Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.Cl.[S:10]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:13])(=[O:12])=[O:11].C(N(CC)CC)C>C(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:17]2[CH2:18][CH2:19][N:14]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:15][CH2:16]2)[CH:7]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2cc(Cl)ncn2)CC1
Yield: 98.2 %

Procedure:
A mixture of 4,6-dichloropyrimidine (39.4 g), 1-mesylpiperazine hydrochloride (55.7 g) and triethylamine (116 ml) in ethanol (500 ml) was stirred at reflux temperature for 4 hours. The mixture was then stirred at room temperature for 12 hours. The solid, which had separated, was collected by filtration, slurry washed with ethanol (2×80 ml, 160 ml) then with diethyl ether (150 ml), and dried to give 1-(6-chloropyrimidin-4-yl)-4-mesylpiperazine as a cream solid (71.9 g). mp 200-202° C.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][CH2:10][S:11]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:16][CH2:15]2)(=[O:13])=[O:12])[CH2:4]1.C(N(CC)CC)C.[CH3:34][O:35][C:36]1[CH:41]=[C:40]([CH3:42])[C:39]([S:43](Cl)(=[O:45])=[O:44])=[C:38]([CH3:47])[C:37]=1[CH3:48].C(=O)(O)[O-].[Na+].Cl.C[Si](C)(C)Cl>O1CCCC1.C(O)C>[CH3:34][O:35][C:36]1[CH:41]=[C:40]([CH3:42])[C:39]([S:43]([N:3]2[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][CH2:10][S:11]([N:14]3[CH2:15][CH2:16][CH:17]([CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[CH2:18][CH2:19]3)(=[O:13])=[O:12])[CH2:4]2)(=[O:44])=[O:45])=[C:38]([CH3:47])[C:37]=1[CH3:48]
Reactant: O=S(=O)(CCC1CCCNC1)N1CCC(CCN2CCCC2)CC1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc(C)c(S(=O)(=O)N2CCCC(CCS(=O)(=O)N3CCC(CCN4CCCC4)CC3)C2)c(C)c1C

Procedure:
1-(2-(Piperidin-3-yl)ethylsulfonyl)-4-(2-(pyrrolidin-1-yl)ethyl)piperidine dihydrochloride (0.15 g, 0.35 mmol) was dissolved in tetrahydrofuran (10 ml) under an inert gas, and triethylamine (0.15 ml, 1.05 mmol) and 4-methoxy-2,3,6-trimethylbenzenesulfonyl chloride (0.1 g, 0.42 mmol) were added. The mixture was refluxed for 2 h, saturated sodium bicarbonate solution (10 ml) was then added and the phases were separated. The aqueous phase was extracted with ethyl acetate (20 ml) and the combined organic phases were washed with saturated sodium chloride solution (20 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with ethyl acetate/methanol/ammonia (25% aq) (300:100:1) and the hydrochloride was precipitated from an ethanol/ethereal solution with 1.2 eq of trimethylchlorosilane. Yield: 0.15 g (70%). MS, m/z=570.3 [MH]+
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1)=[O:10].[NH2:21][OH:22].[OH-].[K+].CO>C1COCC1>[OH:22][NH:21][C:3](=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1)=[O:10]
Reactant: NO
Reactant: COC(=O)CCCCCS(=O)c1ccc(N(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)c1ccc(S(=O)CCCCCC(=O)NO)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of the 6-(4-dimethylamino-benzenesulfinyl)-hexanoic acid methyl ester (1.2 g, 4.0 mmol) in distilled THF (30 mL) containing 50% aqueous hydroxylamine (2.65 mL, 40 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (6.8 mL, 1M, 6.8 mmol) in a dropwise manner. After stirring at 0° C. for 1 h, distilled water (30 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The aqueous solution was extracted with ethyl acetate (3×50 mL) and the combined extracts were washed with brine (100 mL), dried over anhydrous MgSO4, filtered and evaporated to dryness. The solid residue was recrystallised from acetone to give the title compound (728 mg, 61%) as a white powder, mp 95-97° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.Br[CH2:30][C:31]([NH2:33])=[O:32].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][N:19]([CH2:30][C:31]([NH2:33])=[O:32])[CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[CH:6][CH:5]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Reactant: NC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(CC(N)=O)CC4)nc12
Yield: 27508 %

Procedure:
To a suspension of 0.04 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 5 ml acetonitrile were added 0.017 mg 2-bromoacetamide, 0.026 mg sodium carbonate and 0.018 mg sodium iodide. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with dichloromethane/methanol 95:5. Product containing fractions were further purified by chromatography on aluminium oxide with dichloromethane/methanol 95:5 to 4:1 to yield 0.015 g (34%) 2-[2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepin-6-yl]-acetamide as yellow solid; M.p.: 299–302° C.; MS (ISP): m/e 443 (M+H+).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16]Cl)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:24]=1.[CH3:25][N:26]([CH3:28])O.[H-].[Na+]>CN(C)C=O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][N:26]([CH3:28])[CH3:25])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:24]=1
Reactant: CN(C)O
Reactant: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CCl)n1-2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CN(C)C)n1-2

Procedure:
In the manner given in Example 15, 8-methylthio-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine is treated with a cold mixture of N,N-dimethylhydroxylamine and sodium hydride in dimethylformamide to give 8-methylthio-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo [4,3-a][1,4]benzodiazepine, N1 -oxide.
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]([OH:17])=O)[NH:3][C:4](=[O:13])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[NH2:18][C@@H:19]([CH3:43])[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)=[O:21]>>[CH2:40]([O:39][CH:35]([O:36][CH2:37][CH3:38])[C@@H:34]([N:22]([CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)[C:20](=[O:21])[C@@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:2]([CH3:1])[NH:3][C:4]([NH:5][CH2:6][C:7]1[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=1)=[O:13])[CH3:43])[CH3:42])[CH3:41]
Reactant: CN(CC(=O)O)NC(=O)NCc1ccncc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)N
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)NC(=O)CN(C)NC(=O)NCc1ccncc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(pyridin-4-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-6) 100 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide IV-10) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-])=O)=[C:4]([CH3:12])[CH:3]=1.[OH-].[Na+]>[Cl-].[Cl-].[Cl-].[Ti+3]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: [Ti+3]
Agent: [Cl-]
Agent: [Na+]
Product: Cc1cc(Cl)c(Cl)cc1N
Temperature: 25 °C
Yield: 56.1 %

Procedure:
4,5-Dichloro-2-methyl-nitrobenzene 5 (5.0 g, 24.3 mmol) was heated at 100° C. in titanium trichloride (30% in aqueous hdyrochloric acid, 25 mL) for 2 hrs., cooled to RT, the reaction solution was basified to pH 8 with 50% aqueous sodium hydroxide, then extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using 10% ethyl acetate in hexanes to give 2.4 g (56%) of the title product. 1H NMR (400 MHz, CDCl3) δ7.09 (s, 1 H, Ar), 6.74 (s , 1 H, Ar), 3.63 (s, 2 H, NH2), 2.10 (s, 3H, CH3).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.[Li]CCCC.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[O:29][C:28]([CH3:30])=[N:27][C:26]=3[CH3:31])=[O:24])[CH:21]=2)[N:16]=[C:15]([O:32][CH3:33])[C:14]=1[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=1>C1COCC1>[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[O:29][C:28]([CH3:30])=[N:27][C:26]=3[CH3:31])([C:6]3[N:2]([CH3:1])[N:3]=[N:4][CH:5]=3)[OH:24])[CH:21]=2)[N:16]=[C:15]([O:32][CH3:33])[C:14]=1[CH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=1
Reactant: COc1nc2ccc(C(=O)c3oc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: Cn1ccnn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3oc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -40 °C
Reaction time: 0.58 h

Procedure:
To a flask containing 1-methyl-1H-1,2,3-triazole (200 mg, 2.41 mmol, prepared according to PCT Int. Appl., 2008098104) was added THF (20 mL) and the colorless solution was cooled to −40° C. Then, n-BuLi (2.5 M in hexanes, 1.0 mL, 2.5 mmol) was added drop wise which afforded a dark reddish-brown viscous solution. The mixture was stirred at −30° C. for 35 minutes, then a homogeneous THF solution of (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,4-dimethyloxazol-5-yl)methanone (500 mg, 1.05 mmol, in 4 mL THF, Intermediate 51: step b) was introduced at −20° C. The reaction mixture became a dark brown color and was then placed in an ice-water bath and allowed to warm gradually to room temperature. After 45 minutes, the mixture was quenched with aqueous NH4Cl solution and extracted with EtOAc:THF (10:2), 4×50 mL. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to provide a brown oil. Chromatography on silica gel (3% MeOH-DCM increasing to 5% MeOH-DCM) to provide the title compound as a faint amber solid. MS m/e 558.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 8.15 (d, J=2.0 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.54-7.47 (m, 3H), 7.40 (d, J=8.1 Hz, 2H), 7.14 (s, 1H), 4.35 (s, 2H), 4.10 (s, 3H), 4.03 (s, 1H), 3.92 (s, 3H), 2.40 (s, 3H), 1.54 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[C:6]([O:21][CH3:22])=[C:7]([CH:10]=[C:11]([C:13]2[C:14]([O:19][CH3:20])=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].C[Si]([N:27]([Si](C)(C)C)[C:28]1[CH:29]=[C:30]([Mg]Cl)[CH:31]=[CH:32][CH:33]=1)(C)C>C1COCC1>[NH2:27][C:28]1[CH:33]=[C:32]([CH:8]([C:7]2[CH:10]=[C:11]([C:13]3[C:14]([O:19][CH3:20])=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:12]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]=2[O:21][CH3:22])[OH:9])[CH:31]=[CH:30][CH:29]=1
Reactant: C[Si](C)(C)N(c1cccc([Mg]Cl)c1)[Si](C)(C)C
Reactant: COc1ncccc1-c1cc(C=O)c(OC)c(C(C)(C)C)c1
Solvent: C1CCOC1
Product: COc1ncccc1-c1cc(C(O)c2cccc(N)c2)c(OC)c(C(C)(C)C)c1
Reaction time: 8 h
Yield: 54.7 %

Procedure:
step 1—To a solution of 3-tert-butyl-2-methoxy-5-(2-methoxy-pyridin-3-yl)-benzaldehyde (B-2a, R4=tert-Bu, R6═H, 110 mg, 0.368 mmol) in THF (5 mL) at 0° C. was added a solution of 3-(bis-(trimethylsilyl)amino)phenyl magnesium chloride (1.0 M in THF, 0.750 mL, 0.750 mmol). The reaction was gradually warmed RT and stirred overnight. The reaction mixture was quenched with 1N aqueous HCl solution and extracted with EtOAc. The organic layer was washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (25 to 50% EtOAc) to afford 79 mg (55%) of (3-amino-phenyl)-[3-tert-butyl-2-methoxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-methanol (34) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:4][CH3:5].[H-].[Na+].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1COCC1>[C:9]([O:8][C:7]([NH:6][C@@H:3]([CH2:4][CH3:5])[CH2:2][O:1][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@H](COCC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-tert-butyl 1-hydroxybutan-2-ylcarbamate (1 eq, from the previous step) in THF (0.23 M) at 0° C. was added portionwise 60% wt NaH (2 eq). The reaction was stirred at 0° C. for 30 minutes, and then a solution of tert-butyl 2-bromoacetate (1 eq) in THF (0.12 M) was added dropwise. The reaction was warmed to room temperature and stirred for 1 hour. The reaction was quenched slowly with saturated aqueous NH4C1 solution and diluted with ether. The organic layer was washed with water, brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-40% ethyl acetate in hexanes to give the product as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH:13]1([CH2:16][C:17](O)=[O:18])[CH2:15][CH2:14]1.C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.O[Li].O>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:17](=[O:18])[CH2:16][CH:13]3[CH2:15][CH2:14]3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)CC1CC1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li]O
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(CC1CC1)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 42 h
Yield: 75.2 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 2-cyclopropylacetic acid (218 mg, 2.17 mmol), triethylamine (606 μL, 4.35 mmol), and BOP-Cl (203 mg, 2.17 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 42 hours. Then 2M LiOH.H2O (3 mL) was added, and the mixture was stirred for 18 hours. The mixture was then diluted with CH2Cl2 (50 mL). The layers were separated, and the organic layer was dried (MgSO4), filtered, and concentrated in vacuo to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyclopropylacetamide (204 mg, 75% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.04 (s, 1H), 9.40 (s, 1H), 8.34 (d, 1H), 7.61 (s, 1H), 2.24 (d, 2H), 1.10-1.03 (m, 1H), 0.52-0.47 (m, 2H), 0.24-0.20 (m, 1H); LCMS (APCI+) m/z (M+H)+, Retention time=2.92 minutes (Method 2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](Cl)=[N:6][CH:5]=1.C(N(CC)CC)C.[CH3:22][O:23][C:24](=[O:27])[CH2:25][SH:26]>ClCCl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([S:26][CH2:25][C:24]([O:23][CH3:22])=[O:27])=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)CS
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CSc1ncc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6-chloro-5-nitro-nicotinic acid methyl ester (1.0 g) [prepared as described by A. H. Berrie et al. J. Chem. Soc. 2590–2594 (1951)] in dichloromethane (10 ml) containing triethylamine (0.76 ml) was treated with mercapto-acetic acid methyl ester (0.44 ml) and the solution was stirred at room temperature for 1 hour and evaporated to dryness. Sodium bicarbonate solution was added and the mixture was extracted with dichloromethane, dried (anhydrous sodium sulfate) and evaporated to afford a solid (1.0 g).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=2)[N:8]=1.C(#N)C.O.C(O)(C(F)(F)F)=O>Br>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=2)[N:8]=1
Reactant: COc1ccc2cc(C(=O)O)cn2n1
Agent: Br
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=C(O)c1cc2ccc(O)nn2c1
Temperature: 50 °C

Procedure:
2-Methoxypyrrolo[1,2-b]pyridazine-6-carboxylic acid (1.06 g, 5.50 mmol) was suspended in HBr (10 mL, 33% solution in acetic acid) and heated to 50° C. for 2 hrs. The solvent was evaporated in vacuo and used directly (500 mgs). An analytical standard was prepared using reverse phase HPLC with a gradient of acetonitrile/water and 0.05% TFA as modifier. MS m/z 179.1 (M+1). 1H NMR (DMSO-d6, 400 MHz) δ 12.29 (bs, 1H), 11.60 (bs, 1H), 7.89-7.86 (m, 2H), 6.76 (d, J=2.0 Hz, 1H), 6.36 (d, J=9.6 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:26])=[C:16](SC3C=CC=CC=3)[N:17]=2)[C:12](=[O:27])[C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:10]1.[NH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(OCC)(=O)C.Cl>CN(C)C=O.C(OCC)C.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:26])=[C:16]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[N:17]=2)[C:12](=[O:27])[C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:10]1
Reactant: C1CNCCN1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(Sc3ccccc3)c(F)cc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCNCC3)c(F)cc2c1=O
Yield: 60.7 %

Procedure:
In 12 ml of N,N-dimethylformamide were suspended 400 mg of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-phenylthio-1,8-naphthyridine-3-carboxylate and 380 mg of anhydrous piperazine, and the resulting suspension was subjected to reaction at 95° to 100° C. for 6 hours. Subsequently, the solvent was removed by distillation under reduced pressure, and to the residue thus obtained were added 10 ml of ethyl acetate and 30 ml of water, after which the pH thereof was adjusted to 0.5 with 6N hydrochloric acid. The aqueous layer was separated and 30 ml of ethyl acetate was added thereto, after which the pH thereof was adjusted to 9.0 with a 10% by weight aqueous potassium carbonate solution. The organic layer was separated, and the aqueous layer was extracted with two 20-ml portions of ethyl acetate, after which the extracts were combined with the organic layer. The combined layer was washed with 20 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 5 ml of diethyl ether, after which crystals were collected by filtration to obtain 230 mg (yield 60.7%) of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylate. The physical properties of this compound were identical with those of the compound obtained in Example 65.
Reaction SMILES: IC.[Br:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[OH:14].[C:15](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:11])([CH3:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[O:14][CH3:15]
Reactant: CC(C)(C)c1ccc(O)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(C(C)(C)C)cc1Br
Yield: 102.3 %

Procedure:
Iodomethane (10.0 mL, 0.161 mol) was added to a mixture of 2-bromo-4-(tert-butyl)phenol [Intermediate 1, Step 1] (29.5 g, 0.129 mol) and potassium carbonate (42.7 g, 0.309 mol) in dry acetone (400 mL) and the reaction mixture refluxed under nitrogen for 22 hours. The cooled reaction mixture was then concentrated and the residue partitioned between ethyl acetate (400 mL) and 0.3 M aqueous sodium hydroxide solution (300 mL). The organic phase was separated, washed with water (300 mL) and saturated brine (300 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give 2-bromo-4-(tert-butyl)-1-methoxybenzene (32.09 g, 100% yield) as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[F:12][CH:13]1[CH2:16][NH:15][CH2:14]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[C:3]([C:9]([N:15]2[CH2:16][CH:13]([F:12])[CH2:14]2)=[O:11])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1ncc(F)cc1F
Reactant: FC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ncc(F)cc1F)N1CC(F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.6 %

Procedure:
To a solution of 3,5-difluoropicolinic acid (16.40 g, 103.1 mmol), 3-fluoroazetidine (8.59 g, 114 mmol) and triethylamine (27.70 ml, 199.0 mmol) in 100 mL of DMF was added HATU (45.40 g, 119.0 mmol). The mixture was stirred at room temperature for 3 hr, quenched with water, extracted with 3×EtOAc, The combined organic layer was washed with 2×H2O, dried with Na2SO4, and concentrated to provide an oil that was purified by Biotage eluting with 25-40% EtOAc in hexanes to give a yellow solid (11.49 g, 46.3% yield). 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J=2.53 Hz, 1 H) 7.31-7.46 (m, 1 H) 5.27-5.52 (m, 1 H) 4.62-4.79 (m, 1 H) 4.42-4.59 (m, 2 H) 4.22-4.38 (m, 1 H); MS for C9H7F3N2O m/z 217.00 (M+H)+
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[NH:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]5[NH:25][C:24]([C:26]6[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=6)=[N:23][C:21]=5[CH:22]=4)=[N:14][C:12]=3[CH:13]=2)[CH2:4][CH2:3]1.[OH-].[NH4+]>C(O)(C)C.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:16]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]5[NH:25][C:24]([NH:23][C:21]=5[CH:22]=4)=[C:26]4[CH:27]=[CH:28][C:29](=[O:32])[CH:30]=[CH:31]4)[NH:14][C:12]=3[CH:13]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc3[nH]c(-c4ccc5[nH]c(-c6ccc(O)cc6)nc5c4)nc3c2)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CN1CCN(c2ccc3nc(-c4ccc5c(c4)NC(=C4C=CC(=O)C=C4)N5)[nH]c3c2)CC1

Procedure:
Hoechst 33258 (3.0 g, 5 mmol) was dissolved in a hot mixture of isopropanol-water (24 mL/12 mL) and neutralized with ammonium hydroxide (3 mL). The precipitate was filtered, triturated with Et2O and dried in vacuo to obtain the free base of bisbenzimidazole. A 1.0 M solution of Bu4NOH in MeOH (0.6 mL, 0.6 mmol) was added to the solution of bisbenzimidazole (1.635 g, 3.85 mmol) in MeOH (30 mL), stirred for 15 min and concentrated to dryness in vacuo. Iodonaphthoquinone 5 (1.485 g, 3.87 mmol) in DMF (30 mL) was added to the tetrabutyl ammonium salt and the mixture was stirred for 48 h. The reaction mixture was suspended in H2O, the crude product was filtered, washed with H2O, dried and purified by flash chromatography (MeOH/CHCl3 1:9, 1:5) to afford 14 as a yellow solid (790 mg, 30%). 1H NMR (CDCl3/MeOH-d4) 8.21 (s, 1H), 8.09 (d, J=7.6 Hz, 1H), 8.05 (d, J=8.7 Hz, 2H), 7.85-7.95 (m, 2H), 7.48-7.75 (m, 4H), 7.14 (bs, 1H), 7.10-6.98 (m 3H), 4.21 (t, J=6.3 Hz, 2H), 4.08 (t, J=6.2 Hz, 2H), 2.65-2.75 (m, 4H), 2.40 (s, 3H), 1.80-2.15 (m, 4H), 1.60-1.75 (m, 4H). MS (LSIMS, 3-NBA) 725.2 (M++1).