Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([F:24])=[CH:17][C:18]=3F)[N:13]=2)=[CH:7][C:6]=1[CH3:25].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:25][C:6]1[CH:7]=[C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([F:24])=[CH:17][C:18]=3[N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[N:13]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[O:4][CH2:3][CH2:2][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCNC1
Reactant: Cc1cc(-c2nc3cc(F)cc(F)c3c(=O)[nH]2)cc(C)c1OCCBr
Product: Cc1cc(-c2nc3cc(F)cc(N4CCCC4)c3c(=O)[nH]2)cc(C)c1OCCN1CCCC1

Procedure:
A solution of 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-difluoro-3H-quinazolin-4-one (1.38 g, crude) and pyrrolidine (10 mL) was stirred at room temperature for 16 hours. Excess pyrrolidine was evaporated, the residue was purified by column chromatography (silica gel 230-400 mesh; 30-50% ethyl acetate in hexanes as eluent). The compound was further purified by preparative HPLC to give the title compound as a white solid. Yield: 260 mg (13% for two steps). MP 206.6-206.8° C. 1H NMR (400 MHz, DMSO-d6): δ 11.85 (s, 1H), 6.63 (d, J=8 Hz, 1H), 6.51 (d, J=12 Hz, 1H), 3.90 (t, J=4 Hz, 2H), 2.83 (t, J=4 Hz, 2H), 2.50 (s, 6H), 2.30 (s, 4H), 1.89 (s, 4H), 1.70 (s, 4H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[C@@H:3]1[C:10]([O:12][CH:13]1[CH:18]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:16][CH:15]([CH3:22])[CH2:14]1)=[O:11].[C:23](=O)([O-])[O-].[K+].[K+]>CO.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[CH3:23][O:8][C:6]1[CH2:7][C@H:2]([CH3:1])[C@@H:3]([C:10]([O:12][C@H:13]2[C@H:18]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:16][C@@H:15]([CH3:22])[CH2:14]2)=[O:11])[C:4](=[O:9])[CH:5]=1
Reactant: CC1CCC(C(C)C)C(OC(=O)[C@H]2C(=O)CC(=O)C[C@@H]2C)C1
Reactant: O=C([O-])[O-]
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: [K+]
Solvent: CO
Product: COC1=CC(=O)[C@H](C(=O)O[C@@H]2C[C@H](C)CC[C@H]2C(C)C)[C@@H](C)C1
Temperature: 23 °C
Reaction time: 12 h
Yield: 713.6 %

Procedure:
A solution of (1R,3R,4S)-p-menth-3-yl(1R,2S)-2-methyl-4,6-dioxocyclohexanecarboxylate (2, 24.0 g, 77.8 mmol, 1 equiv) in methanol (300 mL) was treated with camphorsulfonic acid (ca. 800 mg, 3.9 mmol, 0.05 equiv) and the resulting solution was stirred at 23° C. for 12 h. The reaction mixture was neutralized by the addition of solid potassium carbonate (1.08 g, 7.78 mmol, 0.10 equiv) and the resulting suspension was filtered and the filtrate was concentrated. The residue was concentrated from toluene (2×15 mL) and then was purified by flash column chromatography (20% ethyl acetate-hexanes) to afford (1R,3R,4S)-p-menth-3-yl(1R,6S)-4-methoxy-6-methyl-2-oxo-3-cyclohexene-1-carboxylate (4) as a white solid (mp 78°-80° C., 17.9 g, 71%). The regioisomeric enone, (1R,3R,4S)-p-menth-3-yl(1R,6S)-2-methoxy-6-methyl-4-oxo-2-cyclohexene-1-carboxylate (5) was isolated in separate fractions and was resubjected to the reaction conditions to establish the equilibrium mixture of enones, in which the desired product 4 is strongly favored. ##STR16##
Reaction SMILES: [Br:1][C:2]1[C:20]([CH3:21])=[CH:19][C:5]([O:6][C@@H:7]2[CH2:10][C@H:9]([NH:11]C(=O)OC(C)(C)C)[CH2:8]2)=[CH:4][C:3]=1[CH3:22].FC(F)(F)C(O)=O>ClCCl.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[C:20]([CH3:21])=[CH:19][C:5]([O:6][C@@H:7]2[CH2:10][C@H:9]([NH2:11])[CH2:8]2)=[CH:4][C:3]=1[CH3:22]
Reactant: Cc1cc(O[C@H]2C[C@@H](NC(=O)OC(C)(C)C)C2)cc(C)c1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(O[C@H]2C[C@@H](N)C2)cc(C)c1Br
Temperature: 0 °C
Reaction time: 5 h

Procedure:
tert-Butyl cis-3-(4-bromo-3,5-dimethylphenoxy)cyclobutylcarbamate (200 mg) and trifluoroacetic acid (0.13 mL) are dissolved in dichloromethane (6 mL). The reaction mixture is stirred at 0° C. for 5 hours, diluted with a saturated aqueous solution of NaHCO3, dried (MgSO4) and concentrated to give the title compound. Yield: 400 mg.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[O:31][CH3:32]>C(O)C.O.Cl>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Yield: 52.4 %

Procedure:
A mixture of 2.00 g (0.0066 mole) of 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1), 1.655 g (0.0099 mole) of 4-amino-3-methoxybenzoic acid and 200 mL of ethanol-water-hydrochloric acid (20:80:1) was refluxed for 18 hours, then concentrated under reduced pressure. The solid was washed with water and then purified by silica gel chromatography, eluting with dichloromethane-methanol-ammonium hydroxide (92:8:0.3) to give 1.500 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-1).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[CH:5]([CH:7]=[O:8])=[O:6]>>[C:7]([OH:2])(=[O:8])[CH:5]=[O:6].[N+:1]([O-:4])([OH:3])=[O:2]
Reactant: O=CC=O
Solvent: O=[N+]([O-])O
Product: O=CC(=O)O

Procedure:
The reaction is carried out at the most desirable temperature, typically 20° to 70° C. If the concentration of the nonoxidizing strong acid is sufficient, the nitric acid concentration of the reaction solution can usually be maintained at 0.1 wt. % or lower when 50 wt. % nitric acid is gradually added (dropwise) to an aqueous solution of glyoxal. The total amount of nitric acid added can be a slight excess in relation to the theoretical amount (2/3 mole of nitric acid per mole of glyoxal). For example, 0.7 to 0.8 moles of nitric acid per one mole of glyoxal can be employed. When nitric acid is used in an excess amount, the nitric acid concentration of the reaction solution is increased slightly to about 0.5 wt. % at the end of the nitric acid addition, but the nitric acid concentration solution does not exceed 1 wt. %. The nitric acid concentration continues to decrease further after completion of the addition of nitric acid and usually reaches 0.005 to 0.03 wt. % in about one hour. Therefore, an aqueous solution of glyoxylic acid having a residual nitric acid concentration of 0.01 wt. % or below can be obtained without purification. In conventional nitric acid oxidation processes, the conversion of glyoxal is scarcely increased merely by adding nitric acid at about 40° C., even when the reaction is promoted by adding about 0.1 mole of sulfuric acid or hydrochloric acid, so that an aging step has generally been carried out by heating the reaction solution to about 80° C. after completion of the nitric acid addition. In this invention, by contrast, aging by heating is not necessary.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18](Cl)=[O:19])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30].Cl.[CH3:32][O:33][C:34](=[O:38])[CH2:35][NH:36][CH3:37]>>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([N:36]([CH3:37])[CH2:35][C:34]([O:33][CH3:32])=[O:38])=[O:19])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30]
Reactant: CNCC(=O)OC
Reactant: COCc1cc(-c2nc(-c3cccc(C(=O)Cl)c3)no2)ccc1-c1ccccc1C
Agent: Cl
Product: COCc1cc(-c2nc(-c3cccc(C(=O)N(C)CC(=O)OC)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described in example 121 starting from 3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoyl chloride, prepared as in example 130, and sarcosine methyl ester hydrochloride. The title compound was obtained as a sticky solid. 1H NMR: (DMSO-d6, 300 MHz) δ 8.42 (brs, 1H), 8.28 (m, 2H), 8.17 (m, 1H), 7.61 (m, 2H), 7.34-7.22 (m, 4H), 7.12 (m, 1H), 4.32 (s, 1H), 4.22 (s, 1H), 3.80 (m, 3H), 3.32 (s, 3H), 3.1 (m, 3H). LC/MS (Method B): 486.2 (M+H)+ no (M−H)−. HPLC (Method A) Rt: 5.66 min (purity: 98.5%).
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:9]1[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:11][CH2:10][C@H:9]2[CH2:12][CH2:13][CH2:14][N:8]2[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 40 °C
Yield: 45 %

Procedure:
A mixture of Boc-D-prolinol (201 mg, 1.0 mmol), p-toluenesulfonyl chloride (400 mg, 2.1 mmol), triethylamine (420 μL, 3.0 mmol), and 4-(dimethylamino)pyridine (12 mg, 0.1 mmol) in dichloromethane (10 mL) was heated at 40° C. for 48 hours, cooled to room temperature, concentrated under vacuum, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated. The residue was purified by column chromatography on silica gel to provide 160 mg (45%) of the desired product.
Reaction SMILES: C(O[C:4]([Cl:6])=O)C.[CH2:7]([S:14][C:15]1[S:16][C:17](CN2CCOCC2)=[CH:18][N:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([S:14][C:15]1[S:16][C:17]([CH2:4][Cl:6])=[CH:18][N:19]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(CSc2ncc(CN3CCOCC3)s2)cc1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Product: ClCc1cnc(SCc2ccccc2)s1
Temperature: 25 °C

Procedure:
5.5 ml of chloroformic acid ethyl ester are added to 8.0 g of 4-(2-benzylsulfanyl-thiazol-5-ylmethyl)-morpholine in 60 ml of tetrahydrofuran, and the mixture is heated at reflux for 5 hours. The mixture is then cooled to room temperature, the solvent is removed by evaporation in vacuo and the residue is purified by chromatography on silica gel with ether-hexane 1:2. 2-Benzylsulfanyl-5-chloromethylthiazole having a melting point of 57-59° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][C:14]2[CH:15]=[N:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[CH:11][C:10]([C:21]([O:23]CC)=O)=[N:9]1.[CH3:26][NH2:27].CO>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][C:14]2[CH:15]=[N:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[CH:11][C:10]([C:21]([NH:27][CH3:26])=[O:23])=[N:9]1
Reactant: CN
Reactant: CCOC(=O)c1cc(Sc2ccc(Cl)nc2)n(-c2ccccc2Cl)n1
Solvent: CO
Product: CNC(=O)c1cc(Sc2ccc(Cl)nc2)n(-c2ccccc2Cl)n1
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of ethyl 1-(2-chlorophenyl)-5-[(6-chloropyridin-3-yl)thio]-1H-pyrazole-3-carboxylate (2.06 g) in methanol (4 mL) was added 40% methylamine-methanol solution (6 mL) at room temperature and the mixture was stirred for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→4:1) to give the title compound as a pale-yellow amorphous form (yield 1.75 g, yield 88%).
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][C:4](=O)[CH3:5].[Cl:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([Cl:19])[C:10]=1[NH:20][NH2:21].C(O)(=O)C>C(O)C>[Cl:8][C:9]1[CH:14]=[C:13]([C:15]([F:16])([F:18])[F:17])[CH:12]=[C:11]([Cl:19])[C:10]=1[N:20]1[C:4]([CH3:5])=[CH:3][C:2]([CH3:1])=[N:21]1
Reactant: CC(=O)CC(C)=O
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(C)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Yield: 85.8 %

Procedure:
Pentan-2,4-dione (0.100 g) was added to a stirred solution of 2,6-dichloro-4-trifluoromethylphenylhydrazine (0.245 g) in ethanol (4.5 ml), followed by glacial acetic acid (0.5 ml), at room temperature. The reaction mixture was heated under reflux for 1 hour, then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using dichloromethane as eluant, to provide a colourless oil initially which crystallised, after removal of extraneous solvent in vacuo, to furnish the title compound (0.265 g), m.p. 87-89° C. δ(CDCl3): 2.10 (s,3H), 2.32 (s,3H), 6.07 (s,1H), 7.72 (s,2H). MS (thermospray): M/Z [M] 309.0; C12H9Cl2F3N2 requires 309.12.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[C:11]([C:24]([NH:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:25])=[N:12][C:13]([CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:14][C:15]=1[CH3:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:36]1[CH:53]=[CH:52][C:39]([CH2:40][C:41]2[CH:51]=[CH:50][CH:49]=[CH:48][C:42]=2[C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:38][CH:37]=1>>[CH2:2]([O:9][C:10]1[C:11]([C:24](=[O:25])[NH:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[N:12][C:13]([CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([C:36]3[CH:53]=[CH:52][C:39]([CH2:40][C:41]4[CH:51]=[CH:50][CH:49]=[CH:48][C:42]=4[C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:38][CH:37]=3)[CH2:22][CH2:23]2)=[N:14][C:15]=1[CH3:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1nc(CC2CCNCC2)nc(C(=O)NCC(=O)OC(C)(C)C)c1OCc1ccccc1
Reactant: CCOC(=O)c1ccccc1Cc1ccc(Br)cc1
Agent: Cl
Product: CCOC(=O)c1ccccc1Cc1ccc(N2CCC(Cc3nc(C)c(OCc4ccccc4)c(C(=O)NCC(=O)OC(C)(C)C)n3)CC2)cc1
Yield: 72 %

Procedure:
In accordance with Example 1-(9), but using tert-butyl ({[5-(benzyloxy)-6-methyl-2-(piperidin-4-ylmethyl)pyrimidin-4-yl]carbonyl}amino)acetate hydrochloride instead of tert-butyl 5-(benzyloxy)-6-methyl-2-(piperidin-4-ylmethyl)pyrimidine-4-carboxylate hydrochloride, and ethyl 2-(4-bromobenzyl)benzoate instead of [(4′-bromobiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane, the title compound (yield 72%) was afforded as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([OH:12])[CH:5]=[CH:4][C:3]=1[C:13](=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16].[C:19]([O:23][C:24](=[O:35])[NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33]O)=[CH:29][CH:28]=1)([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[C:19]([O:23][C:24](=[O:35])[NH:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][O:12][C:6]2[CH:5]=[CH:4][C:3]([C:13](=[O:18])[CH2:14][CH:15]([CH3:16])[CH3:17])=[C:2]([OH:1])[C:7]=2[C:8]([F:9])([F:10])[F:11])=[CH:31][CH:32]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)CC(=O)c1ccc(O)c(C(F)(F)F)c1O
Reactant: CC(C)(C)OC(=O)NCc1ccc(CO)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)CC(=O)c1ccc(OCc2ccc(CNC(=O)OC(C)(C)C)cc2)c(C(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
Mix 1-(2,4-dihydroxy-3-trifluoromethyl-phenyl)-3-methyl-butan-1-one (2 g, 7.63 mmol), (4-hydroxymethyl-benzyl)-carbamic acid tert-butyl ester (1.99 g, 8.39 mmol) and triphenylphosphine (2.20 g, 8.39 mmol) in anhydrous toluene (125 mL) at room temperature under argon gas. Slowly add diisopropyl azodicarboxylate (1.70 g, 8.39 mmol, 1.7 mL) over 30 min. Stir the reaction mixture at room temperature overnight. Concentrate the mixture under reduced pressure and purify the residue by flash chromatography (silica gel) eluting with using 25% ethyl acetate/hexane to provide the product as a white solid (1.5 g, 3.12 mmol, 41% yield). MS (m/z): 480 (M−1).
Reaction SMILES: [C:1]([N:6]=[C:7]=[O:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCCl.C(Cl)(Cl)Cl>[C:1]([NH:6][C:7](=[O:8])[O:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: Oc1ccccc1
Reactant: C=C(C)C(=O)N=C=O
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: C=C(C)C(=O)NC(=O)Oc1ccccc1

Procedure:
A solution of methacryloyl isocyanate (11.1 g; 0.1 mol) in 1,2-dichloroethane (50 ml) was dropise added to a solution of dry phenol (9.4 g; 0.1 mol) in chloroform (20 ml) under nitrogen stream while cooling with ice. After completion of the addition, chloroform and 1,2-dichloroethane were evaporated under reduced pressure. The residue (20.5 g) was recrystallized from a mixture of hexane and benzene to give phenyl N-methacryloylcarbamate as colorless needles. M.P., 94°-95° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.[CH2:11]([Mg]Br)[CH3:12].[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH2:11][CH3:12])=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-Bromo-2-fluorobenzaldehyde (5.1 g) in tetrahydrofuran (50 mL) was added 1M tetrahydrofuran solution of ethylmagnesium bromide (41 mL) at 0° C., and then the reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous solution of ammonium chloride under ice-cooling, and the reaction mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (3.78 g) as a colorless liquid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([N:20]4[CH2:24][CH2:23][CH2:22][C@@H:21]4[CH3:25])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:26]([O:28]C)=[O:27])[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[N:3]=[N:2]1.[OH-].[Na+].O>CO>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([N:20]4[CH2:24][CH2:23][CH2:22][C@@H:21]4[CH3:25])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:26]([OH:28])=[O:27])[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]nnc4c3)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc2[nH]nnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a solution of (S)-methyl 2-(1H-benzo[d][1,2,3]triazol-5-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (130 mg, 0.33 mmol) in methanol (30 mL) was added sodium hydroxide (40.2 mg, 1.00 mmol) and water (1 mL) with stirring for overnight at room temperature. The resulting mixture was concentrated under vacuum and dissolved in water (25 mL), and adjusted to pH 4 with HCl (3N) to give the precipitate, which was collected by filtration to afford (S)-2-(1H-benzo[d][1,2,3]triazol-5-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid (90.3 mg, 72%).
Reaction SMILES: [I-].[CH2:2]([N+:6]1[N:10]=[C:9]([CH3:11])[S:8][C:7]=1[CH3:12])[CH2:3][CH2:4][CH3:5].C1CCN2C(=NCCC2)CC1.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29]([N:31]=[C:32]=[O:33])[CH:30]=1>O>[CH2:2]([N:6]1[N:10]=[C:9]([CH3:11])[S:8]/[C:7]/1=[CH:12]\[C:32]([NH:31][C:29]1[CH:30]=[C:25]([Cl:24])[CH:26]=[CH:27][C:28]=1[O:34][CH3:35])=[O:33])[CH2:3][CH2:4][CH3:5]
Reactant: COc1ccc(Cl)cc1N=C=O
Reactant: CCCC[n+]1nc(C)sc1C
Agent: [I-]
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCN1N=C(C)S/C1=C\C(=O)Nc1cc(Cl)ccc1OC

Procedure:
A solution of the product from Example 47A (149 mg, 0.5 mmol), DBU (105 μL, 0.75 mmol) and 5-chloro-2-methoxy phenyl isocyanate (91 mg, 0.5 mmol) was stirred overnight. The solution was diluted with water (10 mL), extracted with dichloromethane (3×5 mL). The organic layers were combined, washed with brine, dried with sodium sulfate and concentrated in vacuo. The residue was purified by the HPLC procedure specified in Example 47B to obtain the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.5 Hz, 3 H), 1.27-1.39 (m, 2 H), 1.64-1.75 (m, 2 H), 2.36 (s, 3 H), 3.82-3.91 (m, 5 H), 5.81 (s, 1 H), 6.92-7.01 (m, 2 H), 8.36 (d, J=2.4 Hz, 1 H), 8.68 (s, 1 H); MS (ESI) m/z 354 (M+H)+. Anal. Calcd for C16H20ClN3O2S.0.5 C2HF3O2: C, 48.92; H, 4.92; N, 9.99. Found: C, 49.28; H, 5.09; N, 10.07.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5](=O)[CH:6]([O:9][CH3:10])[O:7][CH3:8].Cl.[CH:14]1([C:18](=[NH:20])[NH2:19])[CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(O)C>[CH:14]1([C:18]2[N:19]=[C:5]([CH:6]([O:9][CH3:10])[O:7][CH3:8])[CH:4]=[CH:3][N:20]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: COC(OC)C(=O)C=CN(C)C
Reactant: N=C(N)C1CCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(OC)c1ccnc(C2CCC2)n1
Yield: 12.5 %

Procedure:
To a solution of 4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (2.0 g, 11.5 mmol) in ethanol was added cyclobutanecarboximidamide hydrochloride (3.0 g, 22.3 mmol) and triethylamine (2.33 g, 23.0 mmol) under nitrogen at room temperature. The reaction mixture was refluxed for 16 h. The solvent was removed under reduced pressure. To the residue was added water and the mixture was extracted with ethyl acetate. The combined organics were dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified via column chromatography to afford 2-cyclobutyl-4-(dimethoxymethyl)pyrimidine as a colorless liquid (300 mg, 12%). MS (ES+APCI) (M+H) 209.2; LCMS retention time: 3.257 minutes (Method J).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:22][C:21]=2[O:34]COC)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>CO>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:22][C:21]=2[OH:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCOc1cc(OCc2ccccn2)ccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OCc4ccccn4)cc3O)[nH]c2c1
Temperature: 80 °C

Procedure:
Methyl 3-cyclohexyl-2-[2-(methoxymethoxy)-4-(pyridin-2-ylmethoxy)phenyl]-1H-indole-6-carboxylate was dissolved in MeOH (0.5 M). 3N HCl (2 eq) was added, followed by more MeOH. The mixture was warmed to 80° C. for 6 h. By this time a clear solution had formed. All volatiles were evaporated in vacuo and the residual material was dissolved in DCM. The solution was washed with sat. aq. NaHCO3 and brine. After drying over Na2SO4 all volatiles were evaporated in vacuo leaving a beige amorphous solid (quant). (ES+) m/z 457 (M+H)+.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[O:5]1[CH2:9][CH2:8][C@@H:7]([N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:6]1.N1C=CC=CC=1>C(Cl)Cl>[O:15]=[C:11]1[N:10]([C@@H:7]2[CH2:8][CH2:9][O:5][CH2:6]2)[CH2:14][CH2:13][N:12]1[C:1]([Cl:4])=[O:2]
Reactant: O=C(Cl)Cl
Reactant: O=C1NCCN1[C@@H]1CCOC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cl)N1CCN([C@@H]2CCOC2)C1=O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
A 0° C. solution of phosgene (20% in toluene, 1.132 mL, 2.151 mmol) in DCM (9 mL) was treated slowly with a solution of (R)-1-(tetrahydrofuran-3-yl)imidazolidin-2-one (0.28 g, 1.793 mmol) and pyridine (0.290 mL, 3.59 mmol) in DCM (9 mL) and stirred at 0° C. for 45 min. The mixture was concentrated to dryness to afford crude (R)-2-oxo-3-(tetrahydrofuran-3-yl)imidazolidine-1-carbonyl chloride (100% yield assumed) which was used without further purification.