Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=C[C:8]([C:11]([CH3:40])([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:39])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:29]2C=CC(CC(C)C)=CC=2)([CH3:28])[C:25]([OH:27])=[O:26])[C:12]([OH:14])=[O:13])=CC=1)C(C)C.[OH-].[K+]>C(O)C.O>[O:39]=[C:19]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])[CH2:18][CH2:17][CH2:16][CH2:15][C:11]([CH3:8])([CH3:40])[C:12]([OH:14])=[O:13]
Reactant: CC(C)Cc1ccc(C(C)(CCCCC(=O)CCCCC(C)(C(=O)O)c2ccc(CC(C)C)cc2)C(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(CCCCC(=O)CCCCC(C)(C)C(=O)O)C(=O)O
Yield: 86 %

Procedure:
According to the procedure given for 210f, 209c (30.0 g, 81.0 mmol) was saponified with KOH (85%, 18.9 g, 286 mmol) in ethanol (143 mL) and water (48 mL) at reflux for 5 h. The solid product obtained after extraction and drying was purified by flash chromatography (silica; hexanes/ethyl acetate=90/10) to afford 210c (22.0 g, 86%) as a white solid. Mp 60-61.5° C. 1H NMR (CDCl3): δ 11.40 (br., 2H), 2.41 (t, 4H, J=7.3), 1.62-1.48 (m, 8H), 1.32-1.18 (m, 4H), 1.18 (s, 12H). 13C NMR (CDCl3=77.0 ppm): δ 211.11, 184.74, 42.49, 42.14, 40.42, 24.92, 24.62, 23.99. HRMS (LSIMS, gly): Calcd for C17H31O5 (MH+): 315.2171, found: 315.2183. HPLC: 94.5% pure. Anal. (C17H30O5) C, H.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)[CH3:2].[Cl:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][NH2:21])[CH:16]=[CH:17][CH:18]=1.[BH4-].[Na+]>C(O)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][NH:21][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: NCCc1cccc(Cl)c1
Reactant: CCOc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cccc(CNCCc2cccc(Cl)c2)c1
Reaction time: 15 h

Procedure:
Combine 3-ethoxybenzaldehyde (3.38 g, 22.5 mmol), 2-(3-chlorophenyl)ethylamine (2.33 g, 15.0 mol), and 3 Å molecular sieves (2.88 g) in ethanol (230 ml). Stir the reaction mixture at reflux for 4 hours. Filter to remove the molecular sieves and then slowly add sodium borohydride (1.70 g, 45.0 mmol) to the filtrate and stir at ambient temperature. After 15 hours, concentrate the reaction mixture to a residue, dissolve the residue in 1 N NaOH, and extract with dichloromethane. Combine organic extracts, wash with brine, dry over Na2SO4, and concentrate to a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give the title compound. The HCl salt was prepared in ethyl acetate to give the title compound: mp 178-180° C.; MS (ACPI): m/e 290.1 (M+1); Analysis for C17H21Cl2NO: Calcd: C, 62.58; H, 6.49; N, 4.29. Found: C, 62.65; H, 6.53; N, 4.32.
Reaction SMILES: Cl[C:2]([C:6]1[C:7]([Cl:12])=[N:8][CH:9]=[CH:10][CH:11]=1)=[CH:3][C:4]#[N:5].Cl.[CH2:14]([CH:16]1[CH2:18][CH:17]1[NH2:19])[CH3:15].C(N(CC)CC)C>C(#N)C>[Cl:12][C:7]1[C:6]([C:2]([NH:19][CH:17]2[CH2:18][CH:16]2[CH2:14][CH3:15])=[CH:3][C:4]#[N:5])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CCC1CC1N
Reactant: N#CC=C(Cl)c1cccnc1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC1CC1NC(=CC#N)c1cccnc1Cl
Yield: 57.3 %

Procedure:
To a solution of 3-chloro-3-(2-chloropyridin-3-yl)acrylonitrile (1.4 g, 7.03 mmol, 1 eq.) in 15 ml of acetonitrile was added 2-ethylcyclopropanamine hydrochloride (1.02 g, 8.44 mmol, 1.2 eq.) followed by triethylamine (TEA) (1.06 g, 10.55 mmol, 1.5 eq.). The reaction was microwaved (130° C., 2000 s, fixed hold, high absorption) and the solvent evaporated. The residual oil was triturated in ethyl acetate and the white solid removed by filtration. After concentration under vacuum, the residual oil was subjected to column chromatography to give 3-(2-chloropyridin-3-yl)-3-[(2-ethylcyclopropyl)amino]acrylonitrile (0.998 g, 51% yield).
Reaction SMILES: [CH:1]1[CH2:2][C:3](=O)[CH:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.[OH2:12]>>[CH3:4][CH:5]1[C:10](=[O:12])[C:2]2=[CH:1][C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=[C:3]2[CH2:6]1
Reactant: O=C1C=c2ccccc2=CC1
Reactant: O
Product: CC1Cc2cc3c(cc2C1=O)CCCC3

Procedure:
The reaction is diluted with water and extracted with dichloromethane. After drying (Na2SO4) the solvent is removed to give an oil. The product is purified by chromatography (silica, ethyl acetate/hexane) to give a geometrical mixture of isomers containing 2-Methyl-1,2,6,7,8,9-hexahydro-cyclopenta[.a.]naphthalen-3-one and the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([CH3:12])=[CH:10][C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)=[N:8][C:7]=12)#[CH:2].Br[C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[CH3:12][C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:24]3[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=3)=[C:7]2[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc2c(C#Cc3ccc(S(N)(=O)=O)cc3)cnn12

Procedure:
The title compound was prepared from 3-ethynyl-7-methyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.12) (75 mg, 0.25 mmol) and 4-bromo-benzenesulfonamide (59 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (62 mg, 54%). MS (ISN) 454.9 [(M−H)−]; mp 282-284° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[N:37]1([CH2:43][C:44]([NH2:46])=[O:45])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:40]3[CH2:41][CH2:42][N:37]([CH2:43][C:44]([NH2:46])=[O:45])[CH2:38][CH2:39]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NC(=O)CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12j) and 2-piperazin-1-yl-acetamide (Matrix) in an analogous manner as described in example 25. LR-MS: 647.3 [(M+H)+]
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:35][CH2:34][CH2:33][CH:32]2[C:36]2[CH:37]=[C:38]([C:53](O)=[O:54])[CH:39]=[C:40]3[C:45]=2[O:44][C:43]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[CH:42][C:41]3=[O:52])[CH:27]=[C:28]([F:30])[CH:29]=1.CCN(C(C)C)C(C)C.Cl.[NH:66]1[CH2:71][CH2:70][S:69](=[O:72])[CH2:68][CH2:67]1>C(Cl)Cl>[F:30][C:28]1[CH:27]=[C:26]([N:31]2[CH2:35][CH2:34][CH2:33][CH:32]2[C:36]2[CH:37]=[C:38]([C:53]([N:66]3[CH2:71][CH2:70][S:69](=[O:72])[CH2:68][CH2:67]3)=[O:54])[CH:39]=[C:40]3[C:45]=2[O:44][C:43]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[CH:42][C:41]3=[O:52])[CH:25]=[C:24]([F:23])[CH:29]=1
Reactant: O=S1CCNCC1
Reactant: O=C(O)c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1)N1CCS(=O)CC1
Reaction time: 2.5 h
Yield: 57.8 %

Procedure:
TBTU (176 mg, 0.55 mmol) was added in one portion to a stirred solution of 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (125 mg, 0.27 mmol) and DIPEA (0.286 mL, 1.64 mmol) at room temperature and stirred for 2.5 h. Thiomorpholine 1-oxide hydrochloride (85 mg, 0.55 mmol) was added to the reaction mixture and stirring was continued for 3 h. The reaction mixture was diluted with DCM, washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by preparative HPLC. The fractions were evaporated to dryness, the residue was dissolved in DCM, dried over MgSO4 and concentrated. The remaining solid was triturated with diethyl ether, filtered, washed with diethyl ether and dried under vacuum at 50° C. to afford 8-[1-(3,5-difluorophenyl)pyrrolidin-2-yl]-2-morpholino-6-(1-oxo-1,4-thiazinane-4-carbonyl)chromen-4-one (87 mg, 57%) as a pale beige solid.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[CH2:18][CH:17]2Br>C1COCC1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[CH:18]=[CH:17]2
Reactant: COc1ccc2c(c1)C(Br)CC2=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C=CC2=O
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
DBU (9.2 mL, 61.7 mmol) was added to a solution of 5-methoxy-3-bromo-1-indanone (14.8 g, 61.7 mmol) in THF (100 mL) at −10° C. dropwise over 10 minutes. The resulting solution was stirred at −10° C. for 20 minutes, quenched via addition of saturated aqueous NH4Cl (100 mL), and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO4, and concentrated. The crude product was purified by column chromatography (SiO2) using a 0-35% ethyl acetate-hexanes gradient to afford 5.4 g (55%−two steps) of the subtitle compound. 1H NMR (CDCl3 300 MHz) δ 7.42 (d, 1H), 7.38 (d, 1H), 6.62 (s, 1H), 6.60 (d, 1H), 5.89 (d, 1H), 3.85 (s, 3H) ppm. MS calculated for C10H8O2+H: 161, observed: 161.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:6][C:5]=1[C:15]([NH2:17])=[O:16])[CH3:2].[CH3:18][C:19]([CH3:21])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:1]([N:3]1[C:4]2[CH:8]=[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)[S:6][C:5]=2[C:15](=[O:16])[NH:17][C:19]1([CH3:21])[CH3:18])[CH3:2]
Reactant: CC(C)=O
Reactant: CCNc1cc(-c2ccncc2)sc1C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCN1c2cc(-c3ccncc3)sc2C(=O)NC1(C)C
Temperature: 70 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A mixture of 3-(ethylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (0.100 g, 0.400 mmol), acetone (3.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred overnight at 70° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (100 mL). Extraction with ethyl acetate-tetrahydrofuran (2:1, 100 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. The oil was purified by column chromatography (Combiflash, 12 g silica gel, hexane to ethyl acetate) to afford the title compound (0.0898 g, 63%) as a yellow solid:
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].[Cl-].[Al+3].[Cl-].[Cl-].Cl>O>[C:7]([C:11]1[CH:16]=[CH:15][C:14]([CH:2]([OH:1])[C:3]([Cl:6])([Cl:5])[Cl:4])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1ccccc1
Reactant: O=CC(Cl)(Cl)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(C)(C)c1ccc(C(O)C(Cl)(Cl)Cl)cc1
Temperature: 5 °C

Procedure:
A solution of 22 g (0.15 mole) of chloral and 15g of tert-butylbenzene was added in ten portions alternatively with 4.4g (0.03 mole) of aluminum chloride to a 120g portion of tert-butylbenzene with vigorous stirring at 5°C. The mixture was stirred at 20°C. for 0.5 hr. and again cooled to 5°C. before 40 ml of 6N HCl was added dropwise. The mixture was diluted with 20 ml of water and the organic products were extracted into ethyl ether (2 × 100 ml). The etheral solution was washed with 5% HCl, water, aqueous sodium carbonate and brine, dried over magnesium sulfate and concentrated. A 27g portion of the 33g residue was distilled via short path to provide 18.4g of a colorless, viscous product: Bp 144°C (0.2mm); ir (film) 2.85 (s), 3.4 (s), 9.4 (s), 12.1 (s), 12.8 (s) microns; nmr (CDCl3) 7.40 (4H, m), 5.06 (1H,s), 3.56 (1H, s), 1.28 (9H, s) ppm.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:36]([CH3:37])=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][C:5]=1[CH3:38].[F:39][C:40]([F:51])([F:50])[C:41]1[CH:46]=[CH:45][C:44]([N:47]=[C:48]=[O:49])=[CH:43][CH:42]=1.C(N(CC)CC)C>O1CCCC1>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:15]3[N:14]([CH3:33])[C:13]4[CH:34]=[C:9]([O:8][C:7]5[CH:6]=[C:5]([CH3:38])[C:4]([NH:3][C:48]([NH:47][C:44]6[CH:43]=[CH:42][C:41]([C:40]([F:39])([F:50])[F:51])=[CH:46][CH:45]=6)=[O:49])=[C:36]([CH3:37])[CH:35]=5)[CH:10]=[CH:11][C:12]=4[N:16]=3)=[CH:32][CH:31]=2)[S:28]1
Reactant: Cc1cc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc(C)c1N
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc(C)c1NC(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 74.5 %

Procedure:
A mixture of 5-[4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (288 mg), α,α,α-trifluoro-p-tolyl isocyanate (112 mg), triethylamine (121 mg) and anhydrous tetrahydrofuran (10 ml) was stirred at room temperature for 40 hours. The reaction mixture was concentrated and diluted with water. The precipitate was isolated by filtration and washed with water and ethyl acetate to afford the title compound (257 mg, mp 206-208° C.).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[I:15](O)(O)(O)(O)(O)=O.II.S(=O)(=O)(O)O>O.C(O)(=O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][C:10]([I:15])=[CH:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: [O-][I+](O)(O)(O)(O)O
Reactant: Brc1ccc2oc3ccccc3c2c1
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Brc1ccc2oc3ccc(I)cc3c2c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
2-Bromodibenzofuran (2.5 g, 10.1 mmol), orthoperiodic acid (0.49 g, 2.15 mmol), iodine (1.02 g, 4.02 mmol), sulfuric acid, H2O (2 ml) and acetic acid (10 ml) are put into a reaction vessel and the mixture is stirred at 70° C. for 3 hours. After cooling to room temperature the reaction mixture is poured into water and filtered. The white solid is washed by methanol and the desired product is obtained (1.92 g, 51%).
Reaction SMILES: Cl[C:2]1[C:11](/[CH:12]=[CH:13]/[CH2:14][OH:15])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:16][O-:17].[Na+]>CO.C(OCC)(=O)C>[CH3:16][O:17][C:2]1[C:11](/[CH:12]=[CH:13]/[CH2:14][OH:15])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[O-]
Reactant: OC/C=C/c1cc2ccccc2nc1Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1nc2ccccc2cc1/C=C/CO
Yield: 80 %

Procedure:
A mixture of (E)-3-(2-chloro-3-quinolinyl)-2-propen-1-ol (5.74 g) and sodium methoxide (28% in methanol; 10 ml) in MeOH (30 ml) was refluxed for 2 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried and concentrated. The residue was washed with cyclohexane-i-Pr2O to give the titled compound (4.50 g; 80%) as a colorless solid.
Reaction SMILES: [C:1]([CH2:5][N:6]=[C:7]=[O:8])([O:3][CH3:4])=[O:2].[OH:9][C:10]1[CH:15]=[CH:14][NH:13][C:12](=[O:16])[CH:11]=1>O1CCOCC1>[C:1]([CH2:5][NH:6][C:7]([N:13]1[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][C:12]1=[O:16])=[O:8])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)CN=C=O
Reactant: O=c1cc(O)cc[nH]1
Solvent: C1COCCO1
Product: COC(=O)CNC(=O)n1ccc(O)cc1=O
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A 2.49 g quantity of carbomethoxymethylisocyanate was added to a suspension of 2.00 g of 4-hydroxy-2(1H)-pyridone in 60 ml of dioxane, and the mixture was stirred at 90° C. for 30 minutes. The solvent was distilled off, and ether was added to the residue. The precipitate thus formed was filtered, giving 2.20 g of the title compound in a yield of 54%.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]=[C:10]=[S:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[NH2:12][C:13]1[S:14][CH:15]=[CH:16][N:17]=1.C(OCC)(=O)C>CN(C)C=O>[C:1]1([CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[S:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: S=C=NCCC1=CCCCC1
Reactant: Nc1nccs1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: S=C(NCCC1=CCCCC1)Nc1nccs1
Temperature: 25 °C
Yield: 49.7 %

Procedure:
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (3.3 g, 20 mmol) and 2-aminothiazole (2.0 g, 20 mmol) in N,N-dimethylformamide (20 mL) was heated at 100° C. for 24 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 2.66 g (50%) of the title product:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:12]=[O:13])=[N:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.[CH2:14](O)[CH2:15][OH:16].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:13]1[CH2:14][CH2:15][O:16][CH:12]1[C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[C:6]([N+:9]([O-:11])=[O:10])[N:5]=1
Reactant: COc1ccc([N+](=O)[O-])nc1C=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc([N+](=O)[O-])nc1C1OCCO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 884.2 %

Procedure:
A mixture of 0.55 g (0.3 mmol) 3-methoxy-6-nitro-pyridine-2-carbaldehyde, 0.8 ml (15 mmol) of ethylene glycol, and 10 mg (catalytic amount) of p-toluene sulfonic acid was refluxed in 50 ml of toluene using a Dean-Stark trap to trap water. After 90 minutes, the reaction mixture was cooled to room temperature and the solvent evaporated. The residue was chromatographed on silica using 5:1 (chloroform/ethyl acetate) as the elutant. Appropriate fractions were combined and evaporated to yield 0.6 g of 2-[1,3]dioxolan-2-yl-3-methoxy-6-nitro-pyridine as an oil. TLC: Rf=0.9 (1:1 chloroform/ethyl acetate). 1H NMR (CDCl3) δ 8.25 (d, 1H), 7.40 (d, 1H), 6.30 (s, 1H), 4.30 (m, 2H), 4.10 (m, 2H), 4.0 (s, 3H). Mass Spectrum: m/e=227.2 (p+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16](I)=[C:15]([Cl:20])[CH:14]=1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)=[C:15]([Cl:20])[CH:14]=1
Reactant: Clc1cc(Br)ccc1I
Reactant: OCc1ccc(B(O)O)cc1
Product: OCc1ccc(-c2ccc(Br)cc2Cl)cc1
Yield: 12 %

Procedure:
In accordance with Example 4-(2), but using [4-(hydroxymethyl)phenyl]boronic acid instead of 4-bromophenylboronic acid, and 4-bromo-2-chloro-1-iodobenzene instead of tert-butyl[2-(4-iodophenyl)ethoxy]dimethylsilane, the title compound (yield 12%) was afforded as a yellow solid.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([CH:12]=[O:13])[CH:9]=[CH:8][C:7]=1[O:14][CH3:15])(=[O:4])=[O:3].S(=O)(=O)([OH:18])N.Cl([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:15][O:14][C:7]1[CH:8]=[CH:9][C:10]([C:12]([OH:18])=[O:13])=[CH:11][C:6]=1[O:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: NS(=O)(=O)O
Reactant: COc1ccc(C=O)cc1OS(C)(=O)=O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C(=O)O)cc1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 268.1 %

Procedure:
5-formyl-2-methoxyphenyl methanesulfonate (3.3 g, 14 mmol) was dissolved in acetic acid (50 ml) and sulfamic acid (500 mg, 5.15 mmol) was added. Sodium chlorite (3 g, 33.2 mmol) was dissolved in H2O (20 ml) and added dropwise. The reaction was stirred at RT overnight, then the precipitate was filtered and washed with HCl 1 M, MeOH and dried in the vacuum oven, to give 3.4 g of the desired product (Yield: 99%).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11]3[N:16]4[CH:17]=[N:18][CH:19]=[C:15]4[CH:14]=[CH:13][C:12]=3[C:20](O)=[O:21])=[C:6]([F:23])[CH:5]=2)[CH2:3][CH2:2]1.[CH:24]([O:26][CH2:27][CH2:28][O:29][NH2:30])=[CH2:25].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:24]([O:26][CH2:27][CH2:28][O:29][NH:30][C:20]([C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:17]=[N:18][CH:19]=2)[C:11]=1[NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:5][C:6]=1[F:23])=[O:21])=[CH2:25]
Reactant: O=C(O)c1ccc2cncn2c1Nc1ccc(C2CC2)cc1F
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1ccc2cncn2c1Nc1ccc(C2CC2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.8 %

Procedure:
To a mixture of 5-(4-cyclopropyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (400 mg, 1.29 mmol), O-(2-vinyloxyethyl)-hydroxylamine (265 mg, 2.57 mmol) and HOBt (225 mg, 1.67 mmol) in DMF (5 mL) was added EDCI hydrochloride (320 mg, 1.67 mmol), and DIPEA (0.290 mL, 1.67 mmol) before the reaction mixture was stirred at room temperature for 18 hours. The products were partitioned between ethyl acetate and saturated aqueous NaHCO3, the organic layer separated and washed with brine then dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0-35% ethyl acetate in cylcohexane) to give the title compound (270 mg, 53%). LCMS (Method B): RT 2.79 [M+H]+ 397.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.C(OC([NH:25][C@H:26]1[C@H:29]([CH3:30])[N:28]([S:31]([O-:34])(=[O:33])=[O:32])[C:27]1=[O:35])=O)(C)(C)C>C(O)=O.C(Cl)Cl>[NH2:25][C@H:26]1[C@H:29]([CH3:30])[N:28]([S:31]([OH:34])(=[O:32])=[O:33])[C:27]1=[O:35]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1S(=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: O=CO
Product: C[C@H]1[C@H](N)C(=O)N1S(=O)(=O)O
Reaction time: 5 h

Procedure:
(3S-trans)-3-[(t-Butoxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinesulfonic acid tetra-n-butylammonium salt (6.3 g) is dissolved in 30 ml of 97% formic acid and stirred for 5 hours during which time a precipitate forms. The slurry is diluted with 30 ml of methylene chloride and filtered. The solids are further washed with methylene chloride and dried to yield 1.53 g of analytically pure product [αD21 =-41.0[c=1, water].
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:7]=2[NH2:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18].C(OCC)C>ClC1C=CC=CC=1Cl>[F:16][C:13]([F:14])([F:15])[C:10]1[CH:9]=[C:7]2[C:6](=[CH:12][CH:11]=1)[N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:17](=[O:18])[NH:8]2
Reactant: Nc1cc(C(F)(F)F)ccc1-n1ccnc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: Clc1ccccc1Cl
Solvent: CCOCC
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2n2ccnc12
Yield: 75.4 %

Procedure:
To a solution of 2-(1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (17.00 g; 74.8 mmol; 1 eq) in anhydrous 1,2-dichlorobenzene (375 mL), commercially available carbonyldiimidazole (24.72 g; 149.7 mmol; 2 eq) is added under an argon atmosphere. This reaction mixture is allowed to stir under reflux for 2 hours. The expected quinoxalinone precipitates as a grey powder during the reflux. The initial crystal clear solution quickly turns black after heating and becomes non homogeneous. This crude reaction mixture is allowed to precipitate at 4° C. during 48 hours. The grey powder formed is then filtered off on a fritted glass. This solid is transferred in a 1 L flask, diluted in fresh ethyl acetate (500 mL) and heated to gentle reflux for two hours. Hot filtration and then several washings of the solid with diethyl ether afforded the title compound (14.28 g; 56.4 mmol; 75%) as a grey powder.