Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1)=[O:4].C([N:29]=[C:30]=[S:31])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:30]([NH2:29])=[S:31])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCC(N)CC1
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Product: COC(=O)C1CCC(NC(N)=S)CC1
Yield: 26.7 %

Procedure:
4-Thioureido-cyclohexanecarboxylic acid methyl ester (150 mg) compound was prepared following general procedure D using 4-Amino-cyclohexanecarboxylic acid methyl ester (500 mg, 11.0 mmol), and Fmoc-isothiocyanate (730 mg). Purification: (Silica gel, ethyl acetate/hexane 1:1). LCMS m/z: 217.0 (M+1)+.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[C:14]1([CH3:23])[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:22]([CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([CH3:23])=[CH:15][CH:16]=1)[CH2:11]2
Reactant: Cc1ccc(CCN)cc1
Reactant: COC(=O)c1c(I)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(CCN2Cc3cccc(I)c3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.107 g, 0.3 mmol), 2-p-tolyl-ethylamine (0.072 mL, 0.5 mmol), and K2CO3 (0.083 g, 0.6 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-(2-p-tolyl-ethyl)-2,3-dihydro-isoindol-1-one (0.060 g, 53%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.28 (s, 3H), 2.94 (t, 2H), 3.81 (t, 2H), 4.76 (s, 2H), 7.12-7.36 (m, 6H), 7.86 (d, 1H). GC-MS: m/z 377 (M)+, 272(M−105)+.
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].[Cl:10][C:11]1[N:16]=[C:15](Cl)[CH:14]=[CH:13][N:12]=1.CN1C(=O)CCC1>O>[Cl:10][C:11]1[N:16]=[C:15]([NH:1][C:2]([CH3:9])([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4])[CH:14]=[CH:13][N:12]=1
Reactant: CCC(C)(N)C(=O)OC
Reactant: Clc1ccnc(Cl)n1
Solvent: CN1CCCC1=O
Solvent: O
Product: CCC(C)(Nc1ccnc(Cl)n1)C(=O)OC
Temperature: 80 °C
Yield: 98.1 %

Procedure:
A 250 mL flask was charged with methyl 2-amino-2-methylbutanoate (8.4 g, 54.4 mmol), 2,4-dichloropyrimidine (8.9 g, 59.8 mmol), TEA (5.5 g, 54.4 mmol) and 80 mL NMP. The reaction mixture was heated to 80° C. for ˜18 hours. After cooling, water (300 mL) was added and the mixture extracted with MTBE. The organic extracts were washed with water and dried over sodium sulfate. Filtration and evaporation under vacuum afforded 13 g of an orange oil which was purified by flash chromatography, (0-100% ethyl acetate-hexane affording 4.6 g (34%) methyl 2-((2-chloropyrimidin-4-yl)amino)-2-methylbutanoate as an oil. 1H NMR: (CDCl3) δ 8.05-7.88 (m, 1H), 6.28 (δ, 1H), 5.95 (δ, 1H), 4.2-4.0 (μ, 1H), 3.86 (m, 1H), 2.46 (m, 1H), 2.10 (m, 1H), 2.01 (m, 1H), 1.72 (m, 3H), 0.89 (m, 3H). m/e, m+1 244.1
Reaction SMILES: [C:1]1([C:7]2[N:12]=[N:11][C:10](O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)([Br:16])=O>C1(C)C=CC=CC=1>[Br:16][C:10]1[N:11]=[N:12][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][CH:9]=1
Reactant: Oc1ccc(-c2ccccc2)nn1
Reactant: O=P(Br)(Br)Br
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccccc2)nn1
Temperature: 90 °C
Yield: 31.8 %

Procedure:
6-Phenylpyridazin-3-ol (5.0 g, 29.06 mmol) is dissolved in toluene (100 mL) and heated to 90° C. Phosphorous oxybromide (25 g, 87.19 mmol) is added in several portions and the reaction is heated for 30 minutes. The resulting yellow solution is cooled to room temperature, poured onto ice water, and extracted with ethyl acetate. The organic layers are further washed with water and 1M sodium hydroxide, dried over magnesium sulfate, filtered, and evaporated to a yellow solid. Recrystallization from CHCl3 gives 2.17 g of 3-bromo-6-phenylpyridazine.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]([NH:20][NH2:21])=[O:19])[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.O.CN(C)[CH:32]=[O:33]>>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:19][C:32]([OH:33])=[N:21][N:20]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CN(C)C=O
Reactant: CSc1ccc(-c2coc3ccc(C(=O)NN)cc23)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: CSc1ccc(-c2coc3ccc(-c4nnc(O)o4)cc23)cc1
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 3-[4-(methylthio)phenyl]-1-benzofuran-5-carbohydrazide (0.25 g, 0.83 mmol) and triethylamine (0.17 mL, 1.25 mmol) in N,N-dimethylformamide (5 mL) was added N,N′-carbonyldiimidazole (0.27 g, 1.68 mmol) at 0° C., and the resulting mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (0.20 g, yield 74%) as colorless crystals.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([OH:13])[C:10]3[CH2:14][CH2:15][CH2:16][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][O:13][C:11]2[C:10]3[CH2:14][CH2:15][CH2:16][C:9]=3[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:12]=2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Oc1nc(-c2ccccc2)nc2c1CCC2
Product: Fc1ccc(COc2nc(-c3ccccc3)nc3c2CCC3)cc1

Procedure:
The title compound was prepared from 2-phenyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ol (which was obtained in Intermediate 5) and 4-fluorobenzyl bromide according to Method A; LC retention time 3.26 min; MS: m/z (ESI) 321 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][C:19]2[CH:23]=[C:22](OC(C)C)[NH:21][N:20]=2)=[N:4][C:5]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)[CH3:10])=[N:6][CH:7]=1.Cl[C:29]1N=C(NC2C=C(C)NN=2)C(Cl)=CN=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:1][C:2]1[C:3]([NH:18][C:19]2[CH:23]=[C:22]([CH3:29])[NH:21][N:20]=2)=[N:4][C:5]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)[CH3:10])=[N:6][CH:7]=1
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)ncc2Cl)n[nH]1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)ncc2Cl)n[nH]1
Temperature: 160 °C
Yield: 135.2 %

Procedure:
A mixture of (S)-1-(5-fluoropyridin-2-yl)ethanamine (Method 6; 146 mg, 1.04 mmol), 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 38; 244 mg, 1.04 mmol) and DIEA (0.39 ml) in n-BuOH (3 ml) was charged into a microwave reaction vessel. The vessel was sealed and heated in microwave reactor at 160° C. for 6 hrs. The solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% acetonitrile/H2O, 15 min) to give the title compound as solid (489 mg). 1H NMR: 12.02 (s, 1H), 8.50 (d, 1H), 7.87-7.97 (m, 114), 7.64 (ddd, 1H), 7.33-7.46 (m, 1H), 5.85 (s, 1H), 4.75-5.24 (m, 1H), 2.16-2.21 (m, 3H), 1.45 (d, 3H); m/z 349.
Reaction SMILES: S(Cl)(Cl)=O.O[CH2:6][CH2:7][NH:8][C:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=1)=[O:10].C(OCC)C.[OH-].[Na+]>CO>[O:10]1[CH2:6][CH2:7][N:8]=[C:9]1[C:11]1[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(C(=O)NCCO)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Solvent: CO
Product: O=C(O)c1ccc(C2=NCCO2)cc1
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
2.2 ml of thionyl chloride was added to 2.23 g of methyl 4-(2-hydroxyethyl)aminocarbonylbenzoate. The mixture was stirred for 15 minutes. Thereto was added 10 ml of diethyl ether. The reaction mixture was added to 20 ml of a 5N aqueous sodium hydroxide solution being cooled with an ice-methanol cryogen. The mixture was stirred for a while. The resulting precipitate was collected by filtration and water-washed to obtain a white powder. The powder was dissolved in 20 ml of methanol. Thereto was added 4 ml of 5N sodium hydroxide. The mixture was stirred at 40° C. for 15 minutes and then concentrated under reduced pressure. To the residue was added ice water. The mixture was made acidic with acetic acid. The resulting crystals were collected by filtration, washed with water and methanol in this order, and dried to obtain 1.6 g of 4-(2-oxazolin-2-yl)benzoic acid as a white powder.
Reaction SMILES: [CH:1]1([C:4]([N:6]([CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=2[C:20]2[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[C:22]([CH:28]([CH3:32])[C:29](O)=[O:30])[CH:21]=2)[CH2:7][CH3:8])=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.C(Cl)(=O)C([Cl:43])=O>C(Cl)Cl.CN(C=O)C>[CH:1]1([C:4]([N:6]([CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=2[C:20]2[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[C:22]([CH:28]([CH3:32])[C:29]([Cl:43])=[O:30])[CH:21]=2)[CH2:7][CH3:8])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C(=O)O)ccc1OC)C(=O)C1CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C(=O)Cl)ccc1OC)C(=O)C1CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To 2-{2′-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-propionic acid (0.096 g, 0.21 mmol) and triethylamine (0.04 mL, 0.26 mmol) in CH2Cl2 (2 mL) at 0° C. was added oxalyl chloride (0.02 mL, 0.26 mmol), followed by DMF (2 drops), and the reaction was stirred at 0° C. for 1.5 hours. The mixture was concentrated to give the title compound.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br.Br.Br.[CH2:18]([C:20]1[C:21]([C:28]2[CH:36]=[C:35]3[C:31]([C:32]([C:37]4[NH:38][C:39]5[CH2:44][CH2:43][NH:42][CH2:41][C:40]=5[N:45]=4)=[N:33][NH:34]3)=[CH:30][CH:29]=2)=[CH:22][C:23]([F:27])=[C:24]([OH:26])[CH:25]=1)[CH3:19]>>[CH2:18]([C:20]1[C:21]([C:28]2[CH:36]=[C:35]3[C:31]([C:32]([C:37]4[NH:38][C:39]5[CH2:44][CH2:43][N:42]([CH2:13][C:10]6[CH:11]=[CH:12][C:7]([N:1]7[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]7)=[N:8][CH:9]=6)[CH2:41][C:40]=5[N:45]=4)=[N:33][NH:34]3)=[CH:30][CH:29]=2)=[CH:22][C:23]([F:27])=[C:24]([OH:26])[CH:25]=1)[CH3:19]
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Reactant: O=Cc1ccc(N2CCCCC2)nc1
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(Cc3ccc(N5CCCCC5)nc3)C4)n[nH]c2c1
Yield: 30.3 %

Procedure:
The title compound was prepared from 3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbaldehyde (38 mg, 198 μmol) and 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 132 μmol) using the method of Example 22. The crude material was purified by HPLC Method A to afford 22.1 mg of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[C:19](S(C3C=CC=CC=3)(=O)=O)[CH:18]=[CH:17][C:16]=2[O:30][CH2:31][CH2:32]Br)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:34]1([S:40](C2C=CC3OCCN(C4CCNCC4)C=3C=2)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:34]1([S:40]([C:18]2[CH:19]=[CH:20][C:15]3[N:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH2:32][CH2:31][O:30][C:16]=3[CH:17]=2)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(S(=O)(=O)c3ccccc3)ccc2OCCBr)CC1
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)N(C1CCNCC1)CCO2
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)OCCN2C1CCNCC1

Procedure:
Similarly prepared using 4-[5-benzenesulfonyl-2-(2-bromo-ethoxy)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester, was 6-Benzenesulfonyl-4-piperidin-4-yl-3,4-dihydro-2H-benzo[1,4]oxazine, MS: 359 (M+H)+, mp: 147.0-149.8° C.
Reaction SMILES: Br[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:7]([CH2:9][N:10]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[N:12]([CH:19]([CH3:21])[CH3:20])[C:11]3=[O:22])=[N:8][C:4]=2[CH:3]=1.[CH2:30](C([Sn])=C(CCCC)CCCC)[CH2:31]CC>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:19]([N:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:10]([CH2:9][C:7]2[N:6]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:5]3[CH:28]=[CH:29][C:2]([CH:30]=[CH2:31])=[CH:3][C:4]=3[N:8]=2)[C:11]1=[O:22])([CH3:21])[CH3:20]
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(Br)ccc21
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=Cc1ccc2c(c1)nc(Cn1c(=O)n(C(C)C)c3ccccc31)n2CCC(C)C
Yield: 32.3 %

Procedure:
A mixture of 1-[5-bromo-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one (90 mg, 0.2 mmol), tributylvinyltin (76 mg, 0.24 mmol) and tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol) in toluene (4 mL) was heated to reflux for 4 h. After cooling, the reaction mixture was diluted with EtOAc and washed with sat. NaHCO3 and brine. The organic layer was dried over MgSO4 and evaporated. The residue was purified by flash chromatography (hexanes:EtOAc 4:1 to 2:1) to give 26 mg (32%) of 1-isopropyl-3-[1-(3-methyl-butyl)-5-vinyl-1H-benzoimidazol-2-ylmethyl]-1,3-dihydro-benzoimidazol-2-one as a off-white solid.
Reaction SMILES: [Mg].[CH:2](Br)=[CH2:3].[CH2:5]([O:21][CH2:22][CH:23]=[O:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl>O1CCCC1.BrC(Br)C.CCOCC>[CH2:5]([O:21][CH2:22][CH:23]([OH:24])[CH:2]=[CH2:3])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C=CBr
Reactant: CCCCCCCCCCCCCCCCOCC=O
Agent: CC(Br)Br
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC(O)COCCCCCCCCCCCCCCCC
Temperature: 0 °C
Yield: 41.5 %

Procedure:
To a stirring mixture of 5.67 g of magnesium in 25 ml of tetrahydrofuran was added 10 drops of dibromoethane as an initiator. After the reaction began another 100 ml of tetrahydrofuran was added followed by the dropwise addition of a solution of 49.85 g of vinyl bromide in 250 ml of tetrahydrofuran at a rate to maintain reflux. After all of the magnesium had reacted, the solution was cooled to 0° C. and a solution of 44.2 g of (hexadecyloxy) acetaldehyde, prepared by the procedure of Example 3, in 175 ml of ether was added dropwise over 1/2 hour. After 1 hour at room temperature dilute hydrochloric acid was added. The tetrahydrofuran was removed and the residue was extracted with ether. The ether layer was washed with brine, dried and the solvent removed. The residue was purified by HPLC [hexane: ether (9:1), two columns, two passes] giving an oil which was distilled via a Kugelrohr apparatus (185°-190° C., 0.2 mm) giving a colorles oil which solidified on standing to give 20.17 g of the desired compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:28][NH:29][CH3:30]>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][N:29]([CH3:30])[CH3:28])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=1
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CN(C)C[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 57 using [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), N-methylmethanamine (0.5 ml, 2.0 M in MeOH), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 305 (M+, 0.4), 85 (2), 84 (3), 63 (2), 59 (4), 58 (bp).
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5].O[C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)([CH3:16])[CH3:15])=[CH:10][CH:9]=1.[C:24](=[O:27])([O-])[O-].[K+].[K+].[I-].[K+]>CSC>[CH3:5][C:4]([CH3:6])=[CH:3][CH2:2][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:27][CH2:24][CH:3]=[C:4]([CH3:6])[CH3:5])=[CH:9][CH:10]=2)([CH3:16])[CH3:15])=[CH:18][CH:19]=1
Reactant: CC(C)=CCBr
Reactant: O=C([O-])[O-]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [I-]
Agent: [K+]
Solvent: CSC
Product: CC(C)=CCOc1ccc(C(C)(C)c2ccc(OCC=C(C)C)cc2)cc1
Temperature: 40 °C
Reaction time: 10 h
Yield: 80.7 %

Procedure:
After a 300-ml flask was charged with 17.9 g (0.12 mol) of 1-bromo-3-methyl-2-butene and 11.4 g (0.05 mol) of bisphenol A to dissolve them in 100 ml of DMS, 16.6 g (0.12 mol) of anhydrous potassium carbonate and 19.9 g (0.12 mol) of potassium iodide were added, and the mixture was stirred for 10 hours at 40° C. Thereafter, the reaction mixture was cooled, and salts formed were removed by filtration, and the filtrate was concentrated. The resultant crude product was dissolved in 100 ml of dichloromethane, and the solution was washed each 3 times with a 5% aqueous solution of potassium hydroxide and saturated saline and dried over magnesium sulfate. The solvent was then distilled off to obtain 14.7 g of bisphenol A bis(3-methyl-2-butenyl) ether [the formula (70)].
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[CH:5]=1.N([C:16]1[NH:17][CH2:18][CH2:19][N:20]=1)[N+]([O-])=O>C1(C)C(C)=CC=CC=1>[Cl:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[CH:3]([OH:11])[CH2:2][NH:1][C:16]1[NH:20][CH2:19][CH2:18][N:17]=1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: O=[N+]([O-])NC1=NCCN1
Solvent: Cc1ccccc1C
Product: OC(CNC1=NCCN1)c1cccc(Cl)c1

Procedure:
A mixture of 9.5 parts of α-(aminomethyl)-m-chlorobenzyl alcohol, 7.15 parts of 2-(nitramino)-2-imidazoline and 40 parts of xylene is stirred in an oil-bath at 150°-160°C. while a great part of the xylene is distilled off. The resulting residue is diluted with a few parts of acetone and the product is allowed to crystallize. It is filtered off and crystallized from 4-methyl-2-pentanone, yielding m-chloro-α-(2-imidazolin-2-ylaminomethyl)benzyl alcohol; m.p. 108.5°C.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([O:13]C(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].[C:21]([C:23]1[CH:31]=[CH:30][C:26](C(Cl)=O)=[CH:25][CH:24]=1)#[N:22].[CH2:32]([N:34]1[C:46]2[CH:45]=[CH:44][C:43]([NH2:47])=[CH:42][C:41]=2[C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH3:33]>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11](=[O:13])[C:26]2[CH:25]=[CH:24][C:23]([C:21]#[N:22])=[CH:31][CH:30]=2)[C@H:8]([C:18]([NH:47][C:43]2[CH:44]=[CH:45][C:46]3[N:34]([CH2:32][CH3:33])[C:35]4[C:40]([C:41]=3[CH:42]=2)=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: C=CCON=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)c2ccc(C#N)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, 4-cyanobenzoyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 43% purity by LC/MS. MS(ESI+): m/z=506.4.
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18](O)=[O:19])=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C(N1C=CN=C1)([N:24]1C=CN=C1)=O.[OH-].[NH4+]>CN(C=O)C>[CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([NH2:24])=[O:19])=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(N)=O)s1
Temperature: 60 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a solution of 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (100 mg, 0.33 mmol) in DMF (3 mL) was added 1,1′-carbonyldiimidazole (64 mg, 0.39 mmol). The resulting reaction mixture was stirred for 1 h at 60° C. and then treated with an ammonium hydroxide solution (490 μL, 3.3 mmol) and stirred for 1 h at room temperature. The reaction mixture was then evaporated. Purification by chromatography (silica, heptane:ethyl acetate=1:0 to 1:1) afforded the title compound (84 mg, 84%) as an off white solid. MS: m/e=306.1 [M+H]+.
Reaction SMILES: [N:1]#[C:2][Br:3].[CH3:4][NH:5][CH2:6][CH2:7][NH:8][CH3:9]>C1(C)C=CC=CC=1>[BrH:3].[CH3:4][N:5]1[CH2:6][CH2:7][N:8]([CH3:9])[C:2]1=[NH:1]
Reactant: CNCCNC
Reactant: N#CBr
Solvent: Cc1ccccc1
Product: Br
Product: CN1CCN(C)C1=N
Temperature: 25 °C

Procedure:
A solution of 52.9 of cyanogen bromide in 300 ml of toluene is added dropwise in the course of 1 hour to a solution of 44.1 g (0.5 mol) of N,N'-dimethyl-ethylenediamine in 300 ml of toluene, with stirring. The reaction mixture is stirred for a further two hours at 80°. The mixture is allowed to cool to room temperature and is filtered and the residue is washed with ether. The crude 1,3-dimethyl-2-imino-imidazolidine hydrobromide obtained after drying in vacuo melts at 153°-160°.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9](OCC)=[O:10])=O)=[CH:4][CH:3]=1.[CH3:16][NH:17][NH2:18]>C(O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]2[NH:18][N:17]([CH3:16])[C:9](=[O:10])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CNN
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Solvent: CCO
Product: Cn1[nH]c(-c2ccc(Cl)cc2)cc1=O
Temperature: 25 °C
Yield: 43.2 %

Procedure:
To a solution of ethyl 4-chlorobenzoylacetate (500 mg) in 4 ml of ethanol was added 202 mg of methylhydrazine and the resulting mixture was stirred over night at room temperature. The solvent was removed under reduced pressure and to the residue was purified by the use of silica gel column chromatography to give 199 mg of 3-(4-chlorophenyl)-1-methylpyrazoline-5-one.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:24][C:25](=[O:57])[NH:26][CH:27]([B:44]3[O:52][CH:51]4[C:46]([CH3:56])([CH:47]5[CH2:53][CH:49]([CH2:50]4)[C:48]5([CH3:55])[CH3:54])[O:45]3)[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([O:37]C(C)(C)C)=[O:36])[C:30]=3[O:42][CH3:43])[CH:21]=2)[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH2:16]1[C:17]2[C:22](=[CH:21][C:20]([CH2:24][C:25]([NH:26][CH:27]([B:44]3[O:52][CH:51]4[C:46]([CH3:56])([CH:47]5[CH2:53][CH:49]([CH2:50]4)[C:48]5([CH3:55])[CH3:54])[O:45]3)[CH2:28][C:29]3[C:30]([O:42][CH3:43])=[C:31]([CH:32]=[CH:33][CH:34]=3)[C:35]([OH:37])=[O:36])=[O:57])=[CH:19][CH:18]=2)[CH2:23][NH:15]1
Reactant: COc1c(CC(NC(=O)Cc2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(CC(NC(=O)Cc2ccc3c(c2)CNC3)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (0.60 mL, 8.08 mmol) was added to a solution of 5-{[2-(3-tert-Butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylcarbamoyl]-methyl}-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (0.285 g, 0.414 mmol) in CH2Cl2 (3.0 mL) under argon. The reaction was stirred at room temperature for 2 hr then concentrated in vacuo and carried to the next step without purification. ESI-MS m/z 533 (MH)+.