Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11](Cl)=[O:12])[C:5]2[CH:24]=[CH:25][NH:26][C:4]=2[C:3]1=[O:27].[CH2:28]([NH2:30])[CH3:29]>O1CCCC1>[CH2:28]([NH:30][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]([C:6]2[C:5]3[CH:24]=[CH:25][NH:26][C:4]=3[C:3](=[O:27])[N:2]([CH3:1])[CH:7]=2)[CH:9]=1)[CH3:29]
Reactant: Cn1cc(-c2cc(C(=O)Cl)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Reactant: CCN
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(Oc2ccccc2)c(-c2cn(C)c(=O)c3[nH]ccc23)c1
Yield: 61 %

Procedure:
A solution of Example 13a (0.040 g, 0.11 mmol) in tetrahydrofuran (1 mL) was treated with ethylamine (0.21 mL of a 2 M solution in tetrahydrofuran, 0.42 mmol) for 2 h. The reaction mixture was concentrated and the residue purified by preparative HPLC (C18, 10-90% acetonitrile in 0.1% TFA in water) to afford the title compound (0.025 g, 61%). 1H NMR (500 MHz, DMSO-d6) δ 1.12 (t, J=7.32 Hz, 3H), 3.25-3.32 (m, 2H), 3.54 (s, 3H), 6.23-6.24 (m, 1H), 6.95-6.99 (m, 3H), 7.11 (t, J=7.48 Hz, 1H), 7.27 (t, J=2.75 Hz, 1H), 7.31-7.37 (m, 3H), 7.84 (dd, J=8.54, 2.44 Hz, 1H), 7.98 (d, J=2.44 Hz, 1H), 8.46 (t, J=5.49 Hz, 1H), 11.99 (s, 1H). MS (ESI+) m/z 388.2 (M+H)+.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[NH2:27].[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41](O)=[O:42]>CN(C=O)C>[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([NH:27][C:26]1[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:24]([O:23][CH3:22])[CH:25]=1)=[O:42]
Reactant: O=C(O)CCCCCBr
Reactant: COc1cc(N)cc(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc(NC(=O)CCCCCBr)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 39.4 %

Procedure:
WSC (2.11 g, 11 mmols) and HOBt (1.68 g, 11 mmols) were added to a DMF (15 ml) solution of 3,4,5-trimethoxyaniline (2.75 g, 15 mmols) and 6-bromohexanoic acid (1.95 g, 10 mmols), and stirred at room temperature for 12 hours. The reaction mixture was extracted with ether. The organic layer was washed with water, 1N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through silica gel column chromatography (developer: hexane/acetone=5/1), and the resulting crystals were recrystallized from ether-hexane to obtain 1.42 g (yield: 40%) of 6-bromo-N-(3,4,5-trimethoxyphenyl)hexanamide as colorless needle-like crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][Si](C)(C)[N-][Si](C)(C)C.[Li+].IC>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH:12]([CH3:16])[C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1CN(Cc2ccccc2)CC(C)C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
To a −78° C. solution of 1-benzyl-3-methyl-piperidin-4-one (4.06 g, 20 mmol) in anhydrous THF (20 mL) was added lithium hexamethyldisilazide (21 mL, 21 mmol of a 1.0 M solution THF). After being stirred at −78° C. for 30 min, a solution of iodomethane (1.31 mL, 21 mmol) in THF (5 mL) was added into the reaction mixture. The resultant solution was stirred at 25° C. for 2 h and quenched with water. The aqueous layer was extracted with CH2Cl2. The organic extracts were combined, washed with brine and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude product. The crude material was purified by flash column chromatography (hexane/EtOAc) to provide 1.37 g (31.5% yield) of 1-benzyl-3,5-dimethyl-piperidin-4-one.
Reaction SMILES: [CH2:1]([C:5]1[CH2:6][C:7]2[C:12]([C:13]=1OC)=[CH:11][C:10]1[O:16][CH2:17][O:18][C:9]=1[CH:8]=2)[CH2:2][CH2:3][CH3:4].P(Br)(Br)[Br:20]>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[CH2:6][C:7]2[C:12]([C:13]=1[Br:20])=[CH:11][C:10]1[O:16][CH2:17][O:18][C:9]=1[CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1=C(OC)c2cc3c(cc2C1)OCO3
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Product: CCCCC1=C(Br)c2cc3c(cc2C1)OCO3
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.2 %

Procedure:
Dissolved in 100 ml of chloroform was 9.3 g of 2-n-butyl-3-methoxy-5,6-methylenedioxyindene, followed by a dropwise addition of 15.4 g of phosphorus tribromide over 1 hour under ice cooling. After stirring the resultant mixture for further 4 hours, the reaction mixture was stirred for additional 4 hours at room temperature. The reaction mixture was washed with water, a 5% aqueous solution of sodium hydroxide and water successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: a 20:1 mixture of n-hexane and ether) to give 7.6 g of 2-n-butyl-3-bromo-5,6-methylenedioxyindene having a melting point of 63.0°-64.0° C. as crystals (yield: 68%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(N(CC)CC)C>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: Clc1ncccn1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1ccc(CNc2ncccn2)cc1
Temperature: 110 °C
Reaction time: 24 h
Yield: 10.8 %

Procedure:
A mixture of 4-nitrobenzylamine (6.09 g, 40.0 mmol), 2-chloropyrimidine (4.82 g, 42.1 mmol), triethylamine (11.2 ml, 80.4 mmol) and ethanol (120 ml) was stirred at 110° C. for 24 hours, and the mixture was concentrated under reduced pressure. To the residue was added water, and the mixture wasextractedwithethylacetate-THF. Theorganiclayerwas dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-ethanol to give N-(4-nitrobenzyl)-N-(2-pyrimidinyl)amine (0.99 g, 4.3 mmol, 11%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]3[CH:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([N:25]1[CH2:24][CH:23]2[CH:27]([C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:20][CH2:21][C:22]2=[O:28])[CH2:26]1)=[O:11]
Reactant: Cc1ccccc1CC(=O)O
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.67 h
Yield: 42.2 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 2-(2-methylphenyl)acetic acid (1.05 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 40 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.3 g) and triethylamine (0.98 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with distilled water (2×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 2 cm, height 16 cm), eluting with ethyl acetate and collecting 45 cc fractions. Fractions 2 to 4 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from a mixture of acetonitrile (8 cc) and isopropyl ether (7.5 cc). The crystals are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-2-[(2-methylphenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (1.25 g) melting at 196° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[C:6]([NH2:13])[N:5]=[C:4]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([F:23])[CH:21]=3)[N:16]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[N:15]=2)[N:3]=1.[H-].[Na+].ClC(Cl)(Cl)S(O[CH2:40][C:41]([F:44])([F:43])[F:42])(=O)=O.O>C1COCC1>[NH2:1][C:2]1[C:7]([N:8]([CH2:40][C:41]([F:44])([F:43])[F:42])[C:9](=[O:12])[O:10][CH3:11])=[C:6]([NH2:13])[N:5]=[C:4]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([F:23])[CH:21]=3)[N:16]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[N:15]=2)[N:3]=1
Reactant: COC(=O)Nc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc1N
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N(CC(F)(F)F)c1c(N)nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc1N
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A quantity of 3.470 g (8.138 mmol) of the compound from Example 1 was suspended in 35 ml of THF, admixed at 0° C. with 358 mg (8.952 mmol) of sodium hydride (60% suspension in mineral oil) and stirred at 0° C. for 90 min, in the course of which a solution was formed. A quantity of 2.519 g (8.952 mmol) of 2,2,2-trifluoroethyl trichloromethanesulphonate was added and the mixture was stirred at RT for 48 h. It was then stirred with water and concentrated on a rotary evaporator. The residue was taken up in ethyl acetate, and the organic phase was washed twice with water and dried over sodium sulphate. This gave 5.005 g of the target compound (79% of theory, purity by HPLC 65%). A quantity of 250 mg of the residue was purified by means of preparative HPLC (mobile phase: methanol/water, gradient 30:70→90:10).
Reaction SMILES: [C:1]([C:3](=[CH:9][NH:10][C:11]1[C:16]([CH2:17][CH2:18][CH3:19])=[CH:15][CH:14]=[CH:13][N:12]=1)[C:4](OCC)=[O:5])#[N:2].[NH:20]1C(C2C(=O)N3C=CC=CC3=NC=2)=N[N:22]=[N:21]1>>[CH2:17]([C:16]1[C:11]2=[N:10][CH:9]=[C:3]([C:1]3[NH:2][N:22]=[N:21][N:20]=3)[C:4](=[O:5])[N:12]2[CH:13]=[CH:14][CH:15]=1)[CH2:18][CH3:19]
Reactant: CCCc1cccnc1NC=C(C#N)C(=O)OCC
Reactant: O=c1c(-c2nnn[nH]2)cnc2ccccn12
Product: CCCc1cccn2c(=O)c(-c3nnn[nH]3)cnc12
Yield: 27.6 %

Procedure:
The title compound (m.p. 269°-272° with decomposition, 27.6% yield) was prepared from ethyl 2-cyano-3-(3-n-propyl-2-pyridylamino)acrylate in a manner similar to that described for the preparation of 3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one in Example 2 of U.S. Pat. No. 4,122,274.
Reaction SMILES: C([O:4][C@@H:5]([CH3:37])[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[C:24]([S:25][C:26]3[S:27][C:28]4[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:29]=4[N:30]=3)=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[NH2:36])[CH2:10][CH2:9]1)=[O:7])(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[NH2:36][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[C:22]=1[N:23]=[C:24]([S:25][C:26]1[S:27][C:28]3[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:29]=3[N:30]=1)[N:16]2[CH2:15][CH2:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6](=[O:7])[C@@H:5]([OH:4])[CH3:37])[CH2:13][CH2:12]1
Reactant: CC(=O)O[C@@H](C)C(=O)N1CCC(CCn2c(Sc3nc4cccc(Cl)c4s3)nc3c(N)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@H](O)C(=O)N1CCC(CCn2c(Sc3nc4cccc(Cl)c4s3)nc3c(N)ncnc32)CC1
Reaction time: 2 h

Procedure:
The crude product from Step 2 was suspended in methanol and K2CO3 was added and stirring continued for 2 h. The title product was isolated after preparative HPLC purification as a trifluoroacetate salt. LC-MS [M+H]+ 518.1
Reaction SMILES: [C:1]([O:5][C:6]([N-:8][S:9]([N:12]1[CH:17]=C[C:15](=[N+](C)C)[CH:14]=[CH:13]1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].C[NH2+]C1CC[O:26][CH2:25]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:17][N:12]([CH:13]1[CH2:14][CH2:15][O:26][CH2:25]1)[S:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])(=[O:10])=[O:11]
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Reactant: C[NH2+]C1CCOC1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C1CCOC1)S(=O)(=O)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A flask was charged with N-tert-butoxycarbonyl-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide (2.19 g, 7.27 mmol), N-methyltetrahydrofuran-3-aminium chloride (1.00 g, 7.27 mmol) and triethyl amine (1.01 mL, 7.27 mmol) in 10 mL of CH2Cl2. After 2 h, the solution was concentrated in vacuo and purified by flash column chromatography (10-100% EtOAc/hexanes) to afford tert-butyl {[methyl(tetrahydrofuran-3-yl)amino]sulfonyl}carbamate. tert-butyl {[methyl(tetrahydrofuran-3-yl)amino]sulfonyl}carbamate (1.47 g, 5.23 mmol) was dissolved in 70 mL of CH2Cl2 and 45 mL of trifluoroacetic acid. After 1 h the solution was concentrated in vacuo, diluted in CH2Cl2, washed with saturated aqueous NaHCO3 and brine, then dried over Na2SO4. The solution was concentrated in vacuo to afford the title compound. 1H NMR (600 MHz, DMSO-d6) δ 4.25-4.31 (m, 1H); 3.79-3.84 (m, 1H); 3.58-3.66 (m, 2H); 3.47-3.52 (m, 1H); 2.56 (s, 3H), 2.04-2.10 (m, 1H); 1.81-1.88 (m, 1H).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][C:4]=2[CH:3]=[C:2]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[H-].[Na+].[CH3:24]I>C1COCC1>[CH3:24][N:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][C:4]=2[CH:3]=[C:2]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CI
Reactant: CCOC(=O)c1cc2c([nH]1)CCN(C(=O)OC(C)(C)C)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(n1C)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C

Procedure:
To a solution of 5-tert-butyl 2-ethyl 1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-2,5-dicarboxylate (1.0 eq) in THF at 0° C. was added NaH (1.2 eq) and stirred for half an hour at room temperature. Methyl iodide (1.3 eq) was added and resulting reaction mixture was stirred for 3 hrs. Reaction mixture was then quenched with water and extracted with ethyl acetate, dried over sodium sulphate and concentrated to dryness. Crude mass was then purified by silica gel column chromatography to afford 5-tert-butyl 2-ethyl 1-methyl-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-2,5-dicarboxylate.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[C:23]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[N:24][NH:25][CH:26]=4)[CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37]O>>[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][N:25]1[CH:26]=[C:22]([C:20]2[CH:19]=[CH:18][N:17]=[C:16]([NH:15][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:14][CH:13]=3)[N:21]=2)[C:23]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[N:24]1
Reactant: CN(C)CCO
Reactant: Cc1ccc(-c2n[nH]cc2-c2ccnc(Nc3ccc(CN4CCN(C)CC4)cc3)n2)cc1
Product: Cc1ccc(-c2nn(CCN(C)C)cc2-c2ccnc(Nc3ccc(CN4CCN(C)CC4)cc3)n2)cc1

Procedure:
The title compound is prepared as described in Example 55 starting from [4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine (Example 60) and 2-dimethylamino-ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: C1CCNC1
Product: O=C(c1ccc(Br)cc1F)N1CCCC1

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-fluoro-benzoic acid and pyrrolidine.)
Reaction SMILES: [C:1]1(=[O:23])[N:5]([C:6]2[CH:15]=[C:14]3[C:9]([C:10]([CH3:17])=[CH:11][C:12]([CH3:16])=[N:13]3)=[CH:8][CH:7]=2)[C:4](=[O:18])[C:3]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:2]12.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)Cl>[C:4]1(=[O:18])[N:5]([C:6]2[CH:15]=[C:14]3[C:9]([C:10]([CH3:17])=[CH:11][C:12]([CH3:16])=[N+:13]3[O-:32])=[CH:8][CH:7]=2)[C:1](=[O:23])[C:2]2=[CH:22][CH:21]=[CH:20][CH:19]=[C:3]12
Reactant: Cc1cc(C)c2ccc(N3C(=O)c4ccccc4C3=O)cc2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(C)[n+]([O-])c2cc(N3C(=O)c4ccccc4C3=O)ccc12
Temperature: 25 °C

Procedure:
4.25 g (14 mmol) of 7-phthalimido-2,4-dimethyl-quinoline are dissolved in 500 ml of boiling methylene chloride. After cooling to ambient temperature, 4.80 g of 3-chloroperbenzoic acid (about 50% strength) are added. After 3 hours at ambient temperature the reaction solution is washed 1 x with sodium hydrogen carbonate solution and saline solution, dried over sodium sulphate, concentrated by evaporation and recrystallised from ethanol.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([N:7]2[CH:12]([OH:13])[CH2:11][CH2:10][N:9]([CH3:14])[C:8]2=[O:15])=[N:4][N:3]=1.[CH3:16][N:17]=[C:18]=[O:19]>C(N(CC)CC)C>[CH3:1][C:2]1[S:6][C:5]([N:7]2[CH:12]([O:13][C:18](=[O:19])[NH:17][CH3:16])[CH2:11][CH2:10][N:9]([CH3:14])[C:8]2=[O:15])=[N:4][N:3]=1
Reactant: Cc1nnc(N2C(=O)N(C)CCC2O)s1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Product: CNC(=O)OC1CCN(C)C(=O)N1c1nnc(C)s1
Reaction time: 1 h

Procedure:
Tetrahydro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) and methyl isocyanate (3.5 ml; 0.06 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer. The mixture is stirred and triethylamine (1 drop) is added thereto. After the addition is completed the reaction mixture is allowed to stand for a period of about 1 hour. The mixture is then washed with hexane and is dried to yield the desired product tetrahydro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-(N-methylcarbamoyloxy)-2(1H)-pyrimidinone.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=O)[CH:7]3[CH2:14][CH2:15][CH2:16][CH:6]3[C:5]=2[CH:4]=1)#[N:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>COCCOC>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[S:26])[CH:7]3[CH2:14][CH2:15][CH2:16][CH:6]3[C:5]=2[CH:4]=1)#[N:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: N#Cc1ccc2c(c1)C1CCCC1C(=O)N2
Solvent: COCCOC
Product: N#Cc1ccc2c(c1)C1CCCC1C(=S)N2

Procedure:
8-Cyano-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (70 mg, 0.33 mmol) is heated to 80° C. with Lawesson's reagent (146 mg, 0.36 mmol) for 2 hours in DME (20 ml). The batch is concentrated by evaporation and purified by column chromatography (SiO2) with ethyl acetate-hexane: 50 mg (66%) of product.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7]1)=[O:5])[CH3:2].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])(=O)=O>ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH:8]([O:11][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(O)C1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)C1CCC(O[Si](C(C)C)(C(C)C)C(C)C)C1
Reaction time: 3.5 h
Yield: 97.3 %

Procedure:
A solution of 3-hydroxy-cyclopentanecarboxylic acid ethyl ester (prepared as described in PCT Int. Appl. 2008131946, 3.180 g, 20.1 mmol) in dichloromethane (100 mL) was subsequently treated with 2,6-lutidine (4.7 mL, 40.2 mmol) and triisopropylsilyl trifluoromethanesulfonate (8.1 mL, 30.15 mmol). After stirring for 3.5 h, the reaction was quenched with pH 4 buffer. The aqueous layer was extracted with dichloromethane. The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/diethyl ether 1:0 to 9:1 to afford the title compound (6.15 g, 97%) as a light yellow oil and as a 3.5:1 mixture of diastereoisomers. 1H NMR (300 MHz, CDCl3): δ 1.04-1.08 (m, 27H), 1.27 (t, J=7.1 Hz, 4H), 1.70-2.00 (m, 5.2H), 2.04-2.21 (m, 2.6H), 2.66-2.79 (m, 1H), 2.97-3.10 (m, 0.3H), 4.14 (q, J=7.1 Hz, 2.6H), 4.29-4.39 (m, 1H), 4.43-4.50 (m, 0.3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.C([Li])CCC.I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Br:22]>C1COCC1>[CH3:9][O:8][C:4]1[N:3]=[C:2]([C:20]2[CH:19]=[CH:18][C:17]([Br:22])=[CH:16][CH:21]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(Br)n1
Reactant: Brc1ccccc1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc(Br)cc2)n1
Yield: 44.7 %

Procedure:
2-Bromo-6-methoxypyridine (3 g, 17 mmol) is treated as described in EXAMPLE 53, Part A with n-butyl lithium (10.6 mL of a 1.6 M solution in THF, 17 mmol) and iodobromobenzene (4.8 g, 17 mmol). The crude product is purified by chromatography (5% EtOAc/hexanes) to obtain the title compound (2 g, 7.6 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:9])=[N:4][CH:5]=[N:6][C:7]=1[NH2:8].Cl.Br[C:12]([CH3:35])([CH3:34])[C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]23[CH2:28][CH2:27][C:24]([CH2:29][C:30]([O:32][CH3:33])=[O:31])([CH2:25][CH2:26]2)[CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=O>O.C(O)C>[NH2:8][C:7]1[C:2]2[N:1]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]45[CH2:28][CH2:27][C:24]([CH2:29][C:30]([O:32][CH3:33])=[O:31])([CH2:25][CH2:26]4)[CH2:23][CH2:22]5)=[CH:19][CH:20]=3)[C:12]([CH3:35])([CH3:34])[O:9][C:3]=2[N:4]=[CH:5][N:6]=1
Reactant: COC(=O)CC12CCC(c3ccc(C(=O)C(C)(C)Br)cc3)(CC1)CC2
Reactant: Nc1ncnc(O)c1N
Agent: Cl
Solvent: O
Solvent: CCO
Product: COC(=O)CC12CCC(c3ccc(C4=Nc5c(N)ncnc5OC4(C)C)cc3)(CC1)CC2
Temperature: 100 °C
Yield: 64.2 %

Procedure:
To a solution of 5,6-diaminopyrimidin-4-ol (280 mg, 2.2 mmol) in water (8 mL), absolute ethanol (25 mL) and 1M HCl (2.2 mL, 2.2 mmol) was added a solution of methyl {4-[4-(2-bromo-2-methylpropanoyl)phenyl]bicyclo[2.2.2]oct-1-yl}acetate (Intermediate 9; 877 mg, 2.15 mmol) in absolute EtOH (80 mL). The solution was heated to 100° C. overnight then allowed to cool to ambient temperature, evaporated to dryness, and the residue treated with 2M NaOH to adjust the pH to 10. The resulting suspension was filtered to provide a yellow solid which was purified on a 12 g presearch silica cartridge dry loading on silica (2 g) and eluting with 0-2.5-5% MeOH-DCM to provide the title compound as a white solid (601 mg, 1.38 mmol, 64%) 1H NMR δ 1.59-1.63 (12H, m), 1.79-1.83 (6H, m), 2.16 (2H, s), 3.59 (3H, s), 6.91 (2H, s), 7.39 (2H, d), 7.64 (2H, d), 7.95 (1H, s); MS m/e MH+ 435.
Reaction SMILES: CC(=[N:4][OH:5])C.CC(C)([O-])C.[K+].[Br:12][C:13]1[CH:14]=[CH:15][C:16](F)=[C:17]([C:19]([C:21]2[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[CH:24]=[C:23]([CH:30]([CH3:32])[CH3:31])[C:22]=2[O:33][CH2:34][CH3:35])=O)[CH:18]=1>C1COCC1>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[O:5][N:4]=[C:19]([C:21]3[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[CH:24]=[C:23]([CH:30]([CH3:32])[CH3:31])[C:22]=3[O:33][CH2:34][CH3:35])[C:17]=2[CH:18]=1
Reactant: CC(C)=NO
Reactant: CCOc1c(C(=O)c2cc(Br)ccc2F)cc(C(C)C)cc1C(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1c(-c2noc3ccc(Br)cc23)cc(C(C)C)cc1C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
Acetone oxime (172 mg, 2.35 mmol) was added to a solution of potassium t-butoxide (264 mg, 2.35 mmol) in 10 ml of THF. This was stirred for 30 min. at ambient temperature under a nitrogen atmosphere, then a solution of (5-bromo-2-fluoro-phenyl)-(2-ethoxy-3,5-diisopropyl-phenyl)-methanone (800 mg, 1.96 mmol) in THF was added. After 2 hrs., the reaction was quenched with saturated ammonium chloride solution (20 mL) and extracted with ether (2×20 mL). The organic layers were combined, dried over MgSO4 and evaporated. The residue was dissolved in ethanol (10 mL) and 1N HCl solution (10 mL) and refluxed for 1 h. The reaction mixture was portioned between ether and water after cooling to room temperature. The organic layer was dried over MgSO4 and evaporated. The residue was purified by silica gel column (10% ethyl acetate in hexanes) to give 5-bromo-3-(2-ethoxy-3,5-diisopropyl-phenyl)-benzo[d]isoxazole as a clear oil (313.2 mg, 40%).