Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.Br[CH:14]([CH3:18])[C:15]([NH2:17])=[O:16].O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:14]([CH3:18])[C:15]([NH2:17])=[O:16])[CH:8]=[CH:7]2
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: CC(Br)C(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C(N)=O)n1ccc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A dispersion of 60% NaH (6.85 g, 0.17 mol) was added to an ice-cooled solution of 5-chloroindole (20 g, 0.13 mol) in 250 ml of dry DMF. The stirring was continued for 20 minutes at room temperature, and the mixture was cooled again with an ice bath. After portionwise addition of solid 2-bromopropanamide (24.1 g, 0.15 mol), the reaction mixture was stirred for 1 h 30 at room temperature, then poured into cold water and extracted 3 times with AcOEt. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (AcOEt/hexane 50/50) to give pure 2-(5-chloro-1H-indol-1-yl)propanamide 25 as a white solid.
Reaction SMILES: [Na+].[OH:2][C:3]1[CH:4]=[C:5]([S:27]([O-:30])(=[O:29])=[O:28])[C:6]2[CH:7]=[CH:8][C:9]3[C:18]4[C:17]=2[C:16]=1[CH:15]=[CH:14][C:13]=4[C:12]([S:19]([O-:22])(=[O:21])=[O:20])=[CH:11][C:10]=3[S:23]([O-:26])(=[O:25])=[O:24].[Na+].[Na+].C(N(C(C)C)CC)(C)C.Br[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([O:50]CC)=[O:49]>CO>[C:48]([CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][O:2][C:3]1[CH:4]=[C:5]([S:27]([OH:30])(=[O:29])=[O:28])[C:6]2[CH:7]=[CH:8][C:9]3[C:18]4[C:17]=2[C:16]=1[CH:15]=[CH:14][C:13]=4[C:12]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:11][C:10]=3[S:23]([OH:26])(=[O:24])=[O:25])([OH:50])=[O:49]
Reactant: CCOC(=O)CCCCCBr
Reactant: O=S(=O)([O-])c1cc(O)c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c4ccc1c2c34
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C(O)CCCCCOc1cc(S(=O)(=O)O)c2ccc3c(S(=O)(=O)O)cc(S(=O)(=O)O)c4ccc1c2c43
Reaction time: 8 h

Procedure:
A mixture of 8-hydroxypyrene-1,3,6-trisulfonate sodium salt (2.6 g), diisopropylethylamine (2 g) and ethyl 6-bromohexanoate (7 g) in methanol (150 mL) was refluxed for 24 hours. The solvent was removed by rotary evaporation. The product was purified by HPLC. The isolated ethyl ester was redissolved in methanol (100 mL). About 0.5 g NaOH dissolved in 25 mL water was added. The resulting solution was stirred overnight. The methanol was removed by rotary evaporation. To the remaining aqueous solution was added acid until the solution became acidic. The precipitate was collected by filtration and dried under vacuum to give 8-(5-carboxypentoxy)pyrene-1,3,6-trisulfonic acid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15](OCC)=[O:16])=[N:12][CH:11]=2)=[CH:6][CH:5]=1.O.[NH2:23][NH2:24]>CCO>[F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]([NH:23][NH2:24])=[O:16])=[N:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ncc(-c2ccc(OC(F)(F)F)cc2)o1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ncc(-c2ccc(OC(F)(F)F)cc2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
To a solution of ethyl 5-(4-(trifluoromethoxy)phenyl)oxazole-2-carboxylate (6.4 g, 21.2 mmol) in EtOH (30 mL), was added dropwise hydrazine hydrate (6 mL, 84% in H2O) while stifling at RT. The mixture was then stirred for further 16 h at RT and then concentrated under reduced pressure to half volume. Upon addition of H2O (30 mL) a yellow solid precipitated, which was filtered, washed with H2O (3×30 mL) and dried to afford the title compound as a light yellow solid (4.6 g, 75%). MS (ES+) C11H8F3N3O3 requires: 287. found: 288 [M+H]+;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[CH:19][C:11]3[NH:12][C:13](=[O:18])[O:14][C:15]([CH3:17])([CH3:16])[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>C(N(CC)CC)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][C:15]1([CH3:17])[O:14][C:13](=[O:18])[NH:12][C:11]2[CH:19]=[CH:20][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH:3]=3)=[CH:9][C:10]1=2
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cccc(Br)c3)cc21
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(C#C[Si](C)(C)C)c3)cc21
Temperature: 80 °C
Yield: 91.8 %

Procedure:
A mixture of 6-(3-bromo-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.8 g, 2.4 mmol), trimethylsilylacetylene (1 g, 10 mmol), tetrakis(triphenylphosphine) palladium (0) (0.17 g, 0.24 mmol), and cuprous (I) iodide (0.05 g, 0.28 mmol) in triethyl amine (20 mL) was heated under nitrogen at 80° C. for 3 hours. The reaction mixture was cooled to rt and the solvent was removed. The residue was taken up in ethyl acetate (50 mL) and washed with 1N aqueous HCl (3×20 mL) and brine ( 20 mL). The organic layer was separated and dried (MgSO4). After removal of solvent, the residue was purified by a silica gel chromatography (hexane:ethyl acetate/3:1) to afford the title compound as a white solid (0.77 g, 92%): mp 240-242° C.; 1H-NMR (DMSO-d6) δ10.3 (s, 1H), 7.74-7.69 (m, 2H), 7.61-7.58 (m, 2H), 7.48-7.40 (m, 2H), 6.96 (d, 1H, J=7.98 Hz), 1.67 (s, 6H), 0.25 (s, 9H); MS (EI) m/z 349([M+], 50%); Anal. Calc. For C21H23NO2Si0.2 EtOAc: C, 71.32, H, 6.75, N, 3.82. Found: C, 71.08, H, 6.64, N, 3.82.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[C:3]=1[S:23][CH3:24].ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl.ClCCl>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:21])([F:20])[F:22])[C:3]=1[S:23]([CH3:24])=[O:33]
Reactant: CSc1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CS(=O)c1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reaction time: 6 h

Procedure:
A stirred solution of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylthio-3-trifluoromethylpyrazole (1.0 g) in chloroform (40 ml) was treated with m-chloroperbenzoic acid (0.42 g), portionwise at room temperature. After stirring for 6 hours, the solution was diluted with dichloromethane and washed in turn with sodium sulphite solution, sodium hydroxide solution, and water. The solution was dried over anhydrous magnesium sulphate, and evaporated in vacuo to give a yellow oil. Purification by chromatography on silica (Merck, 230-400 mesh, 0.7 kg cm-2) eluting with dichloromethane-ethylacetate (4:1) gave 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylsulphinyl-3-trifluoromethylpyrazole in the form of a white solid, m.p. 142°-145° C. with decomposition.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[CH:18]([OH:21])[CH2:19][CH3:20])[C:3]1=[O:22].Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34]([F:37])([F:36])[F:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1.C(N(CC)CC)C>CCO>[OH:21][CH:18]([C@@H:8]1[CH2:9][C@H:10]([N:13]([CH:15]([CH3:16])[CH3:17])[CH3:14])[CH2:11][CH2:12][C@@H:7]1[N:4]1[CH2:5][CH2:6][CH:2]([NH:1][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:34]([F:36])([F:37])[F:35])[CH:32]=3)[N:27]=[CH:26][N:25]=2)[C:3]1=[O:22])[CH2:19][CH3:20]
Reactant: CCC(O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCC(O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CCC(Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 100 °C
Yield: 60.9 %

Procedure:
A solution of (S)-3-amino-1-((1S,2R,4R)-2-(1-hydroxypropyl)-4-(isopropyl(methyl)amino)cyclohexyl)pyrrolidin-2-one (47.6 mg, 0.153 mmol) in EtOH (3 mL) was charged with 4-chloro-6-(trifluoromethyl)quinazoline (46.3 mg, 0.2 mmol) and triethylamine (0.064 mL, 0.46 mmol). The mixture was heated for 30 min at 100° C. in the microwave oven. Solvent was evaporated off, and the residue was purified by flash chromatography on silica gel with elution by 0.8:7.2:92 cNH4OH—MeOH—CH2Cl2 to afford the titled compound 1-((1S,2R,4R)-2-(1-hydroxypropyl)-4-(isopropyl(methyl)amino)cyclohexyl)-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-2-one (47.3 mg) as a solid. MS found: (M+H)+=508.3
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][C:14](O)([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:12][CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccc(C2(O)CCN(C(=O)OCc3ccccc3)CC2)cc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(C2=CCN(C(=O)OCc3ccccc3)CC2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-hydroxy-4-[4-[[(phenylmethoxy)carbonyl]amino]phenyl]-1-piperidinecarboxylic acid phenylmethyl ester (EXAMPLE 17, Step 1, 2.50 g) in dry methylene chloride under N2 is treated with trifluoroacetic acid (0.84 mL), stirred at ambient temperature for three hours, diluted with saturated aqueous potassium carbonate (25 mL) to neutralize excess trifluoroacetic acid, and the layers are separated. The organic phase is washed with water (20 mL) and saline (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is chromatographed on silica gel (230-400 mesh, 300 g), eluting with a gradient of ethyl acetate/hexane (20/80-50/50). Pooling of fractions with an Rf =0.69 by TLC (ethyl acetate/hexane, 50/50) and removal of solvent under reduced pressure gives the title compound, mp 146-148° C.
Reaction SMILES: C1(O[C:8](=[O:20])[NH:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][N:14]=[CH:15]3)C=CC=CC=1.NC1C2C(=CC=CC=2)CCC1.[CH2:32]([CH:39]1[C:48]2[C:43](=[CH:44][C:45]([F:49])=[CH:46][CH:47]=2)[CH2:42][CH2:41][CH:40]1[NH2:50])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[OH-].[Na+]>CS(C)=O.O>[CH2:32]([CH:39]1[C:48]2[C:43](=[CH:44][C:45]([F:49])=[CH:46][CH:47]=2)[CH2:42][CH2:41][CH:40]1[NH:50][C:8]([NH:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][N:14]=[CH:15]2)=[O:20])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: NC1CCc2cc(F)ccc2C1Cc1ccccc1
Reactant: O=C(Nc1cccc2cnccc12)Oc1ccccc1
Agent: NC1CCCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1cccc2cnccc12)NC1CCc2cc(F)ccc2C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Isoquinolin-5-yl-carbamic acid phenyl ester 2-1 (0.005 mole, 1.32 g) was dissolved in 15 mL of DMSO (dimethylsulfoxide) followed by the addition of the aminotetralin 2-2, 1-benzyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamine (0.0044 mole, 1.12 g). The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was poured into 50 mL of water containing 10 mL of 1N NaOH (sodium hydroxide). The precipitated solid was collected by filtration. This solid was chromatographed on silica gel eluting with methylene chloride, 3% methanol. Subsequently the product was further purified by recrystallization from ethyl acetate. The title compound 38, (1-(1-benzyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-isoquinolin-5-yl-urea) was obtained as an off-white solid (1.25 g, 0.00295 mole). MS (MH+): 426; 1H NMR (MeOH): δ 1.35 (m, 1H), 1.9 (m, 1H), 2.1-2.2 (m, 1H), 2.9-3.1 (m, 4H) 3.45 (m, 1H), 4.1-4.2 (m, 1H), 6.7 (t, 1H), 6.8-6.9 (m, 2H), 7.1-7.3 (m, 5H), 7.85 (t, 1H), 8.1 (d, 1H), 8.25 (d, 1H), 8.35 (d, 1H), 8.6 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[O:10][CH3:11].N1C=CN=C1.C(O)(=O)C.C(OC1C=C(C(NC2C=CC(C(N)=N)=CC=2)C2NC(=O)N(C3N=CC=CN=3)N=2)C=CC=1OC)C.[C:55]([Si:59](Cl)([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)([CH3:58])([CH3:57])[CH3:56].Cl>C(OCC)(=O)C>[C:55]([Si:59]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:10][CH3:11])[CH:4]=1)([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)([CH3:58])([CH3:56])[CH3:57]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COc1cc(CO)ccc1F
Agent: CCOc1cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)ccc1OC
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving 9.17 g of (4-fluoro-3-methoxyphenyl)methanol [CAS No. 128495-45-4] in 100 ml of DMT, 5g of imidazole and 17g of t-butyl -chlorodiphenylsilane were added and the mixture was stirred overnight at room temperature. Next, 1N hydrochloric acid was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give t-butyl-(4-fluoro-3-methoxybenzyloxy)diphenylsilane as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][Si@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH2:8][CH2:7]1.[Mg].Cl[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=2)=[CH:25][CH:24]=1>[Ni](Cl)Cl.C1(PCCCPC2C=CC=CC=2)C=CC=CC=1.C1(PCCCPC2C=CC=CC=2)C=CC=CC=1.C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][Si@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:23]3[CH:24]=[CH:25][C:26]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=4)=[CH:27][CH:28]=3)=[CH:16][CH:15]=2)[CH2:8][CH2:7]1
Reactant: Fc1ccc(-c2ccc(Cl)cc2)cc1F
Reactant: COCCC[Si@H]1CC[C@H](CCc2ccc(Br)cc2)CC1
Agent: Cl[Ni]Cl
Agent: [Mg]
Agent: c1ccc(PCCCPc2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCC[Si@H]1CC[C@H](CCc2ccc(-c3ccc(-c4ccc(F)c(F)c4)cc3)cc2)CC1

Procedure:
35.5 g (100 mmol) of 4-(2-(trans-(4-(3-methoxypropyl)-4-silacyclohexyl))ethyl)phenyl bromide was dripped into a mixture of 2.4 g of magnesium (100 mmol) and 60 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 300 ml THF solution of 34.5 g of 4-chloro-3',4'-difluorobiphenyl and a catalytic amount of bis (1,3-diphenylphosphinopropane) nickel (II) chloride. After a conventional after treatment, the reaction mixture thus obtained was purified by means of chromatography to obtain 36.3 g (yield 81%) of the target product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[S:12][C:11]([N:13](CC2C=CC(OC)=CC=2OC)[S:14]([C:17]2[CH:22]=[C:21]([F:23])[C:20](F)=[CH:19][C:18]=2[F:25])(=[O:16])=[O:15])=[N:10][CH:9]=1.[OH:37][C:38]1[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][C:39]=1[I:46]>CS(C)=O.C(OCC)(=O)C>[Cl:7][C:8]1[S:12][C:11]([NH:13][S:14]([C:17]2[CH:22]=[C:21]([F:23])[C:20]([O:37][C:38]3[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][C:39]=3[I:46])=[CH:19][C:18]=2[F:25])(=[O:15])=[O:16])=[N:10][CH:9]=1
Reactant: N#Cc1ccc(O)c(I)c1
Reactant: COc1ccc(CN(c2ncc(Cl)s2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2cc(F)c(S(=O)(=O)Nc3ncc(Cl)s3)cc2F)c(I)c1
Temperature: 65 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
To a suspension of potassium carbonate (0.068 g, 0.000492 mol) and N-(5-chloro-1,3-thiazol-2-yl)-N-(2,4-dimethoxybenzyl)-2,4,5-trifluorobenzenesulfonamide (Preparation 334, 0.200 g, 0.000418 mol) in dimethyl sulfoxide (3.0 mL) was added 4-hydroxy-3-iodobenzonitrile (Preparation 342, 0.108 g, 0.000441 mol) and was stirred at 65° C. under nitrogen for 16 hours. The reaction was diluted with ethyl acetate (10.0 mL). The organic phase was washed with saturated aqueous sodium chloride solution (2×10.0 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was dissolved in dichloromethane (1.5 mL), treated with trifluoroacetic acid (1.5 mL) and stirred at room temperature under nitrogen for 16 hours. Reaction was concentrated in vacuo and residue dissolved in ethyl acetate (10.0 mL). The organic extract was washed with saturated aqueous sodium bicarbonate solution (2×10.0 mL), dried over sodium sulphate, filtered and concentrated in vacuo. The resulting residue was purified using ISCO™ (12 g SiO2) eluting with methanol:dichloromethane (gradient 0:1 to 1:39, by volume) to afford the title compound as an orange solid, 165 mg, 35% yield.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(OCC)(=O)CC(OCC)=O.[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:28])=[C:21]([CH:23]=[CH:24][C:25](=[O:27])[CH3:26])[CH:22]=1>C(O)C>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:28])=[C:21]([CH:23]2[CH2:3][C:2](=[O:1])[CH2:26][C:25](=[O:27])[CH2:24]2)[CH:22]=1
Reactant: CC(=O)C=Cc1cc(F)ccc1C
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CCO
Product: Cc1ccc(F)cc1C1CC(=O)CC(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 20% solution of sodium ethoxide in ethanol (29.7 g) was combined at 0C with diethyl malonate (14.0 g) and then with 4-(5-fluoro-2-methylphenyl)-3-buten-2-one (13.4 g) in portions. The reaction mixture was stirred at room temperature for 30 minutes, and then stirred with heating for 2 hours. After allowing to stand to cool, the solvent was distilled off, and the residue was combined with water and the aqueous layer was washed with ethyl acetate and then concentrated. 2M Sodium hydroxide (46 ml) was added and the mixture was heated under reflux for 1 hour. After allowing to stand to cool, 2.5M sulfuric acid (46 ml) was added over 10 minutes, and the mixture was heated under reflux for 30 minutes. After allowing to stand to cool, the precipitated crystal was recovered by a filtration and washed successively with water and isopropyl ether to obtain 5-(5-fluoro-2-methylphenyl)cyclohexane-1,3-dione (8.6 g) as a colorless crystal.
Reaction SMILES: COC(C1N(CC=O)C=C(C(=O)NCC2C=CC(F)=CC=2)C(=O)C=1OCC1C=CC=CC=1)=O.Cl.Cl.N[C@@H](C)CCNC.[F:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][NH:51][C:52]([C:54]2[C:55](=[O:79])[C:56]([O:71]CC3C=CC=CC=3)=[C:57]3[C:68](=[O:69])[N:61]4[C@@H:62]([CH3:67])[CH2:63][CH2:64][N:65]([CH3:66])[C@@H:60]4[CH2:59][N:58]3[CH:70]=2)=[O:53])=[CH:46][CH:45]=1>>[F:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][NH:51][C:52]([C:54]2[C:55](=[O:79])[C:56]([OH:71])=[C:57]3[C:68](=[O:69])[N:61]4[C@@H:62]([CH3:67])[CH2:63][CH2:64][N:65]([CH3:66])[C@@H:60]4[CH2:59][N:58]3[CH:70]=2)=[O:53])=[CH:46][CH:45]=1
Reactant: C[C@H]1CCN(C)[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4)c(=O)c(OCc4ccccc4)c3C(=O)N12
Agent: CNCC[C@H](C)N
Agent: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Agent: Cl
Product: C[C@H]1CCN(C)[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4)c(=O)c(O)c3C(=O)N12
Yield: 44 %

Procedure:
In a similar manner to that described in example Z-35, from 16 (18 mg, 0.0398 mmol) and [(3S)-3-aminobutyl]methylamine bis hydrochloride (19 mg, 0.109 mmol, (4S,12aS)—N-[(4-fluorophenyl)methyl]-1,4-dimethyl-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide was prepared as a white solid. This material was deprotected in a second step similar to that described in example Z-37 to give the title compound as a tan solid (7 mg, 44% 2 steps), 1H NMR (CDCl3) δ 12.53 (s, 1H), 10.47 (s, 1H), 8.29 (a, 1H), 7.32 (m, 2H), 6.99 (m, 2H), 5.04 (1H), 4.60 (m, 2H), 4.23 (s, 3H), 2.83-2.80 (m, 2H), 2.32 (s, 3H), 2.13 (m, 1H), 1.48 (m, 1H), 1.34 (m, 3H); MS: 4.15 (M+1).
Reaction SMILES: COC([C:5]1[O:6][C:7]2[CH:13]=[C:12]([O:14][C:15]3[S:16][C:17]4[C:18]([N:23]=3)=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:11]=[CH:10][C:8]=2[CH:9]=1)=O.CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)[C:35]([O-])=[O:36].[Na+].[K+]>C(Cl)Cl>[S:16]1[C:17]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[N:23]=[C:15]1[O:14][C:12]1[CH:11]=[CH:10][C:8]2[C:9]([CH2:35][OH:36])=[CH:5][O:6][C:7]=2[CH:13]=1
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Reactant: COC(=O)c1cc2ccc(Oc3nc4ncccc4s3)cc2o1
Agent: CC(C)C[AlH]CC(C)C
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Product: OCc1coc2cc(Oc3nc4ncccc4s3)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a cooled (0° C.) solution of 6-(thiazolo[4,5-b]pyridin-2-yloxy)-benzofuran-2-carboxylic acid methyl ester (6.0 g, 18.3 mmol) in DCM (183 mL) was added DIBALH (1 M in THF, 54.8 mL, 54.8 g, 54.8 mmol) and the reaction mixture was stirred (0° C., 1 h). The reaction mixture was treated with saturated aqueous Rochelle's salt (100 mL) and partitioned with DCM (50 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2×100 mL). The organic layer was dried, filtered and concentrated in vacuo to provide the title compound as yellow solid (4.9 g, 90%). MS (ESI): mass calcd. for C16H10N2O3S, 298.04; m/z found, 299.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 8.53 (dd, J=4.8, 1.7, 1H), 8.40 (dd, J=8.0, 1.7, 1H), 8.00 (s, 1H), 7.86 (d, J=2.1, 1H), 7.84 (s, 1H), 7.45-7.37 (m, 1H), 7.38-7.31 (m, 1H), 5.25 (t, J=5.5, 1H), 4.67 (dd, J=5.5, 0.8, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:25]([O:27]C)=[O:26])=[N:11][N:12]2[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][NH:15][C:14](=[O:24])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:32]>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[C:10]([C:25]([OH:27])=[O:26])=[N:11][N:12]2[CH:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:16][N:15]([CH3:32])[C:14](=[O:24])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)NCC2c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CC(c2ccccc2)n2nc(C(=O)O)c(OCc3ccccc3)c2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-benzyloxy-4-oxo-7-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (28 mg, 0.074 mmol) in anhydrous DMF under inert atmosphere was added sodium hydride (3 mg, 0.111 mmol, 95% dispersion in oil). The mixture was treated with iodomethane (6 μL, 0.089 mmol) and stirred at room temperature for 1 hour. When the methylation was complete, several drops of H2O were added and the mixture stirred at room temperature for 1 hour. The mixture was purified by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA). Collection and concentration of the appropriate fractions yielded the title product as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 12.90 (s, 1H), 7.51-7.49 (m, 2H), 7.39-7.31 (m, 6H), 7.01-7.00 (m, 2H), 5.80 (s, 1H), 5.27 (dd, J=11.2, 25.2 Hz, 2H), 4.21 (d, J=4.8 hz, 1H), 4.18 (d, J=4.4 Hz, 1H), 2.92 (s, 3H); ES MS (M+1)=378.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH:16]=O)[N:6]=1)([CH3:4])[CH3:3].Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH:16]=[N:19][OH:20])[N:6]=1)([CH3:4])[CH3:3]
Reactant: NO
Reactant: CC(C)(C)c1nc(C=O)nc(C(C)(C)C)c1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1nc(C=NO)nc(C(C)(C)C)c1O

Procedure:
A solution of 4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carboxaldehyde (1.5 g, 6.3 mmol), hydroxylamine hydrochloride (2.2 g, 32.7 mmol), and sodium acetate (2.9 g, 34.9 mmol) in ethanol (20 mL) is heated at reflux for 12 hours. The reaction mixture is poured over water (150 mL) and the precipitate is collected by filtration. Recrystallization from ether/hexane gives the desired 4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carboxaldehyde oxime as a mixture of isomers (0.62 g, 39%); mp 205°-220° C.