Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7](=O)([O-])[O-].[Na+].[Na+].[CH2:13](S)[CH2:14]CCCCCCCCCC>O>[C:1]([O:6][CH2:13][CH3:14])(=[O:5])[CH:2]=[CH2:3].[C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=C(C)C(=O)O
Reactant: CCCCCCCCCCCCS
Agent: [Na+]
Solvent: O
Product: C=C(C)C(=O)OC
Product: C=CC(=O)OCC

Procedure:
A monomer emulsion was formed from 1397 g ethyl acrylate, 386 g methyl methacrylate (as well as <2% by weight of total monomer of methacrylic acid, sodium carbonate and n-dodecylmercaptan) with 499 g DI water and 51.8 g anionic surfactant (30% active) which was emulsified with stirring. 9 g anionic surfactant (30% active) and 547 g DI water were charged to a 4L multi-neck flask fitted with mechanical stirring. The flask contents were heated to 75° C. under nitrogen. To the stirred kettle contents were added 67 g monomer emulsion followed by 0.02 g ferrous sulfate heptahydrate and 0.02 g tetrasodium salt of ethylenediamine-tetraacetic acid in 23.5 g DI water and sodium carbonate (<0.5% based on total monomer). Polymerization was initiated by the addition of 1.2 g sodium persulfate in 36 g DI water followed by 0.6 g sodium hydrosulfite in 5 g DI water. Gradual addition of the monomer emulsion was subsequently initiated. Separate solutions of 3.8 g APS in 160 g DI water and 1 g of D-Isoascorbic acid in 160 g DI water were fed concurrently with the monomer emulsion. After half of the monomer was fed, 55 grams of a 50% solution of ureido methacrylate was added to the remainder of the monomer emulsion. Total addition time for the three feeds was 90-100 minutes. Reactor temperature was maintained at 75° C. throughout the polymerization. 32 g DI water was used to rinse the emulsion feed line to the reactor. After completion of the monomer emulsion addition, the reactor was cooled from 75° C. to 60° C. as the residual monomer was reduced by additional redox pair addition. The polymer emulsion was neutralized to pH 8 with sodium hydroxide solution. Less than 2% by weight of anionic surfactant and preservative were then added. Final particle size was 150 nm and solids content was 50%. The polymer is designated Polymer A.
Reaction SMILES: CN1CCCCC1.[C:8]([O:12][C:13]([NH:15][CH:16]([C:20]([CH3:22])=[CH2:21])[C:17]([OH:19])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[C:31]([C:33]1[CH:43]=[CH:42][C:36]([O:37][CH2:38][CH:39]([NH2:41])[CH3:40])=[CH:35][CH:34]=1)#[N:32]>C(Cl)Cl.O>[C:8]([O:12][C:13]([NH:15][CH:16]([C:20]([CH3:22])=[CH2:21])[C:17]([NH:41][CH:39]([CH3:40])[CH2:38][O:37][C:36]1[CH:42]=[CH:43][C:33]([C:31]#[N:32])=[CH:34][CH:35]=1)=[O:19])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: C=C(C)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(N)COc1ccc(C#N)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCCCC1
Solvent: O
Solvent: ClCCl
Product: C=C(C)C(NC(=O)OC(C)(C)C)C(=O)NC(C)COc1ccc(C#N)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 15.7 %

Procedure:
0.5 g of N-methylpiperidine was added to a solution containing 1.1 g of 2-tert-butoxycarbonylamino-3-methyl-3-butenic acid dissolved in 40 ml of methylene chloride, at -20° C. After the mixture was stirred for 10 minutes at the same temperature, 0.7 g of isobutyl chloroformate was added to the mixture at -40° C., and stirred for 1 hour at -20° C. 1.9 g of 2-(4-cyanophenoxy)-1-methylethylamine was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The obtained crude crystal was purified by column chromatography on silica gel, thus obtaining 0.3 g of the desired product in the form of a colorless glutinous substance (yield: 32%).
Reaction SMILES: O[C:2]1([C:8]#[C:9][C:10]2[CH:29]=[CH:28][C:13]3[N:14]=[C:15]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]#[N:24])[CH2:16][C:17](=[O:19])[NH:18][C:12]=3[CH:11]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.IC1C=C(C2CC(=O)NC3C=C(C#CC4C=CC=CC=4)C=CC=3N=2)C=CC=1.C(C1(O)CCOCC1)#C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:5]1[CH2:4][CH:3]=[C:2]([C:8]#[C:9][C:10]2[CH:29]=[CH:28][C:13]3[N:14]=[C:15]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]#[N:24])[CH2:16][C:17](=[O:19])[NH:18][C:12]=3[CH:11]=2)[CH2:7][CH2:6]1
Reactant: N#Cc1cccc(C2=Nc3ccc(C#CC4(O)CCOCC4)cc3NC(=O)C2)c1
Agent: C#CC1(O)CCOCC1
Agent: O=C1CC(c2cccc(I)c2)=Nc2ccc(C#Cc3ccccc3)cc2N1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(C#CC4=CCOCC4)cc3NC(=O)C2)c1

Procedure:
Prepared from 3-[7-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile [prepared from 4-(3-iodophenyl)-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 11) (387 mg, 1.0 mmol) and 4-ethynyl-tetrahydro-pyran-4-ol [CAS-No. 57385-16-7] (315 mg, 2.5 mmol) according to the general procedure F. Obtained as a yellow solid (296 mg)] (50 mg, 0.13 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (16 mg).
Reaction SMILES: [OH:1][CH:2]([CH3:10])[CH2:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[S:9].[CH3:11][I:12]>CC(O)C>[IH:12].[CH3:10][CH:2]([OH:1])[CH2:3][N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[S:9][CH3:11]
Reactant: CC(O)CN1CCNC1=S
Reactant: CI
Solvent: CC(C)O
Product: CSC1=NCCN1CC(C)O
Product: I
Temperature: -10 °C

Procedure:
A solution composed of 32.0 g of 1-(2-hydroxypropyl)-2-imidazolidinethione, 250 ml of 2-propanol and 15 ml of methyliodide was stirred at reflux for 4 hours, then clarified, cooled at -10° C. and the solid collected, washed with 2-propanol, then ether and dried at 60° C. in vacuo, giving 52.7 g of α-methyl-2-(methylthio)-2-imidazoline-1-ethanol, hydroiodide, mp 114°-116° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7](O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C(Cl)(Cl)[Cl:16].O=S(Cl)[Cl:21]>C(Cl)Cl>[ClH:16].[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([Cl:21])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1
Reactant: OC(c1ccccc1)c1ccncc1
Reactant: O=S(Cl)Cl
Reactant: ClC(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: ClC(c1ccccc1)c1ccncc1

Procedure:
To a solution of 27.75 g (0.15 mol) of (4-pyridyl)benzyl alcohol and 200 ml of chloroform is run in dropwise, at room temperature, a solution of 15.25 ml (0.2 mol) of SOCl2 and 50 ml of CH2Cl2.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:10]=3[C:9]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[N:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]5)=[CH:23][CH:22]=4)=[CH:19][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([N:7]2[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:10]=3[C:9]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:25][N:26]=4)=[CH:19][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3cc4c(cn3)c3ccncc3n4-c3ccccc3)nc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-n2c3cnccc3c3cnc(Nc4ccc(N5CCNCC5)cn4)cc32)cc1

Procedure:
A solution of crude compound 372 in DCM (8 mL) was treated with trifluoroacetic acid (2.0 mL, 27 mmol) at room temperature for 2 h. After the volatiles were removed, the residue was subjected to reverse phase preparative HPLC (acetonitrile/H2O containing 0.1% TFA each, 40 min from 10 to 40%). Lyophilization provided compound 370 (12 mg) as a yellow solid (TFA salt). 1H NMR (500 MHz, CD3OD) δ ppm 9.46 (1 H, s), 8.80 (1 H, d, J=0.7 Hz), 8.65 (1 H, d, J=5.6 Hz), 8.53 (1 H, d, J=5.6 Hz), 8.05 (1 H, d, J=2.9 Hz), 7.90 (1 H, dd, J=9.3, 2.9 Hz), 7.77-7.83 (2 H, m), 7.68-7.76 (3 H, m), 7.24 (1 H, d, J=9.3 Hz), 7.14 (1 H, s), 3.46-3.53 (4 H, m), 3.40-3.46 (4 H, m). LCMS-ESI (POS), M/Z, M+1. Found 422.2.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:16]O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(OCC)C>[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:16][Cl:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCc1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: ClCc1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
40.0 g (0.33 mol) of thionyl chloride are added dropwise at room temperature to a suspension of 12.0 g (0.028 mol) of 3,4,5-trisbenzyloxybenzyl alcohol in 100 ml of diethyl ether. Heating is then carried out at reflux for 2 hours, resulting in a clear solution. After removal of excess thionyl chloride and solvent, the residue is recrystallised from isopropanol/hexane.
Reaction SMILES: [NH2:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([O:9]CC)=O.[C:12](OC)(OC)(OC)[CH2:13][CH2:14][CH3:15].C(O)(=O)C.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)C>[CH2:26]([N:33]1[C:7](=[O:9])[C:3]2[N:4]=[CH:5][S:6][C:2]=2[N:1]=[C:12]1[CH2:13][CH2:14][CH3:15])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCCC(OC)(OC)OC
Reactant: CCOC(=O)c1ncsc1N
Reactant: NCc1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: CCCc1nc2scnc2c(=O)n1Cc1ccccc1
Temperature: 90 °C

Procedure:
A mixture of ethyl 5-amino-1,3-thiazole4-carboxylate (prepared by the method of Golankiewicz and Januszczyk Tetrahedron 1985, 41, 5989-5994, 1 equiv), trimethyl orthobutyrate (2 equiv) and acetic acid (0.1 equiv) is heated at 90° C. for 3 h. Excess trimethyl orthobutyrate is removed by distillation. The residue is added to a solution of benzylamine (4.2 g, 40 mmol, 2 equiv) in ethanol (25 mL), and the resulting solution is heated at reflux for 18 h, then cooled and concentrated. The residue is triturated with EtOAc to provide 6-benzyl-5-propyl[1,3]thiazolo[5,4-d]pyrimidin-7(6H)-one (1-1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][NH:12][CH3:13])=[CH:5][NH:6]2.CNCC1C2C=CC=CC=2N2CCCC=12.[NH2:29][C:30]1[N:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38]([OH:40])=O)=[CH:32][CH:31]=1.Cl.O=C1NC2N=CC(/C=C/C(O)=O)=CC=2CC1>>[NH2:29][C:30]1[N:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38]([N:12]([CH2:11][C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])[NH:6][CH:5]=2)[CH3:13])=[O:40])=[CH:32][CH:31]=1
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Reactant: CNCc1c[nH]c2cccc(F)c12
Agent: CNCc1c2n(c3ccccc13)CCC2
Agent: Cl
Agent: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Product: CN(Cc1c[nH]c2cccc(F)c12)C(=O)/C=C/c1ccc(N)nc1
Yield: 35.4 %

Procedure:
According to the procedure of Example 24, except substituting 4-fluoro-3-(methylaminomethyl)-1H-indole (0.31 g, 1.74 mmole) for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene, and substituting (E)-3-(6-amino-pyridin-3-yl)acrylic acid (0.285 g, 1.74 mmole) for the (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride salt, the title compound (0.2 g, 36%) was prepared as a white powder: MS (ES) m/e 325 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11](S(C1C=CC(C)=CC=1)(=O)=O)[C:10]1[C:9]([C:31]([F:34])([F:33])[F:32])([O:26][Si](C)(C)C)[C:8]([F:36])([F:35])[CH2:7][CH2:6][C:5]2=1.[OH-].[K+].CCO>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[NH:11][C:10]1[C:9]([C:31]([F:32])([F:33])[F:34])([OH:26])[C:8]([F:35])([F:36])[CH2:7][CH2:6][C:5]2=1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4cc(Cl)c(Cl)cc42)CCC(F)(F)C3(O[Si](C)(C)C)C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: OC1(C(F)(F)F)c2[nH]c3cc(Cl)c(Cl)cc3c2CCC1(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.7 %

Procedure:
To a solution of 6,7-dichloro-2,2-difluoro-9-tosyl-1-(trifluoromethyl)-1-(trimethylsilyloxy)-2,3,4,9-tetrahydro-1H-carbazole (0.090 g, 0.2 mmol) in THF (5 mL), cooled to 0° C., KOH (0.064 g, 1.0 mmol) in H2O (2 mL), was added and the reaction mixture was slowly cooled to room temperature and stirred for an additional 30 min EtOH (2 mL) was added to the reaction mixture and stirred at 80° C. for 4 h, diluted with water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the crude compound which was purified by column chromatography [EtOAc-hexane (3:17) as eluant] to give the title compound (0.025 g, 31%). 1H NMR (500 MHz, CDCl3, in ppm) 8.26 (bs, 1H), 7.63 (s, 1H), 7.52 (s, 1H), 3.31 (d, J=3.5 Hz, 1H), 2.97-2.94 (m, 2H), 2.61-2.52 (m, 2H).
Reaction SMILES: [Na].[C:2]1([C:8](=[N:17][NH2:18])[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([CH2:25][C:26](OCC)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[C:19]1([C:25]2[C:26](=[O:27])[NH:18][N:17]=[C:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NN=C(C(=O)c1ccccc1)c1ccccc1
Reactant: CCOC(=O)Cc1ccccc1
Agent: [Na]
Solvent: CCO
Product: O=c1[nH]nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Yield: 30 %

Procedure:
Sodium (11.5 g) was allowed to react with ethanol and then benzilmonohydrazone (120 g) and ethyl phenylacetate (84 g) were added and the reaction mixture heated at reflux for 3 hours. The reaction was quenched in water and the suspension acidified. The resulting precipitate was separated and refluxed with acetonitrile, cooled and separated by filtration to obtain 4,5,6-triphenyl-2H-pyridazin-3-one (30 percent yield), m.p. 290°-292° C.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][CH2:11][NH:10][C:9]=2[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:26]([N:10]1[C:9]2[CH:14]=[C:5]([CH2:4][C:3]3[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:2]=3[Br:1])[CH:6]=[CH:7][C:8]=2[O:13][CH2:12][CH2:11]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: Brc1ccc(I)cc1Cc1ccc2c(c1)NCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc(I)cc1Cc1ccc2c(c1)N(Cc1ccccc1)CCO2
Temperature: 50 °C
Yield: 92.3 %

Procedure:
To a stirred solution of 6-(2-bromo-5-iodo-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (9.4 g, 21.86 mmol) in DMF (50 mL) was added potassium carbonate (6.04 g, 43.71 mmol), benzyl bromide (3.2 mL, 26.23 mmol) and the mixture was heated to 50° C. overnight. The reaction mixture was cooled to room temperature, quenched by the addition of water (100 mL), then extracted with ethyl acetate (3×50 mL). The organic layers were combined then washed with water (50 mL), brine (50 mL), dried over sodium sulfate, and concentrated to a residue which was purified by silica gel column chromatography to furnish 4-benzyl-6-(2-bromo-5-iodo-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (10.5 g).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[F:35][C:36]([F:50])([F:49])[C:37]1[CH:42]=[CH:41][C:40]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[CH:39][CH:38]=1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]([N:46]2[CH2:45][CH2:44][N:43]([C:40]3[CH:39]=[CH:38][C:37]([C:36]([F:49])([F:50])[F:35])=[CH:42][CH:41]=3)[CH2:48][CH2:47]2)=[O:18])[N:8]([C:6]([C:29]2[CH:28]=[CH:27][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH3:19])=[CH:31][CH:30]=2)=[O:7])[CH2:12]1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Product: CON=C1C[C@@H](C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, staring from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and 1-[4-(trifluoromethyl)phenyl]piperazine, the title compound was obtained in 89% purity by HPLC. MS(ESI+): m/z=565.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[O:28]1[CH2:33][CH2:32][CH:31]([C:34](O)=[O:35])[CH2:30][CH2:29]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34]([CH:31]5[CH2:32][CH2:33][O:28][CH2:29][CH2:30]5)=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: O=C(O)C1CCOCC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)C1CCOCC1

Procedure:
The title compound, white solid (29.5 mg, 81.6%), MS (ISP) m/z=444.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and tetrahydro-2H-pyran-4-carboxylic acid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][N:10]=[C:9]2[O:18][C:19]1[C:20]([F:29])=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[CH:22]2.[CH3:30][S:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]>CN(C=O)C>[F:29][C:20]1[C:19]([O:18][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH3:17])=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:37]4[CH2:38][CH2:39][N:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:35][CH2:36]4)[CH:7]=3)[N:12]=[CH:11][N:10]=2)=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[C:23]([CH3:28])[NH:24]2
Reactant: COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1OCCCBr
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1OCCCN1CCN(S(C)(=O)=O)CC1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 22.6 %

Procedure:
A solution of 6-(3-bromopropoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-7-methoxyquinazoline (0.3 g, 0.652 mmol) and 1-(methylsulphonyl)piperazine (0.322 g, 1.95 mmol), (prepared as described for the starting material in Example 2), in DMF (4 ml) was stirred at 80° C. for 2.5 hours. The volatiles were removed under vacuum and the residue was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride and methanol. The fractions containing the expected product were combined and evaporated. The residue was triturated under diethyl ether and the resulting solid was filtered, washed with diethyl ether and dried under vacuum to give 4-(4-fluoro-2-methylindol-5-yloxy)-7-methoxy-6-(3-(4-methylsulphonylpiperazin-1yl)propoxy)quinazoline (0.08 g, 23%).
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[N+:7]([O-])=O.C([Sn](CCCC)(CCCC)[C:15]1[N:16]=[CH:17][S:18][CH:19]=1)CCC>>[S:18]1[CH:19]=[C:15]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[NH2:7])[N:16]=[CH:17]1
Reactant: O=[N+]([O-])c1ccsc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Product: Nc1ccsc1-c1cscn1

Procedure:
This amine was prepared from 2-chloro-3-nitrothiophene using Protocols E and F except that 4-(tributylstannyl)thiazole was used. Method[1], MS (ESI) 183.0 [M+H], Retention time=0.518 min.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[N:6]=[C:5]([CH3:9])[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:3]1.[CH3:16][Mg]I.CI.[Mg].[Cl-].[NH4+]>C1C=CC=CC=1.C(OCC)C>[C:10]1([C:4]2[C:5]([CH3:16])([CH3:9])[NH:6][C:7](=[O:8])[N:2]([CH3:1])[N:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1nc(=O)n(C)nc1-c1ccccc1
Reactant: C[Mg]I
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CI
Solvent: CCOCC
Solvent: c1ccccc1
Product: CN1N=C(c2ccccc2)C(C)(C)NC1=O
Reaction time: 1 h

Procedure:
A hot solution of 2,5-dimethyl-6-phenyl-1,2,4-triazin-3(2H)-one (5 g) in benzene (60 ml) was added dropwise to a stirred solution of methylmagnesium iodide prepared from methyl iodide (17.5 g) and magnesium turnings (3 g) in diethyl ether (80 ml) at room temperature. The solution was refluxed under heating for 40 minutes and then allowed to stand for 1 hour at room temperature. The solution was treated with a saturated aqueous solution of ammonium chloride to decompose excess Grignard reagent. The organic layer was separated, dried over magnesium sulfate, treated with activated charcoal, and evaporated to dryness. The resultant solid was recrystallized from a mixture of diispropyl ether and chloroform to give 6-phenyl-2,5,5-trimethyl-4.5-dihydro-1,2,4-triazin-3(2H)-one (4.21 g), m.p. 128°~130° C.
Reaction SMILES: C(OC[N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:16]=[C:17]([CH:42]=[CH:43][CH:44]=2)[C:18]([NH:20][C@@H:21]([CH2:23][C:24]([N:26]2[CH2:31][CH2:30][C@@:29]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)([OH:32])[C:28]([CH3:41])([CH3:40])[CH2:27]2)=[O:25])[CH3:22])=[O:19])=[N:11]1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>O.CC#N>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([C@@:29]2([OH:32])[CH2:30][CH2:31][N:26]([C:24](=[O:25])[CH2:23][C@H:21]([NH:20][C:18](=[O:19])[C:17]3[CH:42]=[CH:43][CH:44]=[C:15]([C:12]4[N:11]=[N:10][NH:14][N:13]=4)[CH:16]=3)[CH3:22])[CH2:27][C:28]2([CH3:41])[CH3:40])=[CH:38][CH:37]=1
Reactant: C[C@H](CC(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1)NC(=O)c1cccc(-c2nnn(COCc3ccccc3)n2)c1
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](CC(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1)NC(=O)c1cccc(-c2nn[nH]n2)c1

Procedure:
Example 4 was prepared from 3-(2-(benzyloxymethyl)-2H-tetrazol-5-yl)-N—((R)-4-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-4-oxobutan-2-yl)benzamide using the conditions described in Example 2. MS (ESI+)=497.2 (M+H)+. 1H NMR (CD3OD, 500 MHz) (NMR shows several rotamers) δ ppm 8.55 (s, 0.6 H), 8.49 (s, 0.4 H), 8.23 (d, J=7.8 Hz, 0.6 H), 8.20 (d, J=7.8 Hz, 0.4 H), 8.05 (d, J=8.2 Hz, 0.6 H), 8.00 (d, J=7.8 Hz, 0.4 H), 7.75-7.66 (m, 1 H), 7.47 (d, J=8.7 Hz, 0.9 H), 7.36-7.28 (m, 2.1 H), 7.22 (d, J=8.7 Hz, 1 H), 4.64-4.48 (m, 1.4 H), 4.11 (dt, J=13.3, 2.5 Hz, 0.6 H), 4.05 (dd, J=12.8, 1.8 Hz, 0.6 H), 3.69-3.54 (m, 1.4 H), 3.13 (td, J=12.9, 3.4 Hz, 0.6 H), 3.10-3.03 (m, 1 H), 2.98 (dd, J=15.1, 6.0 Hz, 0.4 H), 2.70-2.56 (m, 1.6 H), 2.53 (dd, J=15.1, 7.3 Hz, 0.4 H), 1.58-1.48 (m, 1 H), 1.42 (d, J=6.9 Hz, 1.8 H), 1.36 (d, J=6.4 Hz, 1.2 H), 1.35-1.26 (m, 0.6 H), 0.90 (t, J=6.9 Hz, 0.4 H), 0.84 (s, 1.2 H), 0.84 (s, 1.2 H), 0.77 (s, 1.8 H), 0.69 (s, 1.8 H); HPLC Method: Inj. Vol.=5 uL; Start % B=10, 12 Min. 100%, 15 Min. 100%, Flow Rate=1 ml/min, Wavelength 1=220, Wavelength 2=254, Solvent A=0.05% TFA in H2O:MeCN (95:5), Solvent B=0.05% TFA in H2O:MeCN (5:95), Col-1: Sunfire C18 3.5 um, 4.6×150 mm; Retention Time=11.08 min., Col-2: Xbridge Phenyl 3.5 um, 4.6×150 mm; Retention Time=10.57 min.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=[O:8])=[CH:5][NH:4][N:3]=1.[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[CH:23]=[C:22]3[C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[N:13]=1.O>CN(C=O)C>[C:29]([C:22]1[C:21]2[C:25](=[CH:26][CH:27]=[C:19]([NH:18][C:14]3[N:15]=[C:16]([N:4]4[CH:5]=[C:6]([CH:7]=[O:8])[C:2]([CH3:1])=[N:3]4)[CH:17]=[CH:12][N:13]=3)[CH:20]=2)[N:24]([CH3:28])[CH:23]=1)(=[O:33])[CH:30]([CH3:32])[CH3:31]
Reactant: Cc1n[nH]cc1C=O
Reactant: CC(C)C(=O)c1cn(C)c2ccc(Nc3nccc(Cl)n3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(-c2ccnc(Nc3ccc4c(c3)c(C(=O)C(C)C)cn4C)n2)cc1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To a solution of 3-methyl-1H-pyrazole-4-carbaldehyde (273 mg, 2.48 mmol) in anhydrous DMF (5 mL) was added 60% NaH (130 mg, 3.25 mmol) at 0° C. After being stirred for 30 min at room temperature, it was cooled to 0° C. To this, was added intermediate 5 (542 mg, 1.65 mmol) and then stirred for 6 hours at 60° C. Quenching the reaction by addition of ice and 20 mL of water resulted precipitation of brown solids. The resulted solids were collected by filtration, rinsed with water and the dried in vacuo to provide the desired intermediate 6 as a brown solid (424 mg, 80%); MS (ESI) m/z 403 [M+H]+.