Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[ClH:8].Cl.[N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:20]3([C:23]4[N:27]5[CH:28]=[C:29]([C:32]6[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=6)[CH:30]=[N:31][C:26]5=[N:25][CH:24]=4)[CH2:22][CH2:21]3)=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.Cl.[NH2:42][C@@H:43]([C:51]([CH3:54])([CH3:53])[CH3:52])[C:44]([O:46]C(C)(C)C)=[O:45].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[ClH:8].[ClH:8].[CH3:54][C:51]([CH3:52])([CH3:53])[C@H:43]([NH:42][C:36](=[O:37])[C:35]1[CH:39]=[CH:40][C:32]([C:29]2[CH:30]=[N:31][C:26]3[N:27]([C:23]([C:20]4([C:16]5[CH:15]=[C:14]6[C:19](=[CH:18][CH:17]=5)[N:10]=[CH:11][CH:12]=[CH:13]6)[CH2:22][CH2:21]4)=[CH:24][N:25]=3)[CH:28]=2)=[CH:33][CH:34]=1)[C:44]([OH:46])=[O:45]
Reactant: O=C(O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[C@H](NC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triethylamine (230 μL) was added to a mixture of 4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoic acid dihydrochloride (162 mg, 0.339 mmol), tert-butyl (2S)-2-amino-3,3-dimethylbutanoate hydrochloride (75.8 mg, 0.339 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (165 mg, 0.373 mmol) in methylene chloride (10 mL). The mixture was stirred at RT for 3 h, washed with NaHCO3 (7.5%) and brine, dried over Na2SO4, filtered, and concentrated. The residue [LCMS: (M+H)=576.2] was treated with HCl in 1,4-dioxane (4M, 1.0 mL) at RT for 3 h. The solvent was evaporated. The residue was washed with ether and dried to give the desired product.
Reaction SMILES: [CH3:1][Si:2]([CH3:8])([C:4]([CH3:7])([CH3:6])[CH3:5])Cl.[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16].N1C=CN=C1>CN(C)C=O>[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][Si:2]([CH3:8])([CH3:1])[C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCCCl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCCCCCl
Reaction time: 72 h

Procedure:
To 33 g. of dimethyl-tert-butylchlorosilane in 100 ml. of dimethylformamide is added 27 g. of 6-chlorohexan-1-ol and 340 g. of imidazole. The reaction mixture is allowed to stand at room temperature for 3 days to yield 6-chlorohexyloxy-dimethyl-tert-butylsilane, which is worked up by pouring into water, extracting with ether, washing with water, drying over calcium sulfate, removing the solvent by evaporation and purifying by distillation.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]2[N:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH2:6]1.Cl.[NH2:28][C:29]1([C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1>>[F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[O:4][CH:5]1[CH2:6][N:7]([C:9]2[N:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][C:10]=2[C:11]([NH:28][C:29]2([C:32]3[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=3)[CH2:31][CH2:30]2)=[O:13])[CH2:8]1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2ccc(F)cc2F)C1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(C(F)(F)F)cnc3N3CC(Oc4ccc(F)cc4F)C3)CC2)cc1
Yield: 76.5 %

Procedure:
The title compound (D178) (106 mg) was prepared according to the experimental procedure described in Description 144 starting from 2-(3-(2,4-difluorophenoxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinic acid (D127) (95 mg, 0.253 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (57.79 mg, 0.253 mmol).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1.[Na].[CH2:10]([OH:13])[CH2:11][OH:12]>>[OH:12][CH2:11][CH2:10][O:13][CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1
Reactant: OCCO
Reactant: ClCc1cnccn1
Agent: [Na]
Product: OCCOCc1cnccn1

Procedure:
2-Chloromethylpyrazine is reacted with the sodium salt of ethylene glycol to give 2-(2-hydroxyethoxymethyl)pyrazine which is treated with thionyl chloride to give 2-(2-chloroethoxymethyl)pyrazine. Using this intermediate to place of 4-(3-chloropropoxy)methylimidazole in the procedure of Example 22 gives the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[Mg+2].[Cl-].[Cl-].[CH2:22]=[O:23].Cl>C(#N)C>[C:1]([C:5]1[C:6]([OH:11])=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH:22]=[O:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=O
Reactant: CC(C)(C)c1ccccc1O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)c1cccc(C=O)c1O

Procedure:
A mixture of 2-(tert-butyl)phenol (15 g, 0.1 mol), Et3N (37 g, 374 mmol), MgCl2 (14.3 g, 0.15 mol) and paraformaldehyde (20.2 g, 674 mmol) in ACN (200 mL) was heated at reflux for 5 h, cooled, poured into aq. HCl (2N, 200 mL) and extracted with Et2O. The organic layer was concentrated and purified by CC (PE/EA=8/1) to give compound P7a (13 g, 74%) as a colorless oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[S:6][C:7]=1[NH2:8].CN(C1C=CC=CN=1)C.[CH3:24][S:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>C(Cl)Cl.O>[CH3:24][S:25][CH2:26][CH2:27][C:28]([NH:8][C:7]1[S:6][C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:4][C:3]=1[S:2][CH3:1])=[O:29]
Reactant: CSCCC(=O)Cl
Reactant: CSc1nc(-c2cccnc2)sc1N
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: ClCCl
Product: CSCCC(=O)Nc1sc(-c2cccnc2)nc1SC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.8 %

Procedure:
To a nitrogen-purged solution of 4-(methylthio)-5-nitro-2-(pyridin-3-yl)thiazole (253 mg, 1 mmol) in ethyl acetate (50 mL) in a Parr bottle were added glacial acetic acid (601 mg, 10 mmol), followed by Pd on carbon (35 mg, 10% (w)). Hydrogen was added and the mixture was shaken in a Parr shaker for 2 hours and filtered through a bed of Celite®. The filtrate was concentrated under vacuum to give 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine as a pale yellow solid, which was placed under high vacuum to remove residual acetic acid. This crude was found to be 95% pure by GC-MS. The crude 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine was used without further purification to prepare 3-(methylthio)-N-(4-(methylthio)-2-(pyridin-3-yl)thiazol-5-yl)propanamide. To a solution of 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine (100 mg, 0.45 mmol) in methylene chloride (2 mL) were added dimethylaminopyridine (137 mg, 1.12 mmol) followed by 3-(methylthio)propanoyl chloride (68 mg, 0.49 mmol). The mixture was stirred at room temperature for 30 min. The mixture was diluted with dichloromethane (10 mL) and water (5 mL). The organic phase was separated, rinsed with brine, dried over MgSO4 and concentrated in vacuo to give a yellow solid. This solid was purified by silica gel chromatography (methylene chloride-methanol) to give 3-(methylthio)-N-(4-(methylthio)-2-(pyridin-3-yl)thiazol-5-yl)propanamide as a yellow solid (32 mg, 22%): mp 72-74° C., 1H NMR (300 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.08 (m, 1H), 8.64 (d, J=4.8 Hz, 1H), 8.32 (d, J=9.0 Hz, 1H), 7.57 (dd, J=5.1 Hz, 8.4 Hz, 1H), 3.25 (s, 3H), 2.85 (m, 2H), 2.73 (m, 2H), 2.07 (s, 3H); ESIMS m/z 326.1 (M+1), 324.1 (M−1).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[N:14]=1)[N:11]([CH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:10](=[O:27])[C:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:8]2)=[O:4].[NH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:25]([CH:22]([CH2:23][CH3:24])[CH2:21][N:11]1[C:12]2[C:7](=[C:6]([OH:34])[C:5]([C:3]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:4])=[N:14][C:13]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:8]=[C:9]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:10]1=[O:27])[CH3:26]
Reactant: CCC(CC)Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)OC)nc(-c3ccncc3)c21
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC(CC)Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)NCCC(=O)O)nc(-c3ccncc3)c21
Temperature: 25 °C
Yield: 41.2 %

Procedure:
A mixture of 1-(2-ethyl-butyl)-5-hydroxy-2-oxo-3-phenyl-8-pyridin-4-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.066 mmol), β-alanine (585 mg, 6.6 mmol) and NaOMe solution (10 mL, 4.9 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (5-90% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 14 mg of the title compound as an off-white solid. MS: (+) m/z 515.36 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]([CH2:18][OH:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21].N1C=CN=C1>C(Cl)Cl>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]([CH2:18][O:19][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:27])[CH3:26])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC1Cc2ccccc2N(Cc2ccccc2)C1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1Cc2ccccc2N(Cc2ccccc2)C1
Yield: 95.1 %

Procedure:
11.6 g of 1-benzyl-3(R,S)-hydroxymethyl-1,2,3,4-tetrahydroquinoline (Example 29e), 8.54 g of tert-butyldimethylchlorosilane and 4.05 g of imidazole are stirred in 120 ml of methylene chloride at room temperature for 20 h. The precipitate is then filtered off and the crude product obtained after concentration of the filtrate is purified over 900 g of silica gel (mobile phase Z). 16 g of the title compound are obtained as a yellowish oil: Rf (Z)=0.66.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH3:25])=[O:5])C.[N:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=1)=[C:27]=[O:28]>>[CH3:25][O:24][C:10]1[C:9]2[N:8]=[CH:7][C:6]3[C:4](=[O:5])[N:26]([C:29]4[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=4)[C:27](=[O:28])[N:16]([CH:17]4[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]4)[C:15]=3[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCC(C)CC1
Reactant: Cc1cccc(N=C=O)c1
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(C)c3)c(=O)n(C3CCC(C)CC3)c12
Yield: 108.4 %

Procedure:
7-Methoxy-1-(4-methyl-cyclohexyl)-3-m-tolyl-1H-pyrimido[5,4-c]quinoline-2,4-dione (135 mg) was prepared from 8-methoxy-4-(4-methyl-cyclohexylamino)-quinoline-3-carboxylic acid ethyl ester (0.29 mmol) and 1-isocyanato-3-methyl-benzene (0.44 mmol) following general procedure C. LCMS: m/z 430 [M+1]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5](OC)([O:8][CH3:9])[O:6][CH3:7].CO.[C:14]([OH:18])([CH3:17])([CH3:16])[CH3:15]>C(O)(C)(C)C>[NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])([O:8][CH3:9])[O:6][CH3:7]
Reactant: CO[Si](CCCN)(OC)OC
Reactant: CC(C)(C)O
Solvent: CO
Product: CO[Si](CCCN)(OC)OC(C)(C)C
Yield: 94 %

Procedure:
Into a 500 ml 3-necked flask equipped with a magnetic stirrer, heating mantle, thermometers, a 12 in. distilling column packed with 1/8 in. glass helices, addition funnel, distilling head and receiver was added 179.3 g (1.0 mole) of 3-aminopropyltrimethoxysilane. The flask was heated to 160° C. and from the (heated) addition funnel 160 g (2.16 moles) of t-butanol was slowly added with the simultaneous distillation of methanol/t-butanol to the receivers. The rate of addition of t-butanol was kept slow in order to maintain as high a flask temperature as possible (150°-170° C). Periodic sampling of the flask and lites for gas chromotograph analysis indicated that after 2.16 moles t-butanol had been added, approximately an 80% conversion of 3-aminopropyltrimethoxysilane to Compound A* had been achieved. Distillation of this material with four cuts (94°-100° C. at 20 mm Hg) produced 100 g of 94% pure aminopropyl-t-butoxydimethoxysilane (combined cuts 2, 3, 4). Cut one, enriched in 3-aminopropyltrimethoxysilane was 30 grams.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH3:13])[C:10]([NH2:12])=[NH:11].[C:14]([N:18]=[C:19]=[O:20])([CH3:17])([CH3:16])[CH3:15]>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH3:13])[C:10]([NH:12][C:19]([NH:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])=[NH:11]
Reactant: Cc1cccc(C)c1N(C)C(=N)N
Reactant: CC(C)(C)N=C=O
Solvent: Cc1ccccc1C
Product: Cc1cccc(C)c1N(C)C(=N)NC(=O)NC(C)(C)C

Procedure:
To a mixture of 8.7 g. (0.05 mole) of 1-(2,6-dimethylphenyl)-1-methylguanidine and 10 ml. xylene is added 5 g. of t-butylisocyanate (0.05 mole) and the mixture is refluxed for 2 hours. The reaction product is cooled, triturated with heptane and filtered. Recrystallization from 1:1 isopropanol/water results in 1-(2,6-dimethylphenyl-N-methylamidino)-3-(t-butyl)urea.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[N:26]1([NH:25][C:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[CH:20][N:19]=2)=[O:23])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: NN1CCOCC1
Reactant: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)nc1
Product: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)NN2CCOCC2)nc1
Yield: 60 %

Procedure:
As described for example 23f, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid (75 mg, 0.23 mmol) was converted, using 4-aminomorpholine instead of isopropylamine, to the title compound (57 mg, 60%), which was obtained as a white solid after recrystallization from ethyl acetate/hexane. MS: m/e=414.3 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1.CCN(C(C)C)C(C)C.[CH2:32]([C:40]1[CH:41]=[C:42]([NH2:45])[NH:43][N:44]=1)[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH3:7][N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:45][C:42]3[NH:43][N:44]=[C:40]([CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:41]=3)=[O:20])=[CH:21][CH:22]=2)[CH2:12][CH2:13]1
Reactant: Nc1cc(CCc2ccccc2)n[nH]1
Reactant: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)Nc3cc(CCc4ccccc4)n[nH]3)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 4.6 %

Procedure:
Oxalyl chloride (2M in DCM, 250 μl, 0.50 mmol, 1.1 eq) was added dropwise to a mixture of 4-(4-methylpiperazin-1-yl)benzoic acid (100 mg, 0.45 mmol, 1 eq) in DCM (5 ml, containing a few drops of DMF) and DIPEA (171 μl, 0.95 mmol, 2.1 eq) at O° C. After stirring for 1 h at 0° C., a solution of 5-phenethyl-2H-pyrazol-3-amine (128 mg, 0.68 mmol, 1.5 eq) in DCM (2 ml) was added dropwise. The mixture was maintained at 0° C. for 2 h, then gradually allowed to warm to room temperature overnight. The mixture was diluted with DCM (50 ml), washed with aq. NaHCO3 solution (50 ml) and the aqueous layer was extracted with DCM (50 ml). The combined organic layers were concentrated. The crude product was purified by reverse-phase prep. HPLC (basic) using a 30-50% gradient of acetonitrile in water (containing 1% ammonium hydroxide) to yield the title compound (8 mg, 3% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]2[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:4]=2[S:3]1(=[O:14])=[O:13].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6](=[O:7])[C:5]2[CH:8]=[C:9]([CH2:12][Br:15])[CH:10]=[CH:11][C:4]=2[S:3]1(=[O:13])=[O:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(c1)C(=O)N(C)S2(=O)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CN1C(=O)c2cc(CBr)ccc2S1(=O)=O

Procedure:
A solution of 2,5-dimethyl-1,1-dioxo-benzo[d]isothiazole-3-one (5.8 g) in carbon tetrachloride (100 ml) containing 2,2-azo-bis(2-methyl-propionitrile) (50 mg) and 4.8 g of N-bromosuccinimide was heated at reflux for about 2 hours.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:25]([F:28])([F:27])[F:26])=[C:14]([N:17]3[CH:21]=[CH:20][C:19]([CH:22]=[N:23][OH:24])=[CH:18]3)[CH:15]=2)[NH:10][C:9](=[O:29])[C:8]1=[O:30])=[O:5])C.[OH-].[Li+]>O1CCCC1.O>[C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:25]([F:28])([F:26])[F:27])=[C:14]([N:17]3[CH:21]=[CH:20][C:19]([CH:22]=[N:23][OH:24])=[CH:18]3)[CH:15]=2)[NH:10][C:9](=[O:29])[C:8]1=[O:30])([OH:5])=[O:3]
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3ccc(C=NO)c3)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3ccc(C=NO)c3)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.6 g (3.8 mmol) of the compound of Example 74 were dissolved in 100 ml of tetrahydrofuran, and 0.4 g (15.1 mmol) of lithium hydroxide dissolved in 25 ml of water was added. The mixture was stirred at room temperature for 2 h and then the tetrahydrofuran was removed under reduced pressure and the aqueous phase was acidified. The precipitate was filtered off with suction.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][C:13]1([OH:28])[CH2:24][CH2:25][CH2:26]O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:13]2([O:28][CH2:26][CH2:25][CH2:24]2)[CH2:14][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)OCc2ccccc2)C(O)(CCCO)C1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)OCc2ccccc2)C2(CCCO2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
To a solution of 0.80 g of the diol of step D in 15 mL of dichloromethane at 0° C. were added 0.2 mL of methanesulfonyl chloride and 0.8 mL of triethylamine. After being stirred for 1 hour, the mixture was refluxed at 60° C. overnight. Solvent was removed under vacuum. The residue was taken up in EtOAc/water and the two phases were separated. The water phase was extracted with EtOAc twice. The combined organic was dried over Na2SO4. Solvent was removed under vacuum. Column chromatography on silica gel using 15% EtOAc/hexane to 100% EtOAc as eluent provided 0.32 g of the title compound. MS (M+H)+ 377.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][C:13]=1[C:22]1[NH:27][C:26](=[O:28])[N:25]2[C:29]([CH3:35])=[N:30][C:31]([CH2:32][CH2:33][CH3:34])=[C:24]2[N:23]=1)[CH3:10]>ClCCl>[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]2)(=[O:20])=[O:19])=[CH:14][C:13]=1[C:22]1[NH:27][C:26](=[O:28])[N:25]2[C:29]([CH3:35])=[N:30][C:31]([CH2:32][CH2:33][CH3:34])=[C:24]2[N:23]=1)[CH3:10]
Reactant: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nc12
Reactant: CCN1CCNCC1
Solvent: ClCCl
Product: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(CC)CC4)ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
83 mg (0.73 mmol) of N-ethylpiperazine are added to a solution of 100 mg (0.24 mmol) of 4-ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-a]-[1,3,5]triazin-2-yl)-benzenesulfonyl chloride (example VI) in 5 ml of dichloromethane and the reaction mixture is stirred at room temperature for 2 hours. After chromatographic purification (dichloromethane/methanol=95:5), 104 mg (87%) of 2-[2-ethoxy-5-(4-ethyl-piperazine-1-sulfonyl)-phenyl]-6-methyl-8-propyl-3H-imidazo[1,5-a][1,3,5]triazin-4-one are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](OCC3C=CC=CC=3)=O)=[CH:20][C:19]=2[F:35])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]([O:41][CH2:42][C@@H:43]1[O:45]C1)(=[O:40])CCC>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:25][C@H:42]([CH2:43][OH:45])[O:41][C:36]3=[O:40])=[CH:20][C:19]=2[F:35])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(=O)OC[C@H]1CO1
Reactant: O=C(Nc1ccc(NC2CCN(C(=O)OCc3ccccc3)CC2)c(F)c1)OCc1ccccc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(Nc2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 6.6 g (15 mmol) 4-(4-benzyloxycarbonylamino-2-fluoro-phenylamino)-piperidine-1-carboxylic acid benzyl ester in 50 ml THF at −78° C. was added dropwise 12.12 ml nBuli 1.6 M (19.5 mmol). The mixture was further stirred at this temperature for 10 min. The resulting yellow solution was allowed to reach −40° C. over 10 min. 3.0 ml (21 mmol) of (R)-glycidyl butyrate was then added and the solution was allowed to reach slowly RT and further stirred for 16 h. The reaction was quenched with a saturated ammonium chloride solution, diluted with 400 ml of EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered and evaporated to dryness. The residue was purified by chromatography using a CH2Cl2/MeOH 5% mixture.
Reaction SMILES: [O:1]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])S(C(F)(F)F)(=O)=O.[CH3:16][O:17][C:18](=[O:25])[C:19](CO)([CH3:22])[CH2:20][OH:21]>C(Cl)Cl.N1C(C)=CC=CC=1C>[CH3:16][O:17][C:18](=[O:25])[C:19]([CH3:22])([O:1][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11])[CH2:20][O:21][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:10])=[O:1]
Reactant: COC(=O)C(C)(CO)CO
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)C(C)(COS(=O)(=O)C(F)(F)F)OS(=O)(=O)C(F)(F)F

Procedure:
Add Tf2O (80 mL) dropwise to a cold (−78° C.) solution of 3-hydroxy-2-hydroxymethyl-2-methyl-propionic acid methyl ester (32.5 g) in CH2Cl2 (400 mL) and 2,6-lutidine (80 mL). The reaction is allowed to reach room temperature and stir until only product spot detected by TLC analysis (ca. 2 h). Dilute with CH2Cl2 (400 mL) and wash with HCl (3% aqueous solution). Dry the organic layer over MgSO4, filter and concentrate. Subject residue to silica gel chromatography eluting with hexanes/ethyl acetate 5%, to give 2-methyl-2,3-bis-trifluoromethanesulfonyloxy-propionic acid methyl ester as a colorless oil.
Reaction SMILES: [Cl-].[CH3:2][CH:3]1[NH2+:8][CH:7]([CH3:9])[CH2:6][O:5][CH2:4]1.Br[CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23]>>[CH3:9][CH:7]1[N:8]([CH2:11][CH2:12][N:13]2[C:14](=[O:23])[C:15]3[C:16](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:18])[CH:3]([CH3:2])[CH2:4][O:5][CH2:6]1
Reactant: CC1COCC(C)[NH2+]1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: [Cl-]
Product: CC1COCC(C)N1CCN1C(=O)c2ccccc2C1=O

Procedure:
The title compound was prepared by a similar method to Preparation 6 from 3,5-dimethyl-1,4-oxazinan-4-ium chloride [see Preparation 10] and N(2-bromoethyl)phthalimide. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 8:1, by volume, hexane:ethyl acetate to afford 2-[2-(3,5-dimethylmorpholino)ethyl]-1H-isoindole-1,3(2H)-dione (455 mg) as an oil.