Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:15](=[O:25])[C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:15](=[O:25])[C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2ccccc2Cc2cc(Cl)ccc21
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)N2Cc3ccccc3Cc3cc(Cl)ccc32)cc1
Yield: 73.9 %

Procedure:
A solution of 2.1 g of 2-chloro-5-(4-nitro-benzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine in 400 ml of ethyl acetate-ethanol (1:1) and 0.25 g of palladium-on-carbon is hydrogenated in a Parr hydrogenator under 38 pounds per square inch of hydrogen. The mixture is filtered through diatomaceous earth and the filtrate concentrated to dryness. The solid (1.94 g) is dissolved in dichloromethane and the solution filtered through a thin pad of hydrous magnesium silicate. The filter pad is washed with dichloromethane and the filtrate concentrated. The residue is crystallized from dichloromethane-hexane to give 1.43 g of crystals, m.p. 211°-214° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][NH:15]2)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[OH:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][N:15]2[C:30](=[O:31])[C:29]2[CH:33]=[CH:34][CH:35]=[C:27]([OH:26])[CH:28]=2)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: O=C(O)c1cccc(O)c1
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC3CCCCN3)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCCCN3C(=O)c3cccc(O)c3)c2c1N

Procedure:
Prepared as in Example 24a from ethyl 4-amino-2-methyl-5-(piperidin-2-ylmethoxy)-quinoline-3-carboxylate (Example 111b) and 3-hydroxybenzoic acid as a white solid (28%). MS 464 (MH+).
Reaction SMILES: N#N.Br[C:4]1[S:5][C:6]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[CH:7][N:8]=1.[Li]CCCC.CN([CH:26]=[O:27])C.[NH4+].[Cl-]>CCOCC.CCCCCC>[Si:11]([O:10][CH2:9][C:6]1[S:5][C:4]([CH:26]=[O:27])=[N:8][CH:7]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc(Br)s1
Agent: N#N
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1cnc(C=O)s1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)thiazole (WO 2009/077990, p. 92) (2.0 g, 6.49 mmol) in Et2O (14.0 mL) was treated dropwise at −70° C. with n-BuLi (4.25 mL of a 1.6M solution in hexane, 6.81 mmol). The resulting mixture was stirred for 30 min at −70° C. DMF (0.80 mL, 10.38 mmol) was then added and the resulting mixture was stirred for 20 min at −70° C. Sat. aq. NH4Cl was added, the org. layer was extracted with EA (3×20 mL) and the combined org. layers were dried over MgSO4, filtered and the solvent was removed under reduced pressure to give 1.50 g of 5-(((tert-butyldimethylsilyl)oxy)methyl)thiazole-2-carbaldehyde as a yellow oil: TLC: rf (9:1 hept-EA)=0.31. LC-MS-conditions 07: tR=1.00 min, [M+H]+=257.93. A solution of this material in MeOH (10 mL) was treated at 0° C. with NaBH4 (286 mg, 7.25 mmol). After 30 min at 0° C., water followed by EA were added. The org. layer was extracted with EA (3×20 mL) and the combined org. layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a yellow oil: TLC: rf (1:1 hept-EA)=0.33. LC-MS-conditions 07: tR=0.87 min, [M+H]+=260.06.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[F:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.ClCCl.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([F:24])[C:30]=2[F:31])=[CH:17][CH:16]=1
Reactant: OB(O)c1cccc(F)c1F
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2cccc(F)c2F)cc1
Yield: 48.1 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(2,3-difluorobenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.080 g; 0.230 mmol), 2,3-difluorophenylboronic acid (0.041 g; 0.242 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride, complex with dichloromethane (0.019 g; 0.023 mmol), sodium carbonate (0.048 g; 0.460 mmol), sodium iodide (0.069 g; 0.460 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 20 to 80% ethyl acetate in heptane) furnished 0.047 g (48%) of the title compound as a white solid.
Reaction SMILES: C(OC([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](CCOS(C)(=O)=O)[CH:18]=2)[NH:13][C:12]=1C)=O)C1C=CC=CC=1.CC12CC([NH:34]C1)CC(C)(C)C2>O1CCOCC1>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:12]1[NH2:34]
Reactant: CC1(C)CC2CC(C)(CN2)C1
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Solvent: C1COCCO1
Product: Nc1cc2ccccc2[nH]1
Yield: 182.5 %

Procedure:
5-(2-Methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.200 g, 0.510 mmol, 1 eq, Example 56, Step D) was suspended in dioxane (30 mL) under Ar. 1,3,3-trimethyl-6-azabicyclo-[3,2,1]octane (0.235 g, 1.540 mmol, 3 eq) was added. The reaction mixture was stirred and heated to reflux for 18 hours. Then the reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic phases were washed with brine and dried over Na2SO4. After removing the solvent, the residue was loaded on silica gel and chromatographed, eluting with ethyl acetate/methanol/triethyl amine (100/10/1). 0.123 g (54%) of the indole-amine was obtained as a white solid. This was converted to the .HCl salt. LC/MS (ESI+) 446 (M+1); Anal. Calcd for C29H36N2O2.1HCl.1.25H2O: C, 68.55; H, 7.93; N, 5.51; Found: C, 68.66; H, 7.54; N, 5.41.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(=O)C(Cl)=O.CO>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)ccc1Br
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a suspension of 2-bromo-5-methyl-benzoic acid (3.0 g, 14 mmol) in dichloromethane (100 ml) was added a solution of oxalyl chloride in dichloromethane (2 M, 8 ml, 16 mmol) followed by N,N-dimethylformamide (5 drops). After stirring for 30 minutes, methanol (15 ml) was added. After stirring for 3 hours, the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (200 ml) and saturated aqueous potassium carbonate solution (100 ml). The organic layer was concentrated under reduced pressure to provide methyl 2-bromo-5-methyl-benzoate (3.2 g, 99% yield).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]([NH:15]C(=O)OC(C)(C)C)=[N:11][CH:12]=[CH:13][CH:14]=2)O1.Br[C:25]1[C:26]([C:31]#[N:32])=[N:27][CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CO>[CH:14]1[C:9]2=[C:25]3[C:26](=[C:31]([NH2:32])[N:15]=[C:10]2[N:11]=[CH:12][CH:13]=1)[N:27]=[CH:28][CH:29]=[CH:30]3
Reactant: N#Cc1ncccc1Br
Reactant: CC(C)(C)OC(=O)Nc1ncccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCO
Product: Nc1nc2ncccc2c2cccnc12
Temperature: 25 °C

Procedure:
A solution of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ylcarbamate (1.0 eq.) and 3-bromopicolinonitrile (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (2.0 eq.) in toluene/ethanol (2:1, 0.03 M) was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction content was diluted with methanol. The insoluble solids were filtered off, and the filtrate was concentrated en vacuo to obtain a crude residue. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give pyrido[3,2-f][1,7]naphthyridin-6-amine as a white solid. 1H NMR (dmso-d6): δ 9.14 (dd, 1H), 8.98 (dd, 1H), 8.90 (dd, 1H), 7.93 (dd, 1H), 7.60 (bs, 2H), 7.30 (dd, 1H). LRMS [M+H]=197.
Reaction SMILES: C[O:2][C:3]([CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH3:21])[C:13]=1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:4].[OH-].[Li+]>>[C:3]([CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH3:21])[C:13]=1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)([OH:4])=[O:2]
Reactant: COC(=O)C=CCCCCCc1c(-c2cccnc2)n(C)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Product: Cn1c(-c2cccnc2)c(CCCCCC=CC(=O)O)c2ccccc21

Procedure:
Hydrolysis of 50 mg of 3-(7-methoxycarbonylhept-6-enyl)-2-(3-pyridyl)-1-methylindole with 1N aqueous lithium hydroxide yields 3-(7-carboxyhept-6-enyl)-2-(3-pyridyl)-1-methylindole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[OH:12].[CH2:13]=[O:14].ClCCl>[OH-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([CH2:13][OH:14])=[C:7]2[OH:12]
Reactant: Oc1ccnc2c(F)cccc12
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: OCc1cnc2c(F)cccc2c1O

Procedure:
8-Fluoro-4-hydroxyquinoline was reacted with formaldehyde in aqueous sodium hydroxide to give the novel compound 8-fluoro-4-hydroxy-3-hydroxymethylquinoline, m.p. 176°-178° (from dichloromethane).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:11]1([C:15]2[CH:52]=[CH:51][CH:50]=[CH:49][C:16]=2[CH2:17][CH2:18][C:19]2[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][N:22]=[C:21]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([CH:36]4[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]4)=[CH:32][CH:31]=3)[N:20]=2)[CH2:14][CH2:13][CH2:12]1)(=[O:10])[NH2:9]>C(Cl)Cl>[NH:39]1[CH2:40][CH2:41][CH:36]([C:33]2[CH:32]=[CH:31][C:30]([NH:29][C:21]3[N:20]=[C:19]([CH2:18][CH2:17][C:16]4[CH:49]=[CH:50][CH:51]=[CH:52][C:15]=4[C:11]4([C:8]([NH2:9])=[O:10])[CH2:14][CH2:13][CH2:12]4)[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][N:22]=3)=[CH:35][CH:34]=2)[CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C4(C(N)=O)CCC4)n3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3ccc(C4CCNCC4)cc3)ncc2C(F)(F)F)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of TFA (0.5 mL) and tert-butyl 4-(4-((4-(2-(1-carbamoylcyclobutyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate A57 (6.0 mg, 9.6 μL) in DCM (5 mL) was stirred at room temperature overnight. The volatiles were removed in vacuo before 2 M aq. NaOH (5 mL) was added to form a precipitate. The solid was collected by filtration and washed with cyclohexane (10 mL) to give the title compound 52 as a tan solid (1.5 mg, 30%). LCMS-A: rt 4.994 min; m/z 524.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:16])=[CH:9][C:10]([CH3:15])([CH3:14])[O:11]2)=[CH:6][C:5]=1/[C:17](/[CH2:29][CH3:30])=[CH:18]\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([O:25]CC)=[O:24])[CH3:2].[OH-].[Na+]>>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:16])=[CH:9][C:10]([CH3:15])([CH3:14])[O:11]2)=[CH:6][C:5]=1/[C:17](/[CH2:29][CH3:30])=[CH:18]\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([OH:25])=[O:24])[CH3:2]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(/CC)c1cc2c(cc1OCC)OC(C)(C)C=C2C
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc2c(cc1/C(=C\C=C\C(C)=C\C(=O)O)CC)C(C)=CC(C)(C)O2

Procedure:
Following General Procedure G, ethyl 7-(7-ethoxy-2,2,4-trimethyl-2H-chromen-6-yl)-3-methyl-nona-2E,4E,6Z-trienoate (Compound 36, 33 mg, 0.086 mmol) was hydrolyzed with 1M NaOH. Purification by column chromatography (silica gel, 30% ethyl acetate in hexanes) followed by recrystallization from acetonitrile gave rise to the title compound as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12]>C(O)C>[CH3:18][CH2:17][O:16][C:14]([C:13]1[CH:7]([CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]#[N:12])[C:6]2[CH:9]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[O:10][C:11]=1[NH2:12])=[O:15]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CCOC(=O)CC#N
Solvent: CCO
Product: CCOC(=O)C1=C(N)Oc2ccc(Br)cc2C1C(C#N)C(=O)OCC
Temperature: 25 °C
Reaction time: 14 h
Yield: 86 %

Procedure:
To a suspension of the 5-bromosalicylaldehyde (0.010 mol) in dry ethyl alcohol (30 ml) was added ethyl cyanoacetate (0.022 mol) and 3.0 grams of molecular sieve 3Å powder (Aldrich Chemical Company). The resulting mixture was stirred at room temperature overnight (14 h). Most of the 5-bromosalicylaldehyde disappeared within the first 2 hours as layer chromatography (TLC). The molecular sieve was then filtered off and washed 3 times with tetrahydrofuran. The filtrates were combined and the solvent was removed under vacuum. The residue solidified when incubated at −24° for 2 hours. The desired product was obtained by crystallization in 85% ethanol as a single diastereoisomeric pair. The yield was 86%.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:15])[C:9]([OH:14])=[C:10]([CH3:13])[CH:11]=2)[O:6][C:5](=[O:16])[CH:4]=1.[OH-:17].[Na+].Cl>>[OH:14][C:9]1[C:10]([CH3:13])=[CH:11][C:12]2[C:3]([CH2:4][C:5]([OH:16])=[O:17])=[CH:2][O:6][C:7]=2[C:8]=1[CH3:15]
Reactant: [OH-]
Reactant: Cc1cc2c(CCl)cc(=O)oc2c(C)c1O
Agent: Cl
Agent: [Na+]
Product: Cc1cc2c(CC(=O)O)coc2c(C)c1O
Yield: 75 %

Procedure:
4.8 g (20.1 mmol) of 4-(Chloromethyl)-7-hydroxy-6,8-dimethyl-2H-chromen-2-one are heated at reflux for 3 h in 11 of 0.2 N NaOH. The reaction solution is adjusted to pH 3 with HCl and extracted 4 times with ethyl acetate. The combined organic phases are washed with a saturated solution of NaCl, dried over sodium sulfate and concentrated. 3.3 g (75%) of 2-(6-hydroxy-5,7-dimethyl-1-benzofuran-3-yl) acetic acid are obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([F:13])=[C:7]([F:12])[CH:8]=2)[N:3]=1.[NH2:14][NH2:15]>CCO>[NH:14]([C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([F:13])=[C:7]([F:12])[CH:8]=2)[N:3]=1)[NH2:15]
Reactant: Fc1cc2ncc(Cl)nc2cc1F
Reactant: NN
Solvent: CCO
Product: NNc1cnc2cc(F)c(F)cc2n1
Reaction time: 8 h

Procedure:
The foregoing methodology was followed starting with 2-chloro-6,7-difluoroquinoxaline. This compound (4.00 g, 19.9 mmol) was dissolved in 100 ml of absolute EtOH. Hydrazine (1.4 ml, 44 mmol) was added, and the mixture heated at reflux for 21/2 hours. The mixture was cooled and allowed to stand overnight before collecting the resulting precipitate, yielding 3.80 g of an orange, solid 2-hydrazino-6,7-difluoroquinoxaline. This product (3.8 g, 19.4 mmol) was stirred in 30 ml triethylorthoformate and heated at reflux (100° C.) for 5 hours. The resulting product was cooled to room temperature, filtered and dried, yielding 2.63 g of 7,8-difluoro-1,2,4-triazolo[4,3-a]quinoxaline (13).
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:20][CH:21]([F:30])[O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>>[F:20][CH:21]([F:30])[O:22][C:23]1[CH:24]=[CH:25][C:26]([NH:27][C:2]2[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:28][CH:29]=1
Reactant: Nc1ccc(OC(F)F)cc1
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: COCCN1C(=O)C(Nc2ccc(OC(F)F)cc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 4-(difluoromethoxy)aniline in a similar manner as described for Examples 9 and 13. 1H NMR (400 MHz, CD3CN): δ 3.38 (s, 3H), 3.72 (t, 2H), 3.91 (t, 2H), 6.57 (t, 1H), 6.74-6.79 (m, 2H), 6.81-6.86 (m, 2H), 7.10-7.20 (m, 4H), 7.25-7.30 (m, 1H), 7.80 (bs, 1H); Mass Spectrum: M+H+ 425.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:7][NH:6][CH2:5]1.C(N(CC)CC)C.[NH2:15][C:16]1[N:21]=[C:20]([N:22]2[C:31]3[C:26](=[CH:27][C:28]([F:34])=[C:29](F)[C:30]=3[Cl:32])[C:25](=[O:35])[CH:24]([C:36]([OH:38])=[O:37])[C:23]2=[O:39])[C:19]([C:40]#[N:41])=[CH:18][C:17]=1[F:42].C(O)C>CN(C)C=O>[NH2:3][CH:4]1[CH2:7][N:6]([C:29]2[C:30]([Cl:32])=[C:31]3[C:26]([C:25](=[O:35])[CH:24]([C:36]([OH:38])=[O:37])[C:23](=[O:39])[N:22]3[C:20]3[C:19]([C:40]#[N:41])=[CH:18][C:17]([F:42])=[C:16]([NH2:15])[N:21]=3)=[CH:27][C:28]=2[F:34])[CH2:5]1
Reactant: N#Cc1cc(F)c(N)nc1N1C(=O)C(C(=O)O)C(=O)c2cc(F)c(F)c(Cl)c21
Reactant: NC1CNC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1cc(F)c(N)nc1N1C(=O)C(C(=O)O)C(=O)c2cc(F)c(N3CC(N)C3)c(Cl)c21
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 63.9 %

Procedure:
A solution in 300 mg of N,N-dimethylformamide of 40 mg of 3-aminoazetidine dihydrochloride and 80 mg of triethylamine was stirred at 90° C., and 50 mg of 1-(6-amino-3-cyano-5-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-1,4-dihydro-4-oxoquinolone-3-carboxylic acid was added to the solution, and stirred at 90° C. for 10 minutes. To the reaction solution was added 1 ml of ethanol, and the solid precipitate was collected and dried to obtain 36 mg of the title compound as a pale yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][CH:23]=[C:24]([CH2:26][C:27]([NH:29][CH:30]([CH3:32])[CH3:31])=[O:28])[N:25]=2)=[N:10]1.C1C(=O)N([Br:40])C(=O)C1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:40])[NH:12][C:11]([C:21]2[S:22][CH:23]=[C:24]([CH2:26][C:27]([NH:29][CH:30]([CH3:31])[CH3:32])=[O:28])[N:25]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(C)NC(c2nc(CC(=O)NC(C)C)cs2)=NC1c1ccc(F)cc1Br
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)C1=C(CBr)NC(c2nc(CC(=O)NC(C)C)cs2)=NC1c1ccc(F)cc1Br
Yield: 49.8 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-2-(4-(2-(isopropylamino)-2-oxoethyl)thiazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate (1.05 g, 2 mmol) was reacted with NBS (0.39 g, 2.2 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.6 g, 50%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7]([O:11][CH3:12])(=[O:10])[CH:8]=[CH2:9].[C]=O>C(OCC)(=O)C>[C:7]([O:11][CH3:12])(=[O:10])[CH:8]=[CH:9][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccccc1
Reactant: C=CC(=O)OC
Agent: [C]=O
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1ccccc1
Reaction time: 6 h
Yield: 6 %

Procedure:
Charged in an autoclave having an inner capacity of 200 ml, were 16.32 g (209 millimoles) of benzene, 1.745 g (20.26 millimoles) of methyl acrylate and 19.4 mg (0.026 millimole) of Rh4 (CO)12, followed by supply of 60 ml of ethyl acetate. Carbon monoxide under 30 kg/cm2 was introduced into the autoclave and reaction was carried out at 220° C. for 6 hours to obtain 0.197 g (1.22 millimoles) of methyl cinnamate. The yield of methyl cinnamate was 6% based on methyl acrylate and 1170% based on the Rh atom.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[CH2:24][CH2:25][CH2:26][CH:27]([O:29]C(=O)C)[CH3:28])=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].P([O-])([O-])([O-])=O>C(Cl)(Cl)Cl>[CH2:1]([O:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:17]=[CH:18][C:19](/[CH:22]=[CH:23]/[CH2:24][CH2:25][CH2:26][CH:27]([OH:29])[CH3:28])=[CH:20][CH:21]=2)=[N:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1cnc(-c2ccc(/C=C/CCCC(C)OC(C)=O)cc2)nc1
Agent: O=P([O-])([O-])[O-]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCOc1cnc(-c2ccc(/C=C/CCCC(C)O)cc2)nc1
Temperature: 32.5 °C
Reaction time: 40 h
Yield: 45.4 %

Procedure:
A mixture of 4.5 g (10 mmol) of the 5-octyloxy-2-{4-(6-acetoxy-1-trans-heptenyl)-phenyl}-pyrimidine, 140 ml of 0.3 M phosphate buffer solution (pH 7.0), 2 ml of chloroform and 0.5 g of Genus Pseudomonas lipase was stirred at 30-35° C. for 40 hours. The mixture was then extracted with 100 ml of toluene, and the organic layer was washed with water and concentrated under reduced pressure. Separation of the residue thus obtained by silica gel column chromatography gave 1.8 g (yield 46%) of (-)-5-octyloxy-2-{4-(6-hydroxy-1-trans-heptenyl)-phenyl}pyrimidine ([α]D20 =-1.2 (c=1.0, CHCl3)) and 2.3 g (yield 53%) of (-)-5-octyloxy-2-{(4-(6-acetoxy-1-trans-heptenyl)-phenyl}-pyrimidine.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]([OH:12])=[O:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:13]N1C(=O)CCC1=O>CN(C)C=O.O>[Cl:13][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[C:8]([C:10]([OH:12])=[O:11])[CH:9]=2)[NH:1][CH:2]=1
Reactant: O=C(O)c1cnc2[nH]ccc2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cnc2[nH]cc(Cl)c2c1
Temperature: 40 °C
Reaction time: 5 h
Yield: 54.6 %

Procedure:
A suspension of 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (250 mg, 1.5 mmol) in N,N-dimethylformamide (5 mL) was warmed to 40° C. N-chlorosuccinimide (243 mg, 1.62 mmol) was added and the mixture was stirred at 55° C. for 5 hours. The reaction was cooled to room temperature and left stirring for 2 days. The mixture was diluted with water (20 mL) and stirred overnight. The resulting solid was collected by filtration and dried to give the title compound (161 mg, 55%). +ESI (M+H) 197.1; 1H NMR (400 MHz, DMSO-d6, δ): 13.08 (br. s., 1H), 12.39 (br. s., 1H), 8.86 (d, J=1.8 Hz, 1H), 8.40 (d, J=1.2 Hz, 1H), 7.84 (d, J=2.5 Hz, 1H).