Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[C:16](F)[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][C:13]=1[F:22].O>C1COCC1.CO>[Br:11][C:12]1[C:13]([F:22])=[CH:14][C:15]([N+:19]([O-:21])=[O:20])=[C:16]([NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:17]=1
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Reactant: Nc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1cc(F)c(Br)cc1Nc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.4 %

Procedure:
To a solution of 2-chloropyrimidin-4-amine (1.31 g, 10.08 mmol) in THF (55 mL) at 0° C. was added sodium hydride (60% in oil, 806.69 mg, 20.17 mmol) portion-wise. The reaction mixture was stirred at 0° C. to RT for 10 minutes and 1-bromo-2,5-difluoro-4-nitrobenzene (1.2 g, 5.04 mmol) was added. The reaction mixture was stirred at 65° C. for 1 h. The reaction mixture was cooled to RT and water (30 mL) was added. Product extracted into DCM (2×30 mL) and washed with water (20 mL). The combined organics were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography (Biotage) eluted with DCM:MeOH gradient (99:1 to 95:05) to afford the title compound as an orange solid (1005 mg, 56% yield); 1H NMR (250 MHz, DMSO) delta 6.87 (1H, d, J=5.83 Hz), 8.08 (1H, d, J=6.31 Hz), 8.18 (1H, d, J=8.35 Hz), 8.27 (1H, d, J=5.83 Hz), 10.32 (1H, br. s.); LC-MS: m/z+348.70 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([OH:16])=[O:15])[N:2]=1.[OH-].[Na+].S(Cl)(Cl)=O>C(O)CCC>[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([O:16][CH2:14][CH2:3][CH2:4][CH3:5])=[O:15])[N:2]=1
Reactant: O=C(O)c1cc2c(cn1)[nH]c1ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CCCCO
Product: CCCCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Yield: 134.2 %

Procedure:
Compound 17 (2.1 g, 10 mmol), NaOH (0.8 g, 20 mmol), n-butanol (100 ml) and thionyl chloride (5 ml) were added into a 250 ml round-bottom flask. The mixture was refluxed for 6 h. Excessive n-butanol was then removed in reduced pressure. The residues were dissolved in water followed by the addition of ethyl acetate. While being stirred, the mixture was adjusted to pH 8 with NaHCO3 solution. The organic layer was isolated. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, decolorized with activated carbon and concentrated in vacuum. The residues were dissolved in ethyl acetate, and purified by silica gel column chromatography with ethyl acetate as the eluent, the recrystallized with ethyl ether/petroleum ether (2:5) to afford white needle crystals (1.8 g, 67%), and mp 211-212° C. (reference [1]: 210-211° C.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:12][CH2:13][O:14][CH3:15].C([Li])CCC.Cl[C:22]([O:24][CH3:25])=[O:23].C(=O)(O)[O-:27].[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]([O:12][C:13]([O:14][CH3:15])=[O:27])=[C:4]([CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9])[C:22]([O:24][CH3:25])=[O:23]
Reactant: COCOc1cccc(C(F)(F)F)c1Cl
Reactant: COC(=O)Cl
Reactant: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Oc1c(C(=O)OC)ccc(C(F)(F)F)c1Cl
Reaction time: 2 h

Procedure:
To a solution of 2-chloro-1-(methoxymethoxy)-3-(trifluoromethyl)benzene (11.8 g) in THF (100 mL) was added dropwise n-butyllithium (2.5M hexane solution) (21.0 mL) at −10° C., and the mixture was stirred for 2 hr. Then, to the reaction mixture was added dropwise a solution of methyl chloroformate (23.0 g) in THF (50.0 mL), and the mixture was stirred at 10° C. for 16 hr. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (×2). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (6.00 g).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[C:21]3[C:12](=[CH:13][C:14]4[C:15](=O)[C:16]([C:22]#[N:23])=[CH:17][NH:18][C:19]=4[CH:20]=3)[N:11]=[CH:10]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:28])=O>CN(C=O)C>[Cl:28][C:15]1[C:14]2[CH:13]=[C:12]3[N:11]=[CH:10][N:9]([CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[C:21]3=[CH:20][C:19]=2[N:18]=[CH:17][C:16]=1[C:22]#[N:23]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1c[nH]c2cc3c(cc2c1=O)ncn3CCN1CCOCC1
Solvent: CN(C)C=O
Product: N#Cc1cnc2cc3c(cc2c1Cl)ncn3CCN1CCOCC1
Yield: 61 %

Procedure:
A suspension of 190.0 mg (0.59 mmol) of 3-[2-(4-morpholinyl)ethyl]-8-oxo-5,8-dihydro-3H-imidazo[4,5-g]quinoline-7-carbonitrile, 5.45 mL of 2M oxalyl chloride (in methylene chloride) and 5 drops of DMF is heated at reflux temperature for 1.5 hours. After cooling, the solvent is evaporated to dryness. The residue is cooled in an ice bath and neutralized to pH 7 by slow addition of ice-cooled, aqueous saturated sodium bicarbonate solution. The aqueous solution is extracted with methylene chloride. The organic phase is washed with cold brine and dried over sodium sulfate. Removal of the solvent in vacuo gives the crude product. Purification of the crude product by preparative TLC (developing solvent: 5:95 methanol/methylene chloride) gives 122.8 mg (61%) of the product as a yellow solid, mp 205–207° C.
Reaction SMILES: [BH4-].[Na+].[CH:3]([S:6]([N:9]1[C:13]2[CH:14]=[C:15]([C:18]3[N:22]([CH:23]4[CH2:28][CH2:27]C(=O)[CH2:25][CH2:24]4)[CH:21]=[N:20][C:19]=3C3C=CC=CC=3)[CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[NH2:36])(=[O:8])=[O:7])([CH3:5])[CH3:4].[CH3:37][OH:38]>O1CCCC1.O>[CH:3]([S:6]([N:9]1[C:13]2[CH:14]=[C:15]([C:18]3[N:22]([CH:23]4[CH2:24][CH2:25][CH:37]([OH:38])[CH2:27][CH2:28]4)[C:21]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:20][CH:19]=3)[CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[NH2:36])(=[O:7])=[O:8])([CH3:4])[CH3:5]
Reactant: CO
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3c(-c4ccccc4)ncn3C3CCC(=O)CC3)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3cnc(-c4ccccc4)n3C3CCC(O)CC3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Add a solution of sodium borohydride (0.28 g) in methanol (5 mL) to a solution of 1-isopropylsulfonyl-2-amino-6-(1-(cyclohexan-1-on-4-yl)-4(phenyl)-imidazol-5-yl)-benzimidazole (0.35 g, 0.7 mmol) in 10 mL tetrahydrofuran and 10 mL methanol. Stir the reaction mixture for 30 minutes at room temperature, dilute with water (50 mL), and extract with ethyl acetate (2×15 mL). Wash the combined organic extracts with saturated aqueous sodium chloride, dry over sodium sulfate, and concentrate under reduced pressure to provide 0.345 g (98%) of the title compound. MS(ES+): m/z=480.2 (M+H)+
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1>>[C:35]([NH:34][C:30]1[CH:29]=[C:28]([CH:25]2[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][NH:18][C:8](=[O:10])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:11])[CH2:23][CH2:24]2)[CH:33]=[CH:32][CH:31]=1)(=[O:39])[CH:36]([CH3:38])[CH3:37]
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 30 was prepared from 2,2-diphenylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.42 (s, 1H), 7.39–7.18 (m, 12H), 6.89 (d, 1H, J=7.7 Hz), 6.23 (m, 1H), 3.35 (q, 2H, J=6.4), 2.85 (d, 2H, J=10.8 Hz), 2.5 (quintet, 1H, J=7.4 Hz), 2.45–2.36 (m, 1H), 2.28 (t, 2H, J=6.4 Hz), 1.99 (s, 3H), 1.91–1.82 (m, 2H), 1.75–1.68 (m, 2H), 1.65 (t, 2H, J=6.4 Hz), 1.60–1.47 (m, 2H), 1.23 (d, 6H, J=7.0 Hz); ESMS m/e: 512.4 (M+H)+.
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=1>CS(C)=O.O>[F:10][C:7]1[CH:8]=[CH:9][C:4]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([O:19][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:27][CH:28]=2)=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CCOC(=O)C(C)Oc1ccc(N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(C)Oc1ccc(Nc2ccc(F)cc2[N+](=O)[O-])cc1
Reaction time: 24 h

Procedure:
2.5 g of sodium hydride paste (60% in mineral oil) was added in portions to a stirred solution of 9.9 g of 2,5-difluoronitrobenzene and 12.7 g of 1E in 200 ml of dimethyl sulfoxide. The resulting mixture was held at 160°-170° C. for 24 hours, then was cooled, diluted with 1000 ml of water and extracted with ether. The extract was chromatographed on silica gel to give ethyl 2-(4-(4-fluoro-2-nitrophenyl-amino)phenoxy)propionate (7A) as a viscous oil.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[H+].CCOCC.[NH2:12][CH2:13][CH2:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.CC#[N:24]>>[F:1][B-:2]([F:5])([F:4])[F:3].[NH3+:12][CH2:13][CH2:14][C:15]1[CH:21]=[CH:20][C:18]([N+:19]#[N:24])=[CH:17][CH:16]=1.[F:1][B-:2]([F:5])([F:4])[F:3]
Reactant: NCCc1ccc(N)cc1
Reactant: CC#N
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Product: N#[N+]c1ccc(CC[NH3+])cc1
Reaction time: 0.17 h
Yield: 99 %

Procedure:
A 50% solution of tetrafluoroboric acid in Et2O (0.5mL, 3.7 mmol) was added to a solution of 4-(2-aminoethyl)aniline (0.5mg, 3.7 mmol) in MeCN (Amp at −40° C. under argon. The mixture was stirred 10 min, then nitrosyl tetrafluorobbrate (450 mg, 3.8 mmol) was added dropwise. After 30 min of stirring at −40 ° C. Et2O (100 mL) was added. The white precipitate obtained was filtered and washed twice with Et2O to give a white powder (1.18 g, 99%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:14][CH:15]=2)[C:10]([S:31]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:44]([NH:46][CH2:47][CH3:48])[CH3:45]>C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][N:46]([CH2:47][CH3:48])[CH2:44][CH3:45])=[CH:14][CH:15]=2)[C:10]([S:31]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNCC
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3Cc2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2Cc1ccccc1
Temperature: 80 °C
Reaction time: 16.5 h

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.449 g, 0.733 mmol) and diethylamine (2.0 mL, 19 mmol) in THF (7.5 mL) was stirred at 70° C. in a sealed tube for 3 hours. More diethylamine (2.0 mL, 19 mmol) was then added, and the reaction mixture was stirred at 80° C. in a sealed tube for 16.5 hours. After cooling somewhat, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine. It was dried with anhydrous magnesium sulfate, filtered and concentrated. Drying at 82° C. in vacuo for 35 minutes gave {2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-diethyl-amine as a light brown-yellow semi-solid (0.365 g, 97.1% mmol). This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried for 13 hours in vacuo at 81° C. The result was the hydrochloride as a light orange semi-solid (0.332 g); Mass Spectrum (+EI, [M+H]+) m/z 514. 1HNMR (500 MHz, DMSO-d6): δ10.15-10.18 (s, 1H), 8.74-8.76 (m, 1H), 8.56 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.26 (d, 1H, J=8.29 Hz), 8.02-8.05 (m, 1H), 7.78 (d, 1H, J=9.15 Hz), 7.70-7.74 (m, 1H), 7.58-7.65 (m, 2H), 7.26 (s, 1H), 7.08-7.19 (m, 6H), 5.70 (s, 2H), 4.25 (s, br, 2H), 3.39-3.55 (br, s, 2H), 3.15 (br, s, 3H), 1.13-1.19 ppm (s, br, 6H). Elemental Analysis for C30H31N3O3S.1.00 HCl.0.75 mol H2O: Calcd: C, 63.93; H, 5.99; N, 7.46; Found: C, 63.59; H, 5.94; N, 7.23.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:28])[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)=[C:12]([O:26][CH3:27])[CH:11]=2)=[N:6][CH:7]=1.[CH:29](OCC)(OCC)OCC>C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[I:1][C:2]1[CH:3]=[C:4]2[N:28]=[CH:29][N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)=[C:12]([O:26][CH3:27])[CH:11]=3)[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(COc2ccc(CNc3ncc(I)cc3N)cc2OC)cn1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: COc1ccc(COc2ccc(Cn3cnc4cc(I)cnc43)cc2OC)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a stirred suspension of 5-iodo-N2-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)pyridine-2,3-diamine (11.67 g, 23.70 mmol) in ethanol (175 mL) was added triethyl orthoformate (8.90 g, 60.05 mmol) and p-toluenesulfonic acid monohydrate (0.23 g, 1.19 mmol). As the mixture was warmed to reflux, the solids dissolved to provide a brown solution. After 30 min, the reaction mixture was cooled to 0° C., resulting in the formation of a precipitate. The solids were isolated by filtration, washed with a small amount of cold ethanol, and dried to provide 10.34 g (87%) of 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine as an off-white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=O.P(Cl)(Cl)([Cl:15])=O.C1(C)C=CC=CC=1.C(N(CC)CC)C>CC(C)=O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[Cl:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2ccc(I)cc12
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Clc1ncnc2ccc(I)cc12
Temperature: 25 °C
Yield: 88.7 %

Procedure:
In a 500 mL-volume glass vessel equipped with a stirrer, a thermometer and a reflux condenser were placed 50.0 g (184 mmol) of 6-iodoquinazolin-4-one, 33.8 g (221 mmol) of phosphorus oxychloride, and 300 mL of toluene in a nitrogen atmosphere. While the mixture was stirred at room temperature, 22.3 g (221 mmol) of triethylamine was slowly added. The resulting mixture was heated at 60° C. for 30 minutes and then heated at 75° C. for 2 hours, for carrying out reaction. After the reaction was complete, the reaction mixture was cooled to room temperature, and 50 mL of acetone was added. The mixture was then cooled to 0° C. and stirred for 30 minutes. Thus precipitated pale yellow crystalline product of 6-iodo-4-chloroquinazoline was collected by filtration. Subsequently, the crystalline product was placed in 200 mL of water, and 9 mL of aqueous sodium hydroxide (1 mol/L) was added. The aqueous mixture (pH 10-11) was stirred for 30 minutes at room temperature. The crystalline product was collected by filtration, washed successively with 100 mL of acetone, 200 mL of water and 100 mL of acetone, and dried at 60° C. under reduced pressure, to give 47.4 g (isolated yield: 89%, purity 99% in terms of area percentage determined by high performance liquid chromatography) of 6-iodo-4-chloroquinazoline as a yellowish crystalline product.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(N(C(C)C)CC)(C)C>CC(O)C>[C:26]([O:25][C:23]([N:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:18]2[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)[CH2:32][CH2:31]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Yield: 95 %

Procedure:
A stirred mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (23.8 g, 70.5 mmol), 1-BOC-4-aminopiperidine (15.5 g, 77.5 mmol) and diisopropylethylamine (17.0 mL, 98.7 mmol) in propan-2-ol (250 mL) was heated to reflux for approximately 2 hours. After cooling, the resulting suspension was filtered and the solid washed with propan-2-ol and diethyl ether, then air dried to afford 33.6 g (95%) of 4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester as a yellow solid. 1H NMR (400 MHz, CDCl3) δ: 9.12 (br d, 1H), 9.09 (s, 1H), 8.21 (m, 2H), 7.66 (m, 2H), 7.53 (t, 2H), 6.69 (d, 1H), 4.14 (m, 1H), 4.01 (d, 2H), 3.12 (t, 2H), 2.11-2.08 (m, 2H), 1.65-1.64 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([OH:14])=O)=[CH:9][CH:8]=[CH:7][CH:6]=2.ON1C2C=CC=CC=2N=N1.[CH2:31]([C@H:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:32].C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1.CC#N.C(Cl)Cl>[CH2:31]([C@H:33]([NH:40][C:12]([C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:2]=1[NH2:1])=[O:14])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:32]
Reactant: Nc1c(-c2ccccc2)nc2ccccc2c1C(=O)O
Reactant: CC[C@H](N)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC#N
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)c1c(N)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
1.5 g (5.7 mmol) of 3-amino-2-phenylquinoline-4-carboxylic acid (CAS [36735-26-9]) were dissolved in 140 ml of a 7/3 mixture of THF/CH3CN; 1.5 g (11.1 mmol) of 1-hydroxybenzotriazole (HOBT) were added and 1.15 g (8.5 mmol) of (S)-α-ethyl benzylamine dissolved in 10 ml of CH2Cl2 were added dropwise. After cooling of the reaction mixture to 0° C., 1.4 g (6.7 mmol) of dicyclohexylcarbodiimmide (DCC) dissolved in 10 ml of CH2Cl2 were added dropwise. The solution was kept at 0° C. for 30 minutes and then at room temperature overnight. The reaction mixture was evaporated in-vacuo, the residue was dissolved in CH2Cl2 and the solution filtered off, washed with H2O, 20% citric acid, sat. sol. NaHCO3 and sat. sol. NaCl. The organic layer was separated, drive over Na2SO4 and evaporated in-vacuo to dryness to obtain 2.4 g of the crude product. This was triturated with i-Pr2O, then recrystallized with a 10:1 mixture of iPr2O/i-PrOH to yield 1.7 g of the title compound.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[F:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([CH2:12][CH2:13][C:14](O)=[O:15])=O)=[CH:8][CH:7]=1.Cl.C(OCC)(=O)C>ClCCl>[F:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][CH2:12][CH2:13][CH2:14][OH:15])=[CH:17][CH:18]=1
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: OCCCCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.9 %

Procedure:
A suspension of aluminium trichloride (10.2 g, 76.5 mmol) in dichloromethane (250 ml) at 0° C. was added with the borane-tert-butylamine complex (13.2 g, 153 mmol) and the mixture was left under stirring at 0° C. for 15 minutes. After that the mixture was added with 3-(4-fluorobenzoyl)propionic acid (5 g, 25.5 mmol) stirring at room temperature for 20 h, then added slowly with 0.2M HCl (75 ml) and extracted with ethyl acetate (3×100 ml). The combined organic phases were washed with 0.2M HCl and with a NaCl saturated solution, dried and the solvents were removed under reduced pressure. The resulting residue was purified by chromatography through a silica gel column, eluting with hexane:ethyl acetate, 8:2, thereby recovering 2.70 g of the title product as a colourless oil (63% yield).
Reaction SMILES: [CH2:1]([N:4]([CH2:10]Cl)[C:5](=[O:9])[CH:6]([Cl:8])[Cl:7])[CH2:2][CH3:3].[CH2:12]([O:14][CH2:15][CH2:16][OH:17])[CH3:13].[Na].C(OC(O)C)C>O>[CH2:1]([N:4]([CH2:10][O:17][CH2:16][CH2:15][O:14][CH2:12][CH3:13])[C:5](=[O:9])[CH:6]([Cl:8])[Cl:7])[CH2:2][CH3:3]
Reactant: CCOCCO
Reactant: CCCN(CCl)C(=O)C(Cl)Cl
Agent: CCOC(C)O
Agent: [Na]
Solvent: O
Product: CCCN(COCCOCC)C(=O)C(Cl)Cl

Procedure:
A solution containing N-propyl-N-chloromethyldichloroacetamide (21.9 g., 0.1 mole) and 2-ethoxyethanol (30 ml.) is weighed in a flask equipped as in Example 1. A solution prepared from metallic sodium (2.3 g., 0.1 mole) with ethoxyethanol (20 ml.) is added to the solution under stirring and cooling by water in such a rate that the temperature of the mixture is maintained below 35° C. After the addition is complete, the mixture is stirred for an additional 2 hours at room temperature. Then, the bulk of ethoxyethanol is removed under reduced pressure and the residue is dissolved in chloroform (80 ml.). The chloroform solution is washed with water (2×100 ml.), dried over anhydrous sodium sulfate and the solvent is distilled under reduced pressure to give 23.2 g. (90.0%) of the named product as an oil; nD25 =1.4651.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][OH:5].[CH3:9][S:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[CH:19]=[C:18]([CH2:20][CH3:21])[N:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[C:15]=2[N:16]=1.C(Cl)Cl>C1C=CC=CC=1>[CH3:8][O:7][C:3](=[O:6])[CH2:4][O:5][C:13]1[C:14]2[CH:19]=[C:18]([CH2:20][CH3:21])[N:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[C:15]=2[N:16]=[C:11]([S:10][CH3:9])[N:12]=1
Reactant: CCc1cc2c(Cl)nc(SC)nc2n1Cc1cccc(F)c1
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCc1cc2c(OCC(=O)OC)nc(SC)nc2n1Cc1cccc(F)c1
Temperature: 57 °C
Reaction time: 48 h
Yield: 47.5 %

Procedure:
To a suspension of 82 mg (3.43 mmol) of sodium hydride in 4 mL of benzene was added 315 mg (3.43 mmol) of methyl glycolate and a solution of 384 mg (1.14 mmol) of 2-(methylthio)-4-chloro-6-ethyl-7-[(3-fluorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidine in 4 ml of benzene. The mixture was heated at 57° C. and monitored by TLC (silica, methylene chloride) for conversion to product. After 2 days, the reaction was cooled to ambient temperature and partitioned by the addition of 15 mL of 2 M sodium hydrogen sulfate and 15 mL of ethyl acetate. The aqueous phase was extracted twice with 7 mL portions of ethyl acetate. The combined organic phases were dried with sodium sulfate and concentrated 600 mg of solid. The product was purified by flash chromatography (54 g silica, hexane-ethyl acetate gradient 100:0 to 75:25) to provide 211 mg (48%) of [[2-(methylthio)-6-ethyl-7-[(3-fluorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a white solid. nmr (300 MHz, CDCl3) δ1.14 (t, 3H), 2.53 (s, 3H), 2.55 (q, 2H), 3.88 (s, 3H), 5.04 (s, 2H), 5.36 (s, 2H), 6.30 (s, 1H), 6.75 (d, 1H), 6.85 (d, 1H), 6.96 (dt, 1H), 7.26 (dt, 1H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:14](Cl)(=[O:16])=[O:15])[C:5]2[O:10][S:9](=[O:12])(=[O:11])[CH:8]=[CH:7][C:6]=2[CH:13]=1.[NH3:18].Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:14](=[O:16])(=[O:15])[NH2:18])[C:5]2[O:10][S:9](=[O:12])(=[O:11])[CH:8]=[CH:7][C:6]=2[CH:13]=1
Reactant: O=S1(=O)C=Cc2cc(Br)cc(S(=O)(=O)Cl)c2O1
Reactant: N
Agent: Cl
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc(Br)cc2c1OS(=O)(=O)C=C2
Reaction time: 0.5 h

Procedure:
The crystalline product obtained in (c) is dissolved in as small an amount of tetrahydrofuran as possible and the solution is added dropwise to 20 ml of 25% aqueous ammonia solution. After the reaction mixture has been stirred for 30 minutes it is poured into a mixture of ice and 10% hydrochloric acid. Extraction with ether yields 0.3 g of 6-bromo-8-sulfamoyl-2,2-dioxo-1,2-benzoxathiine of m.p. 224°-228° C. (decomposition with black colouration).