Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:13][C:14]([O-:16])=[O:15].[Na+]>CN(C)C=O>[C:14]([OH:16])(=[O:15])[CH2:13][NH:9][C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C([O-])CBr
Reactant: NC(=O)c1ccccc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)c1ccccc1
Yield: 95.8 %

Procedure:
To 150 ml of N,N-dimethylformamide, were added 24 g of benzamide, 14 g of potassium hydroxide and 40 g of sodium bromoacetate. They were reacted at 60° C. for 4 hours with stirring. After the reaction, the reaction solution was treated in the same manner as in Example 65. The resulting distillation residue was recrystallized from distilled water, thereby obtaining 34 g of hippuric acid having a melting point of 187° C.(yield: 69%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH2:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([C:23]2([C:29](O)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1([C@H](CC)C(O)=O)C=CC=CC=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:29]([C:23]3([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:30])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Reactant: O=C(O)C1(c2ccccc2)CCCCC1
Agent: CC[C@H](C(=O)O)c1ccccc1
Product: O=C(N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)C1(c2ccccc2)CCCCC1

Procedure:
The title compound was prepared by substituting (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 33 for (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine and 1-phenylcyclohexanecarboxylic acid for (S)-2-phenylbutanoic acid in Step F of the procedure used to prepare Example 16: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.73 (d, J=8.2, 1H), 7.59 (s, 1H), 7.41 (d, J=7.4, 2H), 7.36 (td, J=2.7, 7.6, 4H), 7.26 (dd, J=6.0, 8.7, 2H), 4.45-4.33 (m, 1H), 3.58 (d, J=13.2, 1H), 3.40 (d, J=13.2, 1H), 2.81 (d, J=7.3, 1H), 2.68-2.59 (m, J=10.2, 2H), 2.41-2.31 (m, J=6.2, 14.8, 3H), 2.28 (d, J=8.8, 1H), 2.20-2.13 (m, 1H), 1.99 (dt, J=7.4, 14.8, 1H), 1.88-1.75 (m, J=9.0, 4H), 1.74-1.53 (m, J=8.8, 36.2, 4H), 1.50-1.40 (m, 1H), 1.36-1.20 (m, 2H); MS (ESI+) m/z 403 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:15])=O.CN(C=O)C>C(Cl)Cl>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:15])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(CBr)cc1
Reaction time: 1 h

Procedure:
4-bromomethylbenzoic acid (25 g, 116.25 mmol) was dissolved in CH2Cl2 (200 ml) and treated with oxalyl chloride (12.2 ml, 139.5 mmol). DMF (0.45 ml) was added slowly then stirred for 1 h. The solvent was removed to give the 4-bromomethylbenzoyl chloride as a white solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](C)=[N:9]2)=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH:20]=[CH2:21].F[C:23](F)(F)S(OC1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=CC=C2)(=O)=O>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:4]2[C:3]([CH:20]=[CH2:21])=[C:2]([CH3:23])[CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][CH:8]=[N:9]3)=[CH:14][CH:15]=1
Reactant: Cc1cc2ncccc2c(-c2ccc(Cl)cc2)c1OS(=O)(=O)C(F)(F)F
Reactant: C=Cc1c(Cl)cc2nc(C)ccc2c1-c1ccc(Cl)cc1
Product: C=Cc1c(C)cc2ncccc2c1-c1ccc(Cl)cc1

Procedure:
Compound 3G was prepared following the procedure used to prepare compound 1G of Example 1, except that 5-(4-chlorophenyl)-7-methylquinolin-6-yl trifluoromethanesulfonate (3F) was used instead of 1F. LCMS-ESI+ (m/z): 280.2, 282.2 (M+H)+.
Reaction SMILES: [Mg].[CH3:2][C:3]1([CH3:14])[C:12]2[C:7](=[C:8](I)[CH:9]=[CH:10][CH:11]=2)[O:6][CH2:5][CH2:4]1.CO[CH:17]=[C:18]=[CH2:19].[Cl-].[NH4+]>BrC(Br)C.C(OCC)C.[Cu]I>[CH3:2][C:3]1([CH3:14])[C:12]2[C:7](=[C:8]([CH2:19][C:18]#[CH:17])[CH:9]=[CH:10][CH:11]=2)[O:6][CH2:5][CH2:4]1
Reactant: C=C=COC
Reactant: CC1(C)CCOc2c(I)cccc21
Agent: [Cu]I
Agent: CC(Br)Br
Agent: [Cl-]
Solvent: CCOCC
Product: C#CCc1cccc2c1OCCC2(C)C
Temperature: 35 °C
Reaction time: 0.25 h

Procedure:
280 mg (11.5 mmol) of magnesium, activated with 1 drop of dibromoethane, are introduced into a three-necked flask under argon. A solution of 3.00 g (10.4 mmol) of 4,4-dimethyl-8-iodochroman in 15 ml of ethyl ether is added dropwise, so as to maintain the reflux of the solvent, and the reaction mixture is stirred at 35° C. for 15 minutes. It is subsequently cooled to −5° C., 40 mg (0.2 mmol) of CuI are added and a solution composed of 1.24 g (17.7 mol) of methoxyallene in 5 ml of ethyl ether is introduced dropwise. The mixture is stirred for one hour at −5° C., allowed to return to room temperature and stirred for two hours. The reaction mixture is poured onto a saturated ammonium chloride solution and extracted with ethyl acetate and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column eluted with heptane. After evaporating the solvents, 1.30 g (65%) of the expected compound are collected in the form of a yellow oil.
Reaction SMILES: Cl.C(OC(=O)C1C=CC(OC[CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[OH:23])[CH2:18][CH2:17]2)=CC=1)C.FC1C=CC(C(C2C=CC(F)=CC=2)(C2CCNCC2)O)=CC=1.BrCC[CH2:64][CH2:65][O:66][C:67]1[CH:72]=[CH:71][C:70]([C:73](=[O:75])[CH3:74])=[CH:69][C:68]=1[O:76][CH3:77].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CN(C)C=O>[F:37][C:34]1[CH:35]=[CH:36][C:31]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)([OH:23])[CH:19]2[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][CH2:64][CH2:65][O:66][C:67]3[CH:72]=[CH:71][C:70]([C:73](=[O:75])[CH3:74])=[CH:69][C:68]=3[O:76][CH3:77])[CH2:17][CH2:18]2)=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 35. A mixture of 3.0 g (0.01 mole) of α,α-bis(p-fluorophenyl)-4-piperidinemethanol, 3.0 g (0.01 mole) of 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone, 5.3 g (0.05 mole of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of dimethylformamide gave, after purification by column chromatography on Florasil® (acetone-benzene). 0.8 g (15%) of off-white powder, m.p. 104°-105° C. after recrystallization from 2-propanol-isopropyl ether.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[C:14]([C:15](=[O:16])[C:4]=2[CH:3]=1)=[CH:13][C:12]1[NH:17][C:18]2[CH:25]=[CH:24][C:23](C)=[CH:22][C:19]=2[C:20](=[O:21])[C:11]=1[CH:10]=3.N(CCO)(CCO)CCO>O>[CH:23]1[CH:22]=[C:19]2[C:20]([C:11]3[C:12]([NH:17][C:18]2=[CH:25][CH:24]=1)=[CH:13][C:14]1[C:15]([C:4]2[C:5]([NH:8][C:9]=1[CH:10]=3)=[CH:6][CH:7]=[CH:2][CH:3]=2)=[O:16])=[O:21]
Reactant: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1
Solvent: O
Solvent: OCCN(CCO)CCO
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Reaction time: 7 h

Procedure:
20 g of C.I. pigment red 122 (in which the content of metal ions having a valence of at least 2 was 400 ppm), 60 g of the same aqueous dispersion of the pigment derivative (g) as obtained in Example 43 and 60 g of deionized water were mixed, 9 g of 2% by weight triethanolamine was added so as to adjust the neutralization ratio of the pigment derivative to 100%, and the mixture was dispersed with a paint shaker in the presence of zirconia beads as media for approximately 7 hours, to obtain a water-based pigment dispersion.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:21]=[CH:22][N:23]([CH2:25][O:26][CH2:27][CH3:28])[CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:37](=[O:41])[CH:38]([F:40])[F:39].[Cl-].[NH4+]>C1COCC1>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:37](=[O:41])[CH:38]([F:40])[F:39])[N:23]([CH2:25][O:26][CH2:27][CH3:28])[CH:24]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)C(F)F
Reactant: CCOCn1cnc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOCn1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)nc1C(=O)C(F)F
Temperature: -78 °C
Reaction time: 17 h
Yield: 72.6 %

Procedure:
4-(tert-Butyldiphenylsilyloxymethyl)-1-ethoxymethyl-1H-imidazole (2.00 g) was dissolved in THF (10 mL), and was cooled to −78° C. while stirring under an argon atmosphere. To the present solution was added dropwise n-butyl lithium (2.69 M hexane solution, 3.18 mL) slowly using a syringe, followed by stirring at the same temperature for 30 minutes. Then, N-methoxy-N-methyl difluoroacetamide (1.41 g) was added using a syringe, and stirring was continued for 17 hours while the temperature was raised to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction solution to terminate the reaction, followed by extraction with ethyl acetate. The combined extract was washed with saturated brine, dried over anhydrous sodium sulfate, and subsequently the solvent was distilled off under reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate/hexane=0%→20%) using silica gel column (product name: SNAP Cartridge KP-Sil 50 g, manufactured by Biotage, Ltd.) to afford the title compound (1.74 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH3:12])[C:8](=[S:11])[NH:9][N:10]=1.IC.Cl[CH2:16]Cl.C([O-])(O)=O.[Na+]>C(O)C>[CH3:12][N:7]1[C:8]([S:11][CH3:16])=[N:9][N:10]=[C:6]1[CH2:5][CH2:4][CH2:3][CH2:2][OH:1]
Reactant: Cn1c(CCCCO)n[nH]c1=S
Reactant: ClCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CSc1nnc(CCCCO)n1C

Procedure:
5-(4-hydroxybutyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (1 g) was dissolved in ethanol (6 ml), Iodomethane (0.4 ml) was added dropwise and the reaction was refluxed for 1 h. Dichloromethane and NaHCO3 saturated solution were added. Solvent was removed under reduced to give a crude product that was purified by flash chromatography on silica gel (eluting with DCM/MeOH from 0 to 10%) to give the title compound (0.73 g).
Reaction SMILES: [N:1]([CH2:4][C:5]1([OH:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[N+:2]=[N-:3].[H-].[Na+].I[CH3:22]>O1CCCC1.O.C(OCC)(=O)C>[N:1]([CH2:4][C:5]1([O:18][CH3:22])[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:9][CH2:10]1)=[N+:2]=[N-:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CN=[N+]=[N-])CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC1(CN=[N+]=[N-])CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound prepared in Example 256 (0.123 g) in tetrahydrofuran (1.5 mL) was added sodium hydride (0.057 g) and iodomethane (0.089 mL) at room temperature. The mixture was stirred at room temperature overnight and then diluted with water and ethyl acetate. The organic layer was dried, evaporated in vacuo and purified by column chromatography on silica gel (5% methanol in dichloromethane) to obtain the title compound (0.071 g) having the following physical data.
Reaction SMILES: [NH:1]1[C:9]2[C:4]3[C:5](=[CH:10][CH:11]=[CH:12][C:3]=3[C:2]1=[O:13])[CH:6]=[CH:7][CH:8]=2.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19]Br>CN(C)C=O>[CH2:17]([N:1]1[C:9]2[C:4]3[C:5](=[CH:10][CH:11]=[CH:12][C:3]=3[C:2]1=[O:13])[CH:6]=[CH:7][CH:8]=2)[CH2:18][CH2:19][N:1]1[C:9]2[C:4]3[C:5](=[CH:10][CH:11]=[CH:12][C:3]=3[C:2]1=[O:13])[CH:6]=[CH:7][CH:8]=2
Reactant: BrCCCBr
Reactant: O=C1Nc2cccc3cccc1c23
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2cccc3cccc(c23)N1CCCN1C(=O)c2cccc3cccc1c23
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thirty four grams of benz[cd]indol-2(1H)-one is added with stirring to 500 ml of dry dimethylformamide. Ten grams of 50% sodium hydride (in oil) is added in portions, the reaction is stirred at room temperature for 1 hour, and then on a steam bath for one hour. A deep red/brown solution results. One hundred twenty grams of 1,3-dibromopropane is added in one portion, the red color disappears and a white suspension appears. The mixture is stirred and heated on a steam bath for 16 hours, concentrated to dryness and the residue dissolved in 250 ml of dichloromethane. The solution is passed through hydrous magnesium silicate and rinsed with 100 ml of dichloromethane; on standing at room temperature crystals formed. The solution is cooled to 0° C., collected and washed with 100 ml of hexane. After numerous fractional crystallizations, 12.6 g of (Bs) 1,1'-(1,3-propanediyl)bisbenz[cd]indol-2(1H)-one, mp. 161°-162° C. and (Bt) 1.4 g of 1-(3 -bromopropyl)benz[cd]indol-2(1H)-one, mp. 74°-76° C., is obtained.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:29])=[C:6]([C:10]2[NH:11][C:12]3[C:17]([C:18]=2[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:16][CH:15]=[C:14]([C:25]([O:27][CH3:28])=[O:26])[CH:13]=3)[CH:7]=[CH:8][CH:9]=1)[CH:2]=[CH2:3]>CCOC(C)=O.[Pd]>[CH:19]1([C:18]2[C:17]3[C:12](=[CH:13][C:14]([C:25]([O:27][CH3:28])=[O:26])=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH2:1][CH2:2][CH3:3])[C:5]=2[OH:29])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C=CCc1cccc(-c2[nH]c3cc(C(=O)OC)ccc3c2C2CCCCC2)c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1cccc(-c2[nH]c3cc(C(=O)OC)ccc3c2C2CCCCC2)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Methyl 2-(3-allyl-2-hydroxyphenyl)-3-cyclohexyl-1H-indole-6-carboxylate was dissolved in EtOAc (0.08M). After adding Pd/C (10%) HOAc was added and the mixture was degassed and flushed with Ar. After degassing, H2-atmosphere was applied and the mixture was left stirring at RT. After 30 min the reaction was complete and the catalyst was filtered off. After evaporation of the solvents the product was obtained as a yellowish solid (98%). (ES+) m/z 392 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][C:30]1([CH3:42])[O:34][C@H:33]([CH2:35][N:36]2[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]2)[CH2:32][O:31]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[N:24]=[C:23]([C:25]([F:26])([F:28])[F:27])[CH:22]=[CH:21][N:20]=3)[CH:13]=[N:12]2)[C:8]([NH:41][C:38]2[CH:39]=[CH:40][N:36]([CH2:35][C@@H:33]3[CH2:32][O:31][C:30]([CH3:42])([CH3:29])[O:34]3)[N:37]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2nccc(C(F)(F)F)n2)cc1=O
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3CCCC3)n3ncc(Oc4nccc(C(F)(F)F)n4)cc3=O)n2)O1

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[6-oxo-4-(4-trifluoromethyl-pyrimidin-2-yloxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 87) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(4-trifluoromethyl-pyrimidin-2-yloxy)-6H-pyridazin-1-yl]-propionamide as an off-white solid as a mixture of diastereoisomers (401.4 mg, 66%).
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[C:3]([O:5][C:6]1[C:11](=[O:12])[N:10]([CH3:13])[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[N:8][C:7]=1[C:21]([O:23][CH3:24])=[O:22])=[O:4].[Br:27]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:27][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:9]2[N:10]([CH3:13])[C:11](=[O:12])[C:6]([O:5][C:3](=[O:4])[C:2]([CH3:26])([CH3:25])[CH3:1])=[C:7]([C:21]([O:23][CH3:24])=[O:22])[N:8]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)c1nc(-c2ccc(C)cc2)n(C)c(=O)c1OC(=O)C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nc(-c2ccc(CBr)cc2)n(C)c(=O)c1OC(=O)C(C)(C)C
Reaction time: 4 h

Procedure:
To a vigorously boiling solution of methyl 5-[(2,2-dimethylpropanoyl)oxy]-1-methyl-2-(4-methylphenyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate in carbon tetrachloride N-bromosuccinimide (1 eq.) and benzoyl peroxide (0.05 eq.) were added as dry powders. After 4 hr the mixture was allowed to reach room temperature and the precipitated succinimide was filtered off. The filtrate was evaporated under vacuum and the solid residue was used as such.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH:15]2[CH2:17][CH:12]1[CH:13]=[CH:14]2>>[CH:12]12[CH2:17][CH:15]([CH:14]=[CH:13]1)[CH2:16][CH:11]2[CH2:10][CH2:9][CH2:8][C:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClCCCC1CC2C=CC1C2
Reactant: O=C1CCCC1
Product: OC1(CCCC2CC3C=CC2C3)CCCC1
Yield: 86 %

Procedure:
1-{3-(5-Norbornen-2-yl)propyl}cyclopentanol (yield: 86%) was obtained in the same manner as in Synthesis Example 1, except that cyclopentanone and 1-chloro-3-(5-norbornen-2-yl)propane were used in place of acetone and 1-chloro-4-(5-norbornen-2-yl)butane, respectively.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[C:13]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:14][N:15]([CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1)=O)C.O>O1CCCC1>[CH2:27]([O:26][C:13]1[C:12]([CH2:10][OH:9])=[CH:16][N:15]([CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:14]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1cn(COCc2ccccc2)nc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cn(COCc2ccccc2)nc1OCc1ccccc1
Reaction time: 3 h
Yield: 99.1 %

Procedure:
To a suspension of lithium aluminum hydride (0.13 g) in tetrahydrofuran (5 mL) was added 3-benzyloxy-1-benzyloxymethyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.65 g) at room temperature, and this mixture was stirred at same temperature for 3 hours. To this reaction mixture was added water, and the insoluble material was removed by filtration. This filtrate was dried over anhydrous magnesium sulfate, and this solvent was removed under reduced pressure to give the title compound (0.57 g).
Reaction SMILES: [CH2:1](C1C=CC=CC=1N)C.[CH2:10]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[OH:21])[CH3:11].C([O-])([O-])=O.[K+].[K+].CI>CC(C)=O.O>[CH2:10]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[O:21][CH3:1])[CH3:11]
Reactant: CCc1ccc([N+](=O)[O-])cc1O
Reactant: CCc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CC(C)=O
Product: CCc1ccc([N+](=O)[O-])cc1OC
Temperature: 70 °C

Procedure:
Following published procedures 2-ethyl aniline was nitrated (Bergman, J.; Sand, P. Tetrahedron 1990, 46, 1085) and then converted to 2-ethyl-5-nitrophenol (PCT WO 1995/15954). A mixture of 2-ethyl-5-nitrophenol (0.320 g, 1.92 mmol), K2CO3 (0.200 g, 1.44 mmol) and MeI (0.300 g, 2.11 mmol) in acetone (4.0 mL) was heated at 70° C. for 15 h. The solution was cooled to rt, diluted with H2O, concentrated and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound (0.347 g) as an orange oil which was used in the next step without further purification. HPLC (Method #1): 3.46 min retention time, (75%); LCMS (ES): m/z 182 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3](=[O:5])[CH3:4].[CH3:6][S:7](Cl)(=[O:9])=[O:8].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:6][S:7]([O:1][CH2:2][C:3]([CH3:4])=[O:5])(=[O:9])=[O:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)COS(C)(=O)=O

Procedure:
Thirty-seven (37) mg of hydroxyacetone was dissolved in 2 ml of chloroform, and to which 0.078 ml of methanesulfonyl chloride was added. After stirring the reaction liquid at room temperature for 30 minutes, saturated aqueous sodium bicarbonate solution was added and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated to provide the title compound.
Reaction SMILES: [OH:1][C:2]1([CH3:20])[CH2:8][CH:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[O:6][C:4](=[O:5])[CH2:3]1.[C:21](OC(=O)C)(=[O:23])[CH3:22].O>N1C=CC=CC=1>[OH:1][C:2]1([CH3:20])[CH2:8][CH:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:21](=[O:23])[CH3:22])=[C:13]([O:18][CH3:19])[CH:12]=2)[O:6][C:4](=[O:5])[CH2:3]1
Reactant: COc1cc(CCC2CC(C)(O)CC(=O)O2)ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(CCC2CC(C)(O)CC(=O)O2)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 100 mg of 3-hydroxy-3-methyl-7-(p-hydroxy-m-methoxyphenyl)-5-heptanolide in 1 ml of pyridine was added 1 ml of acetic anhydride and the mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. Evaporation of the solvent from the extract yielded the desired compound as a colorless oily substance.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH:7]=[C:8]([C:14](=O)[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2].[CH3:19][O:20][C:21]1[NH:25][N:24]=[C:23]([NH2:26])[N:22]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH:7]2[N:24]3[N:25]=[C:21]([O:20][CH3:19])[N:22]=[C:23]3[NH:26][C:14]([CH3:15])=[C:8]2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: COc1nc(N)n[nH]1
Reactant: CCOC(=O)C(=Cc1ccc(C#N)cc1)C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)Nc2nc(OC)nn2C1c1ccc(C#N)cc1
Temperature: 65 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, ethyl 2-(4-cyanobenzylidene)-3-oxobutanoate (297 mg, 1.2 mmol) and 5-methoxy-1H-1,2,4-triazole-3-amine (153 mg, 1.3 mmol, 1.1 eq.) were dissolved in DMF (2.5 ml), and solid sodium bicarbonate (513 mg, 6.1 mmol, 5 eq.) was added. The mixture was stirred at 65° C. for 12 h. The mixture was then filtered, and the DMF from the filtrate was distilled off under reduced pressure. The residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (191 mg, 42% of theory).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([C:22]4[N:23](COCC[Si](C)(C)C)[CH:24]=[CH:25][N:26]=4)([OH:21])[CH3:20])[CH:15]=3)[C:10]([CH3:35])=[N:9]2)[CH:5]=[CH:4][N:3]=1>Cl.O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([C:22]4[NH:26][CH:25]=[CH:24][N:23]=4)([OH:21])[CH3:20])[CH:15]=3)[C:10]([CH3:35])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3nccn3COCC[Si](C)(C)C)ccc12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3ncc[nH]3)ccc12
Reaction time: 1 h

Procedure:
A solution of 4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)but-3-yn-2-ol in 4M HCl in dioxane (2.5 ml) was stirred at 40° C. for 2 h and then at 50° C. for a further 1 hr. The reaction mixture was then concentrated in vacuo and basified using saturated aqueous sodium bicarbonate solution. The product was extracted into DCM (2×3 mL) and the combined organics were washed with brine solution (2 ml), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Biotage, 5-12% methanol gradient in DCM) to give the title compound as an off-white solid: 1H NMR (500 MHz, DMSO) delta 1.90 (3H, s), 2.57 (3H, s), 6.42 (1H, s), 6.83 (1H, s), 6.96 (2H, s), 7.10-6.99 (2H, m), 7.35 (1H, d, J=8.2 Hz), 7.84 (1H, d, J=8.2 Hz), 8.25 (1H, d, J=5.5 Hz), 8.86 (1H, s), 12.01 (1H, s); LC-MS: m/z=+360.05 (M+H)+.