Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH3:15])=[CH:12][CH:13]=2)[C:8]2[CH2:16][CH2:17][N:18]([CH3:20])[CH2:19][C:7]1=2)=[N+]=[N-].[Cl-].[NH4+]>C(O)C.O.[Zn]>[CH3:20][N:18]1[CH2:17][CH2:16][C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=3)[N:6]([CH2:5][CH:4]([C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)[NH2:1])[C:7]=2[CH2:19]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(N=[N+]=[N-])c2ccncc2)CN(C)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)c1c(n2CC(N)c2ccncc2)CN(C)CC1
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 3.4 %

Procedure:
To a solution of 9-(2-azido-2-(pyridin-4-yl)ethyl)-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (800 mg, 2.3 mmol) in ethanol-water (9 mL: 1 mL) were added zinc dust (600 mg, 9.2 mmol) and ammonium chloride (490 mg, 9.2 mmol) and the reaction mixture stirred at 85° C. for 45 min. The reaction mixture was filtered and the filtrate concentrated. The residue was basified with aqueous ammonia and extracted with EtOAc (2×50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by reverse phase HPLC to yield 2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-1-(pyridin-4-yl)ethanamine (25 mg). The racemate can be further separated into the optically active forms by chiral preparative HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.6 (s, 2H), 7.62 (bs, 2H), 7.23 (s, 1H), 7.0 (d, 1H), 6.98 (d, 1H), 4.9 (m, 1H), 4.8-4.58 (m, 3H), 4.0 (bs, 1H), 3.8 (bs, 1H), 3.6-3.4 (m, 2H), 3.1 (bs, 4H), 2.38 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O-:25])=[O:24])=[CH:21][CH:20]=1.[Na+].C(O)C.S(O[CH:45]([CH3:51])[C:46]([O:48][CH2:49][CH3:50])=[O:47])(C1C=CC(C)=CC=1)(=O)=O>O>[F:1][C:2]([F:28])([F:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:25][CH:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH3:51])=[O:24])=[CH:21][CH:20]=1
Reactant: O=C([O-])c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Reactant: CCOC(=O)C(C)OS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)OC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
To a warm mixture of 7 g. sodium 4-[15-(trifluoromethyl)pentadecylamino]benzoate in 100 ml. ethanol is added 4.7 g. ethyl α-tosyloxypropionate. After 17 hours at reflux, the cooled solution is diluted with an equal volume of water and the resultant precipitate is filtered. After washing with cold ethanol and drying, the product is crystallized from acetonitrile to yield the product as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC1C[S:46](=[O:49])(=[O:48])[CH2:45]1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH:14]3[CH2:45][S:46](=[O:49])(=[O:48])[CH2:15]3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: O=S1(=O)CC(Br)C1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(C3CS(=O)(=O)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-bromo-thietane 1,1-dioxide and isolated as white solid. MS (m/e): 387.3 (MH+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([CH2:29][C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)[CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: ClCc1cccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCN(Cc4cccnc4)CC3)c2[N+](=O)[O-])cc1

Procedure:
Compound A2 (0.12 mmol, 50 mg), 3-chloromethyl-pyridine (0.12 mmol, 20 mg) and triethylamine (0.63 mmol, 88 μL) were dissolved in DMF and microwaved at 80° C. for 10 minutes. The reaction mixture was quenched with water and extracted with ethyl acetate. Removal of organic solvent in vacuo provided Compound A6 pure as a yellow solid (39 mg, 66%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.09 (s, 1H), 8.45 (m, 2H), 8.33 (s, 1H), 7.90 (d, 2H), 7.78 (d, 2H), 7.65 (m, 1H), 7.21 (m, 1H), 5.41 (heptet, 1H), 3.52 (m, 2H), 3.01 (s, 3H), 2.65 (m, 2H), 2.47 (m, 2H), 1.98 (m, 2H), 1.94 (m, 2H). LCMS (ESI), m/z 484.3 (M+H+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[O:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][NH2:28])[CH2:22][CH2:21]1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:28][CH2:27][CH2:26][CH:23]2[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NCCC1CCOCC1
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cnc(Oc2ccc(CNCCC3CCOCC3)cc2F)cn1
Reaction time: 8 h
Yield: 67.2 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737, Part E) (0.400 g, 1.53 mmol), 2-(tetrahydropyran-4-yl)ethylamine (0.217 g, 1.68 mmol) and 3 Å molecular sieves in a vial. Add methanol (7.7 mL), cap and stir overnight. Add NaBH4 (0.058 g, 1.53 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 30% (2.0 M NH3 in methanol) in 80% (ethyl acetate in hexanes) to give the title compound (0.385 g, 67%): TOF MS ES+ 375.2 (M+H)+, HRMS calcd for C19H24N4O3F 375.1832 (M+H)+, found 375.1847, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR 8.6 min, 95.4% purity.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14]([C:16]2[O:17][C:18]([Br:21])=[CH:19][CH:20]=2)=O)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]>C(O)CO.C(O)(C)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[N:13]=[C:14]1[C:16]1[O:17][C:18]([Br:21])=[CH:19][CH:20]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(Br)o1
Solvent: OCCO
Solvent: CC(C)O
Product: CCOC(=O)Cn1c(-c2ccc(Br)o2)nc2cccnc21
Yield: 1.1 %

Procedure:
A solution of N-[3-[(5-bromo-2-furanylcarbonyl)amino]-2-pyridinyl]glycine ethyl ester (110 g, 0.30 mole) was refluxed in ethylene glycol (510 ml) for 2 hours. A 20-ml aliquot (0.01 mole) was removed and water was added to the sample. The product was extracted twice into ethyl acetate and the combined organic layer was washed several times with water, dried over magnesium sulfate, charcoaled, filtered, and evaporated under reduced pressure to give 2.5 g of crude title compound (73% yield). The solid was dissolved in hot isopropyl alcohol, filtered while hot, brought to the cloud point by addition of water and cooled to give a solid which was purified on a column of 20 g of silica gel using 1:1 methylene chloride/ethyl acetate as the eluting solvent. Evaporation of the solvent from the pure fraction gave 1.2 g of product which was recrystallized from isopropyl alcohol/water and dried under high vacuum at room temperature overnight to give 0.88 g of title compound, mp 122.5°-125° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[O:13]1COCO[CH2:14]1.O>CS(C)=O.C[O-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:14][OH:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(F)cc1
Reactant: C1OCOCO1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C(CO)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.6 %

Procedure:
To a stirred solution of methyl (4-fluorophenyl)acetate (5.5 g) in DMSO (220 mL) was added 1,3,5-trioxane (3.24 g) and sodium methoxide (88 mg). The mixture was stirred at room temperature for 16 h. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 3.8 g of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:15]([N+:16]([O-])=O)=[CH:14][C:6]2[N:7]3[CH2:13][CH2:12][CH2:11][N:10]=[C:8]3[S:9][C:5]=2[CH:4]=1)[CH3:2].[H][H]>[Pt].C(O)(=O)C>[CH2:1]([C:3]1[C:15]([NH2:16])=[CH:14][C:6]2[N:7]3[CH2:13][CH2:12][CH2:11][N:10]=[C:8]3[S:9][C:5]=2[CH:4]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCc1cc2c(cc1[N+](=O)[O-])N1CCCN=C1S2
Agent: [Pt]
Solvent: CC(=O)O
Product: CCc1cc2c(cc1N)N1CCCN=C1S2

Procedure:
A mixture of 5.26 parts of 8-ethyl-3,4-dihydro-7-nitro-2H-pyrimido[2,1-b]benzothiazole and 100 parts of acetic acid is hydrogenated at normal pressure and at room temperature with 1 part of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is acidified with 2-propanol, saturated with gaseous hydrogen chloride. The precipitated product is filtered off and dissolved in 200 parts of water. The solution is alkalized with ammonium hydroxide. The precipitated product is filtered off, washed with water and crystallized from 2-propanol, yielding 2.2 parts of 8-ethyl-3,4-dihydro-2H-pyrimido[2,1-b]benzothiazol-7-amine; mp. 209.9° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=2)[NH:16][C:15](=[O:24])[CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([Br:35])[C:33]=1[Br:34])[CH2:29]Br>CN(C)C=O.O>[CH2:3]([O:10][CH2:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=2)[N:16]([CH2:29][C:28]2[CH:27]=[C:26]([Br:25])[C:33]([Br:34])=[C:32]([Br:35])[CH:31]=2)[C:15](=[O:24])[CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=c1cc(CCOCc2ccccc2)c2cc(F)ccc2[nH]1
Reactant: BrCc1cc(Br)c(Br)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(CCOCc2ccccc2)c2cc(F)ccc2n1Cc1cc(Br)c(Br)c(Br)c1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (0.675g. of 80% w/w suspension; freed of mineral oil as in Example 1) in dimethylformamide (100ml.) under a nitrogen atmosphere was added 4-(2-benzyloxyethyl)-6-fluoro-1,2-dihydro-2-oxoquinoline (6.0g.). The mixture was stirred at 40° C. for one hour and then treated at this temperature with 3,4,5-tribromobenzylbromide (9.1g.). The mixture was stirred overnight at ambient temperature and then diluted with water (200 ml.) and the product extracted with ethyl acetate (3 × 150ml.). The combined organic extracts were washed with water (2 × 100ml.), dried (MgSO4), and evaporated. The residue was a mixture of O- and N-substituted products. Chromatography of this residue on silica gel using a 50:50 v/v mixture of ether and petroleum ether (b.p. 40°-60° C.) as eluant gave 4-(2-benzyloxyethyl)-6-fluoro-1-(3,4,5-tribromobenzyl)-1,2-dihydro-2-oxoquinoline, as an oil, Infra-Red Spectral Absorption ν max. 1665 cm.-1.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:30])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([I:28])=[C:24]([CH3:29])[CH:23]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[CH3:31][C:32]1([CH3:39])[CH2:37]C(=O)[O:35][C:33]1=[O:34]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[I:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6](=[O:7])[CH2:31][C:32]([CH3:39])([CH3:37])[C:33]([OH:35])=[O:34])[CH2:13][CH2:12]3)=[N:15][CH:16]=2)=[O:30])=[CH:23][C:24]=1[CH3:29]
Reactant: Cc1cc(NC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)ccc1I
Reactant: CC1(C)CC(=O)OC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(NC(=O)c2ccc(N3CCN(C(=O)CC(C)(C)C(=O)O)CC3)nc2)ccc1I
Reaction time: 0.5 h

Procedure:
4-[5-(4-Iodo-3-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (35 mg, 0.07 mmol) was dissolved in 30% TFA in CH2Cl2 solution at room temperature. The mixture was stirred for 30 min and then partitioned between EtOAc and H2O. The water layer was made basic by the addition of Na2CO3. The organic layer was then collected washed with water dried over Na2SO4, filtered and evaporated. The residue was dissolved in CH2Cl2 and treated with 2,2-dimethysuccinic anhydride (13 mg, 0.10 mmol). After stirring at room temperature for 4 h the mixture was concentrated to a residue and washed with excess of hexanes to afford the product. HRMS m/z calcd for C23H27N4O4I [M+H]+: 551.1150. Found: 551.1152.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:13]=[CH:12][S:11][C:4]=2[NH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[C:3]3[CH:13]=[CH:12][S:11][C:4]=3[NH:5][C:6](=[O:10])[C:7]=2[C:8]#[N:9])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: N#Cc1c(Cl)c2ccsc2[nH]c1=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2c(C#N)c(=O)[nH]c3sccc23)CC1

Procedure:
Compounds of structure (III) with R2 as carbonitrile, and R1 and R3 as defined above were also prepared from intermediate 4-chloro-6-oxo-6,7-dihydro-thieno[2,3-b]pyrdine-5-carbonitrile, depicted by formula (50). Intermediate 4-chloro-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile, depicted by formula (50), was reacted with tert-butyl-1-piperazine carboxylate to yield 4-(5-cyano-6-oxo-6,7-dihydro-thieno[2,3-b]-pyridine-4-yl)-piperazine-1-carboxylic acid tert-butyl ester, depicted by formula (53). This intermediate was either reacted with an appropriate halide (R1—X) or boronic acid (R1—B(OH)2) to yield an intermediate of structure (54), which was deprotected and reacted with an appropriate acid chloride (R3—COCl) or acid (R3—COOH) to yield target compounds of structure (III) with R2 as carbonitrile, and R1 and R3 as defined above, as shown in Scheme 28.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[CH:12]([Mg]Br)=[CH2:13].[Cl-].[NH4+]>O1CCCC1>[Cl:11][C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[C:7]2[NH:8][CH:12]=[CH:13][C:6]=12
Reactant: C=C[Mg]Br
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Clc1cnc(Cl)c2[nH]ccc12
Temperature: -20 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
To a solution of 2,5-dichloro-3-nitropyridine (5.00 g, 25.9 mmol) in tetrahydrofuran (164 ml) was added a solution of 1 mol/L vinylmagnesium bromide in tetrahydrofuran (82.9 ml, 82.9 mmol) at −78° C. The mixture was stirred at −20° C. overnight, and then to the reaction solution was added saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate twice. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1→7:3), and then washed with diisopropyl ether to give 4,7-dichloro-1H-pyrrolo[2,3-c]pyridine (1.12 g, 23%) as a pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1>ClCCl>[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:14](=[O:15])[C:13]3[CH:17]=[CH:18][C:10]([F:9])=[CH:11][CH:12]=3)[N:3]=2)=[O:15])=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1cccc(N)n1
Solvent: ClCCl
Product: O=C(Nc1cccc(NC(=O)c2ccc(F)cc2)n1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2,6-Diaminopyridine (10.9 grams, 0.1 mole) was dissolved in 500 milliliters dichloromethane and trietbylamine (28.0 milliliters, 20.2 grams, 0.2 mole) was added. The solution was chilled to 0° C. before 4-fluorobenzoyl chloride (24.0 milliliters, 31.7 grams, 0.2 mole) was added drop-wise over the course of 30 minutes. After stirring for 2 hours at 0° C., the solution was allowed to warm to room temperature (25° C.) and stirred for 18 hours. The resulting precipitate was isolated by filtration and suction dried. The precipitate was recrystallized from 300 milliliters of refluxing ethanol, isolated by filtration, rinsed with ethanol, suction dried, and vacuum dried in an oven overnight. The yield was 34.0 grams of white crystals.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11](Br)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.S(Cl)([Cl:23])=O.[OH-].[Na+]>>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11]([Cl:23])[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(F)c(Br)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(F)c(Cl)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 1-cyclopropyl-6-fluoro-7-bromo-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.2 g) is added thionyl chloride (2 ml) and the mixture is refluxed for 1 hour. After cooling, the reaction mixture is poured into ice-water and made alkaline with 10% aqueous sodium hydroxide solution. After stirring for 30 minutes, the resultant is extracted with dichloromethane. The aqueous layer is made acidic with 10% hydrochloric acid and then extracted with dichloroethane. The solvent is concentrated and the residue is recrystallized from acetic acid to give 1-cyclopropyl-6-fluoro-7-chloro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (80 mg), as white crystals, m.p. 258°-260° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][O:19][NH2:20]>>[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][O:19]/[N:20]=[C:10](/[C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([OH:1])[CH:3]=1)\[CH3:11]
Reactant: NOCc1cccc(F)c1
Reactant: COc1ccc(C(C)=O)cc1O
Agent: Cl
Product: COc1ccc(/C(C)=N/OCc2cccc(F)c2)cc1O
Yield: 81.5 %

Procedure:
Acetophenone 12 (50 mg, 0.301 mmol) was condensed with O-(3-fluorobenzyl)hydroxylamine hydrochloride (26) (59 mg, 0.332 mmol) according to the general procedure II-B defined above. After being heated at reflux for 48 h the reaction mixture was cooled and the solvent removed under reduced pressure. The ensuing residue was dissolved in CH2Cl2 (15 mL), washed with H2O (2×10 mL) then dried (MgSO4), filtered and concentrated under reduced pressure. The oil thus obtained was subjected to flash chromatography (1:19 v/v ethyl acetate/hexane elution) to afford the title compound CP30262 (71 mg, 82%) as a pale-pink oil, Rf 0.6 in 1:1 v/v ethyl acetate/hexane.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[H-].[Na+].[Cl:16][C:17]1[C:22]([CH3:23])=[C:21](Cl)[CH:20]=[CH:19][N:18]=1>CC(N(C)C)=O.CCOCC>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][C:21]2[CH:20]=[CH:19][N:18]=[C:17]([Cl:16])[C:22]=2[CH3:23])[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1c(Cl)ccnc1Cl
Reactant: CC(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: Cc1c(OC2CCN(C(=O)OC(C)C)CC2)ccnc1Cl
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 27 %

Procedure:
4-Hydroxy-piperidine-1-carboxylic acid isopropyl ester (0.496 mL, 2.90 mmol) was dissolved in anhydrous dimethylacetamide (DMA, 5 mL), NaH (60% oil dispersion, 116 mg, 2.90 mmol) was added and this mixture was stirred at 23° C. for 45 min, then this mixture was added dropwise to 2,4-dichloro-3-methyl-pyridine, which was dissolved in anhydrous DMA (4 mL). This mixture was stirred at 23° C. for 2 h then heated at 50° C. for 15 h, after which time the mixture was diluted with Et2O (140 mL), washed with water (14 mL), then brine twice (2×14 mL). The organic layer was separated, dried with MgSO4, and the solvent was evaporated in vacuo to give an oil which was purified by flash chromatography using hexanes-EtOAc, 75:25, v/v, then hexanes-EtOAc, 50:50, v/v, to give 4-(2-chloro-3-methyl-pyridin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester as a solid (223 mg, 27%). 1H NMR (CDCl3, 400 MHz) δ 8.09 (d, 1H), 6.69 (d, 1H), 4.91 (m, 1H), 4.60 (m, 1H), 3.61 (m, 2H), 3.52 (m, 2H), 2.24 (s, 3H), 1.91 (m, 2H), 1.80 (m, 2H), 1.24 d, 6H). LRMS calculated for C15H21ClN2O3: 312.12, Found: (MH)+ 313.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](C)[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([NH:19][OH:20])=[O:18].[N+](C1C=CC(OC(=O)CC2C=CC=CC=2NC2C(C)=CC=CC=2[Cl:46])=CC=1)([O-])=O>>[Cl:46][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([NH:19][OH:20])=[O:18]
Reactant: Cc1cccc(Cl)c1Nc1ccccc1CC(=O)NO
Reactant: Cc1cccc(Cl)c1Nc1ccccc1CC(=O)Oc1ccc([N+](=O)[O-])cc1
Product: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)NO

Procedure:
[o-(3-chloro-o-toluidino)-phenyl]-acetohydroxamic acid, M.P. 135°-136° (from ether/petroleum ether), starting with [o-(3-chloro-o-toluidino)-phenyl]-acetic acid-p-nitrophenyl ester.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[CH:10]([C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1)=[CH2:11].C(N(CC)C(C)C)(C)C>CC(C)=O>[CH:10]([C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=2)=[CH:14][CH:13]=1)=[CH2:11]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C=Cc1ccc(N)cc1
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=Cc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 18.4 g (0.1 mole) of cyanuric chloride in 150 ml of acetone being stirred at 0°-5° C. was added dropwise over a 1/2 hr. period a solution of 11.9 g (0.1 mole) of 4-vinylaniline and 12.9 g (0.1 mole) of N,N-di-iso-propylethylamine. After the addition was complete, the solution was stirred at room temperature for 15 min., and then poured into 1 liter of ice water to isolate the product. The product was collected by filtration, washed with 200 ml of water, and dried in vacuo at room temperature to give 25 g. Recrystallization from 75 ml. of benzene gave 15.0 g (56%) (mp 152°-154°).
Reaction SMILES: Cl[C:2]1[C:6]2[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:5]=2[S:4][N:3]=1.[Na].[CH3:13][OH:14]>>[CH3:13][O:14][C:2]1[C:6]2[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:5]=2[S:4][N:3]=1
Reactant: CO
Reactant: O=C1CCCc2snc(Cl)c21
Agent: [Na]
Product: COc1nsc2c1C(=O)CCC2

Procedure:
A mixture of 3-chloro-4,5,6,7-tetrahydro-1,2-benzisothiazol-4-one 24a (600 mg) and a solution of sodium (506 mg) in methanol (22 mL) was stirred at 90° C. for 1 h. The reaction mixture was evaporated and water (20 mL) was added to the residue. Extractions with methylene chloride (3×30 mL), drying and evaporation gave an oil. Column chromatography on silica gel (eluent: toluene-ethyl acetate 4:1) gave the title compound (251 mg). Mp 45-46° C.