18])[CH:12]=3)[C:3]=12.N1C=CN=C1.CN(C=O)C.[CH3:48][C:49]([Si:52](Cl)([CH3:54])[CH3:53])([CH3:51])[CH3:50]>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23](=[O:37])[C:24]4[C:29]([C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([O:17][Si:52]([C:49]([CH3:51])([CH3:50])[CH3:48])([CH3:54])[CH3:53])[CH:16]=3)[C:3]=12
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cc(F)cc(O[Si](C)(C)C(C)(C)C)c2)c2c(N)ncnc21
Reaction time: 2 h
Yield: 92 %

Procedure:
To a stirred mixture of 3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one (example 40, 0.20 mmol) and imidazole (40.8 mg, 0.60 mmol) in DMF (1 ml) TBDMSCl (45.2 mg, 0.30 mmol) was added at RT and the mixture was stirred for 2 hrs. Additional imidazole (16 mg) and TBDMSCl (36 mg) were added and the mixture was stirred at the same temperature for further 2 hrs. Additional imidazole (27 mg) and TBDMSCl (121 mg) were added and the stirring was continued at room temperature overnight. The reaction mixture was diluted with DCM and washed with 0.5M HCl. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by filtration on silica gel cartridge (DCM to DCM:MeOH=95:5) to afford 3-(1-(4-amino-3-(3-((tert-butyldimethylsilyl)oxy)-5-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one (intermediate Q.1, 112 mg, 0.184 mmol, 92%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([C:30]3([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:16][N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[ClH:37]>>[ClH:37].[ClH:37].[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([CH:15]([C:30]3([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:16][N:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2ccc(-c3cccc(C#N)c3)cc2)C2(O)CCCCC2)CC1
Agent: Cl
Product: N#Cc1cccc(-c2ccc(C(CN3CCNCC3)C3(O)CCCCC3)cc2)c1

Procedure:
In an analogous manner to Example 135, step 4, 1-[1-(3′-cyano-111′-biphenyl-4-yl)-2-piperazin-1-ylethyl]cyclohexanol dihydrochloride was prepared from tert-butyl 4-[2-(3′-cyano-1,1′-biphenyl-4-yl)-2-(1-hydroxycyclohexyl)ethyl]piperazine-1-carboxylate. MS (ES) m/z 390.3 ([M+H]+); HRMS: calcd for C25H31N3O.2.00 HCl, 461.2001; found (ESI), 390.2532.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:17])[C:14]=1[O:15][CH3:16])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.C(OC([NH:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[C:31](O)=[O:32])=O)(C)(C)C.Cl.O1CCOCC1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:17][C:31]([CH:27]3[CH2:28][CH2:29][CH2:30][CH:26]3[NH2:25])=[O:32])[C:14]=1[O:15][CH3:16])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: COc1c(Cl)cc2c([nH]c3cnccc32)c1N
Reactant: CC(C)(C)OC(=O)NC1CCCC1C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: COc1c(Cl)cc2c([nH]c3cnccc32)c1NC(=O)C1CCCC1N
Temperature: 25 °C

Procedure:
6-chloro-7-methoxy-9H-β-carboline-8-ylamine and 2-tert-butoxycarbonylamino-cyclopentanecarboxylic acid were reacted using Method A. To this product was added 5 ml of 4N HCl/dioxane and the resulting mixture was allowed to stir at RT. The reaction was followed by LC-MS until completion. Evaporation was allowed to remove all the solvent which gave a crude HCl salt. The desired product was then purified by preparative HPLC. 1H-NMR (300 MHz, DMSO-d6): δ 1.68 (m, 1H), 1.84 (m, 2H), 2.06 (m, 2H), 2.20 (m, 1H), 3.46 (m, 1H), 3.67 (m, 1H), 3.89 (s, 3H), 8.24 (d, 2H), 8.61 (d, 1H), 8.72 (s, 1H), 8.78 (d, 1H), 9.19 (s, 1H), 10.58 (s, 1H), 13.20 (s, 1H). Retention Time (LC, method: ammonium acetate standard): 1.54 min. MS (M+H+): 359.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])#[N:2]>CCO.[Ni]>[NH2:2][CH2:1][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1C#N
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1CN
Yield: 66 %

Procedure:
A solution of tert-butyl trans-2-cyanocyclohexylcarbamate and Raney-Ni in absolute EtOH was stirred under H2 atmosphere (50 PSI) for 24 hours. Filtration and evaporation of the solvent followed by flash chromatography (SiO2, O-20% MeOH—CH2Cl2, gradient elution) provided the target compound, 14d, as a racemic mixture of trans isomers (286 mg, 66% yield): FIA (M+H) 229.33.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C(N(CC)CC)C.[F:16][C:17]([F:25])([C:21]([F:24])([F:23])[F:22])[C:18](Cl)=[O:19]>O1CCCC1>[C:1]([C:3](=[C:18]([OH:19])[C:17]([F:25])([F:16])[C:21]([F:24])([F:23])[F:22])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: O=C(Cl)C(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)=C(O)C(F)(F)C(F)(F)F
Temperature: 25 °C

Procedure:
To 20 ml of tetrahydrofuran, 3.39 g (30 mmol) of ethyl cyanoacetate and 6.06 g (60 mmol) of triethylamine were dissolved and stirred at room temperature. Successively, 5.47 g (30 mmol) of pentafluoropropionyl chloride was dropwise added and stirred for 5 hours at room temperature. However, formation of desired product could not be confirmed.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[NH:10][C:9](=O)[N:8]=[CH:7]2)([O-:3])=[O:2].P(Cl)(Cl)([Cl:18])=O>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[N:10]=[CH:9][N:8]=[C:7]2[Cl:18])([O-:3])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ncc2cc([N+](=O)[O-])c(Cl)cc2[nH]1
Product: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1Cl
Temperature: 0 °C

Procedure:
4.00 g of the above crystalline 6-nitro-7-chloro-quinazolone was refluxed with 15 mL of phosphoryl chloride for 2 h, then the reaction mixture was poured into ice water, filtered and dried to obtain the intermediate 6-nitro-4,7-dichloro-quinazoline; The intermediate was dissolved into 30 mL of isopropanol, and 3.00 g of 3-chloro-4-(m-fluoro-benzyloxy)-aniline was added. The reaction mixture was reacted under reflux for 2 h and a lot of solid was deposited, which was filtered and dried under vacuum to obtain the solid product of 6-nitro-7-chloro-4-amino substituted quinazoline (3.83 g).
Reaction SMILES: C([N:14]1[CH2:17][C:16]([CH2:19][N:20]([CH3:22])[CH3:21])([F:18])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[F:18][C:16]1([CH2:19][N:20]([CH3:22])[CH3:21])[CH2:17][NH:14][CH2:15]1
Reactant: CN(C)CC1(F)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CC1(F)CNC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 112.9 %

Procedure:
1-(1-Benzhydryl-3-fluoroazetidin-3-yl)-N,N-dimethylmethanamine (0.6 g, 1.0 eq.) was dissolved in ethanol. Pd(OH)2 (0.6 g) was added. The reaction mixture was stirred for 14 h at room temperature under H2 atmosphere. The solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford 300 mg of 1-(3-fluoroazetidin-3-yl)-N,N-dimethylmethanamine (68% yield), which was used in the next step without further purification.
Reaction SMILES: Cl.[CH:2]1([NH2:5])[CH2:4][CH2:3]1.[Na].[C:7]([NH:9][C:10](N)=[NH:11])#[N:8]>C(O)CCC.O>[C:7]([NH:9][C:10]([NH:5][CH:2]1[CH2:4][CH2:3]1)=[NH:11])#[N:8]
Reactant: N#CNC(=N)N
Reactant: NC1CC1
Agent: Cl
Agent: [Na]
Solvent: CCCCO
Solvent: O
Product: N#CNC(=N)NC1CC1
Yield: 62 %

Procedure:
9.36 g (0.1 mole) of cyclopropylamine hydrochloride and 8.9 g (0.1 mole) of the sodium salt of cyanoguanidine are suspended in 100 ml of n-butanol and 8 ml of water. The mixture is heated under reflux for 2 hours. The suspension is filtered and the filter cake is washed with 100 ml of n-butanol. The filtrate is evaporated under reduced pressure. The residual oil is taken up in 300 ml of acetonitrile. The mixture is heated to reflux, filtered hot and the filter cake is washed with acetonitrile. The filtrate is evaporated off and the oil obtained crystallizes slowly. 7.7 g of N-cyano-N'-cyclopropylguanidine are obtained. Yield: 62%. M.P.: 106° C. (isopropyl alcohol/diethyl ether).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[CH:18]=[CH:17]2)[C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:6].CI.Cl[CH2:27]Cl>CN(C)C=O>[CH3:3][N:4]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[CH:18]=[CH:17]2)[C:5]([N:7]([CH3:27])[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:6]
Reactant: CN(C(=O)Nc1cccnc1)c1ccc2c(ccn2C)c1
Reactant: ClCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C(=O)N(C)c1ccc2c(ccn2C)c1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a suspension of 80% sodium hydride (0.06 g; 2 mM) in dimethylformamide (5 ml), was added the monomethyl urea (E9) (0.5 g; 1.79 mM). After stirring at room temperature for 0.5 h, methyl iodide (0.12 ml; 1.93 mM) was added dropwise. Stirring was continued at room temperature for 1 h, then heated at 50° C. for 1 h. The reaction mixture was cooled in ice, then quenched with water. The mixture was then extracted with dichloromethane, washed with water, dried over sodium sulphate and evaporated to give the crude product (0.59 g). Chromatography on silica using dichloromethane as eluant afforded the title compound (0.31 g; 60%) which was recrystallised from cyclohexane to give a white solid (160 mg) m.p. 91°-92.5° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.[OH:27][CH:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1.O>CN(C=O)C>[OH:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[CH:14]=3)=[CH:5][CH:4]=2)[CH2:29]1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Reactant: OC1CCCNC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CN4CCCC(O)C4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 73.8 %

Procedure:
In DMF (3 ml) was dissolved (E)-N-[4—(chloromethyl)phenyl]-3—(4-methylphenyl)cinnamamide (200 mg), and to the mixture was added 3-hydroxypiperidine (168 mg). The mixture was stirred at room temperature for 13 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4—(3-hydroxypiperidino-methyl)phenyl]-3—(4-methylphenyl)cinnamamide (Compound 67) (174 mg) as colorless crystals.
Reaction SMILES: Br[C:2]1[N:3]([CH3:17])[CH:4]=[C:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:24]1(B(O)O)[CH2:26][CH2:25]1>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:24]1([C:2]2[N:3]([CH3:17])[CH:4]=[C:5]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])[N:6]=2)[CH2:26][CH2:25]1
Reactant: OB(O)C1CC1
Reactant: Cn1cc(C(=O)OCc2ccccc2)nc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(C(=O)OCc2ccccc2)nc1C1CC1
Temperature: 100 °C

Procedure:
Into a solution of benzyl 2-bromo-1-methyl-1H-imidazole-4-carboxylate (2.8 g, 9.49 mmol) in THF (40 ml) and water (20 ml), cesium carbonate (7.71 g, 23.7 mmol) and cyclopropyl boronic acid (1.22 g, 14.2 mmol) were added under argon atmosphere at RT. The resulting mixture was degassed and purged with argon for 10 min. Pd(PPh3)2Cl2 (0.332 g, 0.04 mmol) was added to the mixture and heated at 100° C. for 12 h. The reaction mixture was filtered through a celite bed and the filtrate was diluted with water and extracted with EtOAc. The organic layer was concentrated and purified by flash chromatography. Yield 1.1 g. 1H-NMR (400 MHz; CDCl3): δ 0.95-1.02 (m, 2H), 1.07-1.11 (m, 2H), 1.72-1.78 (m, 1H), 3.70 (s, 3H), 5.32 (s, 2H), 7.29 (s, 1H), 7.42-7.62 (m, 5H), LC-MS: [M+1]=257.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8]Cl)(=O)C.[OH:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=1>>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(=O)OCCCCCl
Product: O=C(O)c1ccc(OCCCCO)cc1
Yield: 70 %

Procedure:
The 4-hydroxyphenyl acrylate required can be obtained by selective monocleavage of hydroquinone bisacrylate using sodium methoxide analogously to DE 44 42 831 (corresponds to U.S. Pat. No. 5,654,471) in a yield of 91%. The monoacrylate is liquid at room temperature. The acid component to the above ester, 4-(4-acryloyloxybutoxy)benzoic acid, can be obtained by reacting 4-chlorobutyl acetate with methyl 4-hydroxybenzoate, hydrolyzing the resultant alkylated methyl ester to give free 4-(4-hydroxybutoxy)benzoic acid, and esterifying the latter on the hydroxybutoxy radical using acrylic acid. This acid melts at 124° C. (yield 70%) and can be converted into the acid chloride by conventional reaction with thionyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([F:17])[C:14]([NH2:18])=[CH:13][C:3]=1[O:4][C:5]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6]1.CN(C)C1C=CC=CC=1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30].Cl>C1COCC1>[Cl:1][C:2]1[CH:16]=[C:15]([F:17])[C:14]([NH:18][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:13][C:3]=1[O:4][C:5]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6]1
Reactant: CCOC(=O)C1(Oc2cc(N)c(F)cc2Cl)CC1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cc(OC2(C(=O)OCC)CC2)c(Cl)cc1F

Procedure:
The obtained ethyl 1-(2-chloro-4-fluoro-5-amino-phenoxy)cyclopropanecarboxylate (1 equivalent) and dimethylaniline (1 equivalent) are added to THF and ethyl chloroformate (1 equivalent) is gradually added in drops thereto. After completion of addition, to the reaction solution is added aqueous diluted hydrochloric acid and the mixture is extracted with ethyl acetate. After concentrating the organic layer, the residue is subjected to chromatography to give ethyl 1-(2-chloro-4-fluoro-5-ethoxycarbonylaminophenoxy)cyclo-propanecarboxylate.
Reaction SMILES: [CH3:1][NH+:2]1[CH2:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH2:4][CH2:3]1.[Cl-]>O.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][CH2:5][CH:6]([C:8]([OH:10])=[O:9])[CH2:7]1
Reactant: C[NH+]1CCC=C(C(=O)O)C1
Agent: [Pd]
Agent: [Cl-]
Solvent: O
Product: CN1CCCC(C(=O)O)C1
Reaction time: 0.08 h
Yield: 91.2 %

Procedure:
Arecaidine hydrochloride (4 grams) (22.6 mmoles) was hydrogenated in water (100 ml) using 10% Pd—C at 40 psi at 25° C. for 24 hours. The catalyst was filtered off and washed with water. The aqueous solution was shaken with BioRad AG1X8 resin (OH− form) (23 ml bed) and after 5 minutes the resin was filtered off and washed with water. The aqueous solution was evaporated to give the title compound (Yield: 2.95 grams, 92%).
Reaction SMILES: [Cl-].[Li+].C(O[C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1)CCCCCCC.[CH2:21]([C:27]1[CH:35]=[CH:34][C:30]([CH:31]2[O:33][CH2:32]2)=[CH:29][CH:28]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CN(C=O)C>[CH2:28]([C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:32][CH:31]([C:30]3[CH:34]=[CH:35][C:27]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:28][CH:29]=3)[O:33][C:19]2=[O:20])=[CH:16][CH:17]=1)[CH2:27][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCc1ccc(C2CO2)cc1
Reactant: CCCCCCCCOc1ccc(N=C=O)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(N2CC(c3ccc(CCCCCC)cc3)OC2=O)cc1
Temperature: 25 °C
Yield: 14.1 %

Procedure:
4 mg of lithium chloride and 1.0 ml of DMF were placed in a 20 ml-three necked flask. Under refluxing and stirring in nitrogen atmosphere, a solution of 0.97 g (3.92 mM) of 4-octyloxyphenyl isocyanate and 0.80 g (3.92 mM) of (-)-4-hexylstyrene oxide in 1.8 ml of DMF was added dropwise to the mixture in 5 minutes, followed by refluxing for 5 minutes under stirring. After the reaction, the reaction mixture was cooled to room temperature and poured into ice water to precipitate a crystal. The crystal was recovered by filtration, washed with water and dissolved in a toluene-ethyl acetate mixture solvent, followed by drying with anhydrous sodium sulfate and evaporation under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography and recrystallized from an acetone/methanol mixture solvent to obtain 0.25 g of optically active 3-(4-octylphenyl)-5-(4-hexylphenyl)-2-oxazolidinone (Yield: 14.1%). This compound showed the following phase transition series.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][NH2:12])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.[CH3:13][C:14]([CH3:21])([CH3:20])[C:15](=O)[CH2:16][C:17]#[N:18]>CCO>[C:14]([C:15]1[CH:16]=[C:17]([NH2:18])[N:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[NH:2][N:3]=[CH:4]3)[N:12]=1)([CH3:21])([CH3:20])[CH3:13]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1ccc2[nH]ncc2c1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2ccc3[nH]ncc3c2)n1
Yield: 60 %

Procedure:
A mixture of (1H-indazol-5-yl)-hydrazine hydrochloride and 4,4-dimethyl-3-oxo-pentanenitrile (19 g, 1.05 eq) in EtOH (200 mL) was heated at reflux overnight. The reaction was concentrated and the residue purified by column chromatography to yield 3-t-butyl-1-(1H-indazol-5-yl)-1H-pyrazol-5-amine (23 g, 60% for two steps). 1H NMR (300 MHz, DMSO-d6): δ 8.24 (s, 1 H), 8.06 (s, 1 H), 7.75 (d, J=9.0 Hz, 1 H), 7.45 (dd, J=9.0 Hz, 1.8 Hz, 1 H), 5.7 (s, 1H), 1.31 (s, 9 H); MS (ESI) m/z: 256 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([CH:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[OH:6])[CH:3]=[CH2:4].Br[CH2:15]Br>CCOCC.[Zn].[Cu]Cl>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([CH:5]([OH:6])[CH:2]([CH:3]2[CH2:15][CH2:4]2)[CH3:1])=[CH:8][CH:9]=1
Reactant: C=CC(C)C(O)c1ccc(Cl)cc1
Reactant: BrCBr
Agent: Cl[Cu]
Agent: [Zn]
Solvent: CCOCC
Product: CC(C1CC1)C(O)c1ccc(Cl)cc1
Yield: 72.7 %

Procedure:
3-Methyl-4-(4-chlorophenyl)but-1-en-4-ol (63.68 g, approximately 90% pure, approximately 292 mmol), dibromomethane (45.5 ml, 648 mmol), zinc dust (84.75 g, 1.296 mol) and copper(I) chloride (12.83 g, 130 mmol) in dry ether (180 ml) were heated under reflux in a sonic bath for 31/2 hours. The mixture was then filtered (celite) and the filtrate poured into 2M hydrochloric acid. The mixture was extracted with ether and the combined extracts washed with water, saturated aqueous sodium bicarbonate solution and water, dried and evaporated in vacuo. Chromatography [SiO2, hexane-ethyl acetate (100:0) to (80:20)] gave 1-(4-chlorophenyl)-2-cyclopropylpropan-1-ol (44.72 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[CH3:19][N:20]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:25][CH:22]1[CH2:23][CH2:24][N:20]([CH3:19])[CH2:21]1)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Reactant: CN1CCC(N)C1
Product: COc1ccc2nc3cc(Cl)ccc3c(NC3CCN(C)C3)c2c1

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 6,9-dichloro-2-methoxyacridine and 1-methylpyrrolidin-3-amine, the title compound was obtained; MS (Found M+1=356)
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9]CC)=[O:8].[OH-].[Na+].Cl>C(O)C.O>[CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1ccsc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1sccc1C(=O)O
Temperature: 0 °C
Yield: 0.1 %

Procedure:
Ethyl 2-methyl-3-thiophenecarboxylate (3.42 g, 20.09 mmol; see step (ii) above) was dissolved in ethanol (5 mL) to which was added a solution of sodium hydroxide (3.2145 mg, 80.362 mmol) in water (10 mL). The reaction mixture was heated under reflux for 2 h. The volume was reduced to half under reduced pressure at 40° C. and the residue was cooled with ice water. Dilute HCl was added dropwise with stirring until pH 2. The white solid material was filtered off, washed with water and dried under reduced pressure at 50° C. to give the required material (2.1850 mg, 77% yield), m.p. 115-117° C., lit. m.p. 116-117° C. (see D. W. Knight, A. P. Nott J. Chem. Soc., Perkin Trans. 1 791-794 (1983)).