Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:7]([O:15][CH2:16][O:17][CH3:18])=[N:6][C:5]=2[N:4]([CH3:19])[N:3]=1.[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:20][CH2:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:7]([O:15][CH2:16][O:17][CH3:18])=[N:6][C:5]=2[N:4]([CH3:19])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCOc1nc2c(c(C)nn2C)c2ccccc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COCOc1nc2c(c(CBr)nn2C)c2ccccc12
Temperature: 25 °C
Yield: 74.3 %

Procedure:
1,3-Dimethyl-5-methoxymethoxy-3H-pyrazolo[3,4-c]isoquinoline (1.03 g), N-bromosuccinimide (0.72 g) and benzoyl peroxide (0.05 g) were dissolved in carbon tetrachloride (20 mL), and the mixture was heated under reflux for 4 hrs. After the completion of the reaction, the reaction mixture was cooled to room temperature, washed with saturated aqueous sodium hydrogen carbonate and dried over magnesium sulfate. The solvent was evaporated. The obtained solid was collected by filtration and washed with ether to give 1-bromomethyl-3-methyl-5-methoxymethoxy-3H-pyrazolo[3,4-c]isoquinoline (1.0 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[N:11]([CH2:19][C:20]2[O:21][CH:22]=[CH:23][N:24]=2)[C:10]=1[CH:25]([CH3:27])[CH3:26])=[O:8].[CH2:32](I)[CH2:33][CH3:34]>>[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:32][CH2:33][CH3:34])=[CH:15][CH:16]=2)[N:11]([CH2:19][C:20]2[O:21][CH:22]=[CH:23][N:24]=2)[C:10]=1[CH:25]([CH3:27])[CH3:26])=[O:8]
Reactant: CCCI
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ncco1
Product: CCCOc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ncco3)c2c1

Procedure:
The title compound was prepared from N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-3-carboxamide (Compound 210) and n-propyl iodide by General Procedure N.
Reaction SMILES: C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.C[O:19][C:20](=O)/[CH:21]=[C:22](\[CH3:39])/[CH2:23]/[CH:24]=[CH:25]/[C@H:26]([CH3:38])[C@@H:27]([O:30][Si:31]([CH2:36][CH3:37])([CH2:34][CH3:35])[CH2:32][CH3:33])[CH2:28][CH3:29].O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(OCC)C>[CH3:39]/[C:22](/[CH2:23]/[CH:24]=[CH:25]/[C@H:26]([CH3:38])[C@@H:27]([O:30][Si:31]([CH2:34][CH3:35])([CH2:36][CH3:37])[CH2:32][CH3:33])[CH2:28][CH3:29])=[CH:21]\[CH2:20][OH:19]
Reactant: CC[C@H](O[Si](CC)(CC)CC)[C@@H](C)/C=C/C/C(C)=C/C(=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC[C@H](O[Si](CC)(CC)CC)[C@@H](C)/C=C/C/C(C)=C/CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
1M toluene solution (1.76 ml, 1.76 mmol) of diisobutylaluminum hydride was added dropwise to an toluene (6 ml) solution of methyl-(2E,5E,7S,8S)-3,7-dimethyl-8-[(triethylsilyl)oxy]deca-2,5-dienoate (0.22 g, 0.64 mmol) at −78° C. and the reaction solution was stirred at the same temperature for 30 minutes. The reaction solution was diluted with diethyl ether, followed by addition of a saturated potassium sodium tartrate tetrahydrate aqueous solution (1.0 ml) and was warmed to room temperature and stirred for two hours. After the organic layer was dried over anhydrous sodium sulfate and the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Merck, commercial name Silica Gel 60, 230-400 mesh; hexane:diethyl ether=8:1) to obtain the title compound (150 mg) as a colorless oil.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[CH2:9]1)C1C=CC=CC=1.[CH3:19][NH2:20]>>[CH3:19][NH:20][C:13]1[CH:12]=[CH:11][C:10]2[CH2:9][NH:8][CH2:17][CH2:16][C:15]=2[N:14]=1
Reactant: CN
Reactant: Clc1ccc2c(n1)CCN(Cc1ccccc1)C2
Product: CNc1ccc2c(n1)CCNC2

Procedure:
6-Benzyl-2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine was reacted with methylamine; deprotection afforded N-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][N:17]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]([NH:15][CH2:14][C@@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]2)=[N:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CNc1ncnc2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c(NC[C@@H]3CCCCN3)ncnc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-2-(Quinazolin4-ylaminomethyl)-piperidine-1-carboxylic acid tert butyl ester (1.2 g) was dissolved in trifluoroacetic acid (60 ml) and stirred at room temperature for 2 hours. The solution was then evaporated and the residue chromatographed over silica gel, eluting with 0 to 10% (9:1 methanol-concentrated ammonia solution) in dichloromethane. The title compound was obtained as a white foam (0.84 g), MH+ 243.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([C:21]([NH:23][C:24]5[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=5)[C:27]([O:29]CC)=[O:28])=[O:22])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([C:21]([NH:23][C:24]5[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=5)[C:27]([OH:29])=[O:28])=[O:22])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:35][CH:36]=1
Reactant: CCOC(=O)c1cccc(NC(=O)N2CCc3c(cnc4c3cnn4Cc3ccc(OC)cc3)C2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)Nc2cccc(C(=O)O)c2)CC4)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.1 %

Procedure:
To a solution of ethyl 3-(3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxamido)benzoate (0.162 g, 0.33 mmol) in methanol (5 mL) was added aqueous NaOH (0.13 g in 3 mL H2O, 3.3 mmol). The reaction was stirred at room temperature for 16 hours. On completion of the reaction the solvent was removed and the resulting aqueous solution was acidified to pH<2 using 2N HCl. A solid precipitated out, which was filtered, washed with water and dried to give the desired product, 3-(3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxamido)benzoic acid (0.136 g, 90%) as a pale yellow solid. M.p.>136° C.; 1H NMR (400 MHz, DMSO-d6) δ12.95 (s, 1H), 8.93 (s, 1H), 8.41 (s, 1H), 8.19 (s, 1H), 8.10 (m, 1H), 7.78 (m, 1H), 7.53 (m, 1H), 7.36 (dd, J1=J2=8.4 Hz, 1H), 7.18 (m, 2H), 6.84 (m, 2H), 4.86 (m, s, 2H), 3.85 (t, J=6.0 Hz, 2H), 3.68 (s, 3H), 3.50 (m, 2H), 3.16 (t, J=6.0 Hz, 2H); LCMS [M+H]: 458.
Reaction SMILES: [CH2:1]([N:5]([CH2:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[C:11]([O:13]C)=O)[CH3:6])[CH2:2][CH2:3][CH3:4].O.[OH-].[Li+].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[ClH:55].Cl.[NH2:57][C@@H:58]([CH2:72][C:73]1[CH:78]=[C:77]([F:79])[CH:76]=[C:75]([F:80])[CH:74]=1)[C@H:59]([OH:71])[CH2:60][NH:61][C:62]1([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH2:64][CH2:63]1>C(OCC)(=O)C.O1CCCC1.CO.O>[ClH:55].[ClH:55].[CH2:1]([N:5]([CH2:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[C:11]([NH:57][C@@H:58]([CH2:72][C:73]1[CH:74]=[C:75]([F:80])[CH:76]=[C:77]([F:79])[CH:78]=1)[C@H:59]([OH:71])[CH2:60][NH:61][C:62]1([C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH2:64][CH2:63]1)=[O:13])[CH3:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C)Cc1cc(C)cc(C(=O)OC)c1
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2ccccc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCN(C)Cc1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNC2(c3ccccc3)CC2)c1
Reaction time: 2 h

Procedure:
Analogous to the method in Example SP-188, methyl 3-{[butyl(methyl)amino]methyl}-5-methylbenzoate (170 mg, 0.68 mmol) is dissolved in 2:1:1 tetrahydrofuran/methanol/water (4 mL), and lithium hydroxide monohydrate is added (57 mg, 1.4 mmol), and the reaction stirred 2 h. The solution is concentrated under reduced pressure. The residue is redissolved in DMF (3 mL), and diisopropylethylamine (472 μL, 2.7 mmol), HATU (322 mg, 0.85 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(1-phenylcyclopropyl)amino]butan-2-ol dihydrochloride prepared by the method in Example S-XYZ (275 mg, 0.68 mmol) are added. The reaction stirred at room temperature 16 h. The reaction mixture is diluted with ethyl acetate, washed with water, saturated sodium bicarbonate, brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/methylene chloride) provides the title compound as the free base. The residue is dissolved in diethyl ether (3 mL) and 1N hydrochloric acid in diethyl ether (1 mL) is added. The mixture is concentrated under reduced pressure to yield the title compound. ESI MS m/z 550.3 [M+H]+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][SH:8])=[CH:3][CH:2]=1.[H-].[Na+].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](F)[N:13]=1>O1CCCC1>[CH2:7]([S:8][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([F:11])[N:13]=1)[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: SCc1ccccc1
Reactant: Fc1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1cccc(SCc2ccccc2)n1
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
A solution of benzylthiol (5.4 g) in tetrahydrofuran (25 cm3) was added dropwise to a stirred suspension of sodium hydride (1.9 g of a 55% of a dispersion in oil) in tetrahydrofuran (350 cm3) under a nitrogen atmosphere. The mixture was stirred for 30 minutes and a solution of 2,6-difluoropyridine (5 g) in tetrahydrofuran (25 cm3) was added dropwise. The mixture was stirred for a further 3 hours and then carefully quenched with water. The products were extracted into diethyl ether and the combined ether extracts were washed with water and brine solution, then dried over anhydrous magnesium sulphate, filtered and concentrated by evaporation under reduced pressure. The residual dark liquid was purified by chromatography on a silica gel support, eluting with hexane containing 5% by volume ethyl acetate. Fractions containing 15-20 cm3 of eluent were collected separately during the elution, the product being collected in fractions 11 to 19. Evaporation of the eluent gave the title product (7.1 g) as a clear liquid.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=1)(=[O:7])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[S:59]1C=CC=C1CC(O)=O>C1COCC1>[SH:59][CH2:2][CH2:3][N:4]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: O=C(O)Cc1cccs1
Reactant: CCCCOc1ccc(S(=O)(=O)N(CCO)Cc2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCOc1ccc(S(=O)(=O)N(CCS)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.1 %

Procedure:
Part B: To a solution of 3.0 g (8.2 mmol) of N-(2-hydroxyethyl)-N-(phenylmethyl)-4-(n-butoxy)benzenesulfonamide from Part A and 2.38 g (9.1 mmol) of triphenylphosphine in 40 mL of anhydrous THF at 0 C, was added 1.4 mL (9.1 mmol) of diisopropylazodicarboxylate, followed by 0.65 mL (9.1 mmol) of thiolacetic acid. After stirring at room temperature for 15 hours, the reaction was concentrated and the residue chromatographed on 150 g of silica gel using 20-50% ethyl acetate/hexane to afford 2.4 g of the desired product, which was recrystallized from ethyl acetate/hexane to afford 1.7 g of pure product, m/e=428 (M+Li).
Reaction SMILES: [ClH:1].[OH:2][NH:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][C:10]2=[N:15]O)=[NH:5].N[N:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[N:20]=[C:19]1[NH2:31]>C(O)(C)C>[ClH:1].[ClH:1].[OH:2][NH:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][C:10]2=[N:15][N:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[N:20]=[C:19]1[NH2:31])=[NH:5]
Reactant: COc1cccc(-c2cn(N)c(N)n2)c1
Reactant: N=C(NO)c1cccc2c1CCC2=NO
Agent: Cl
Solvent: CC(C)O
Product: COc1cccc(-c2cn(N=C3CCc4c(C(=N)NO)cccc43)c(N)n2)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
6.0 ml of 32% hydrochloric acid (Merck, Darmstadt, Germany; p.a.) are added, with stirring, to a mixture of 4.1 g (0.02 mol) of 4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 4.08 g (0.02 mol) of 1,2-diamino-4-(3-methoxyphenyl)-imidazole and 100 ml of isopropanol, and the reaction mixture is stirred at 80° C. for 18 hours. The reaction mixture is filtered while hot and the filtration product is washed with isopropanol and dried. In that manner there is obtained the title compound, m.p. 257°-259° C., 1H-NMR (DMSO/D2O): δ=8.24 (d, 1H); 7.91 (s, 1H); 7.75 (d, 1H); 7.61 (t, 1H); 7.38 (t, 1H); 7.25 (m, 2H); 6.95 (m, 1H); 3.76 (s, 3H), 3.27 (s, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@@H:9]([CH3:14])[CH2:10][C:11]([NH2:13])=[O:12])=[CH:4][CH:3]=1.Cl[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17].CC(C)([O-])C.[Li+]>C(OCC)(=O)C.O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C@@H:9]([CH3:14])[CH2:10][C:11]([NH:13][C:16](=[O:17])[O:18][CH:19]([CH3:21])[CH3:20])=[O:12])=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)Cl
Reactant: C[C@@H](CC(N)=O)Nc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)OC(=O)NC(=O)C[C@H](C)Nc1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
(3S)-3-[(4-bromophenyl)amino]butanamide (for a preparation see Intermediate 13, 24.9 g, 97 mmol) was taken up in Ethyl acetate (850 mL) and cooled to <−9° C. (internal). Isopropyl chloroformate (116 mL, 116 mmol, Aldrich) was added followed by slow addition of Lithium tert-butoxide (18.61 g, 232 mmol) in Tetrahydrofuran (THF) (232 mL) keeping the temperature below 0° C. The reaction was stirred for 30 mins then checked by LCMS which showed a complete reaction. The mixture was partitioned between EtOAc (1000 ml) and 2N HCl (2000 ml). The organic layer was washed with brine (2000 ml) and then dried with Na2SO4, filtered and concentrated to yield the product as a brown oil (17.9 g) LCMS (Method B): Rt=1.09, MH+=343
Reaction SMILES: [CH2:1]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH:21]([S:35]([OH:38])(=[O:37])=[O:36])=[CH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[CH2:1]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][S:35]([OH:38])(=[O:37])=[O:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCc1ccccc1
Reactant: CCCCCCCCCCCCC=CS(=O)(=O)O
Product: CCCCCCCCCCCCCCc1ccccc1CCCCCCCCCCCCCCS(=O)(=O)O

Procedure:
(Tetradecylphenyl) tetradecylsulfonic acid was prepared according to procedures described in U.S. U.S. Pat. No. 6,043,391 from tetradecylbenzene and tetradecenylsulfonic acid.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:14][CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18].[OH-].[Na+].Cl>C(O)C>[CH3:13][S:10]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:15][CH2:16][C:17]([F:18])([F:20])[F:19])=[C:4]([CH:9]=1)[C:3]([OH:21])=[O:2])(=[O:12])=[O:11]
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1OCCC(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(OCCC(F)(F)F)c(C(=O)O)c1
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
To 5-methanesulfonyl-2-(3,3,3-trifluoro-propoxy)-benzoic acid methyl ester (620 mg) in ethanol at 60° C. was added 1N NaOH solution (3.8 mL), and the reaction mixture was stirred for 15 minutes. After such time, 3.8 ml of 1N HCl was slowly added to the reaction mixture, and the ethanol was evaporated in vacuo. The precipitate was then washed with water several times to give the title compound (497 mg). MS (m/e): 311.0, M−H+, 100%).
Reaction SMILES: [NH2:1][NH2:2].[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[C:6](F)[CH:5]=1>>[Br:3][C:4]1[CH:5]=[C:6]2[C:7]([CH:8]=[N:1][NH:2]2)=[CH:10][CH:11]=1
Reactant: NN
Reactant: O=Cc1ccc(Br)cc1F
Product: Brc1ccc2cn[nH]c2c1
Temperature: 125 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
To a 100 mL round-bottomed flask was added hydrazine (30 mL, 832 mmol) and 4-bromo-2-fluorobenzaldehyde (4.69 g, 23 mmol). The solution was stirred at 125° C. for 3 hours. After cooling to ambient temperature, the solution was concentrated under reduced pressure. The solution was quenched by pouring it into a mixture of ice water (100 mL), and then extracting with EtOAc (3×100 mL). The organic layers were combined, dried over sodium sulfate, and filtered. The solution was evaporated to dryness, and adsorbed onto silica gel. The crude product was purified using column chromatography through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% EtOAc in hexanes, to provide 6-bromo-1H-indazole (4.6 g, 18 mmol, 76% yield). LCMS (M+H) 197.9 calc. for C7H5BrN2 197.0, 1H NMR (400 MHz, CD3OD): δ ppm 8.03 (s, 1H), 7.67-7.72 (2H, m), 7.24-7.26 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Cu][C:13]#[N:14]>CN(C)C=O>[CH3:11][O:10][C:4]1[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([CH:3]=1)[C:13]#[N:14]
Reactant: COc1cc(Br)cnc1OC
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: COc1cc(C#N)cnc1OC
Temperature: 180 °C

Procedure:
To a solution of 5-bromo-2,3-dimethoxypyridine (7-2, 0.300 g, 1.38 mmol, 1.0 equiv) in dimethylformamide (3.9 mL) was added copper (I) cyanide (0.15 g, 1.65 mmol, 1.2 equiv) and the reaction mixture was heated for 40 minutes at 180° C. in a microwave reactor. The reaction mixture was cooled and partitioned between EtOAc (50 mL) and water (50 mL). The organic phase was washed with water (2×30 mL) and brine (1×30 mL), dried over magnesium sulfate and concentrated. The residue was purified via normal phase chromatography (0 to 40% EtOAc in hexanes, silica) to afford the desired product (7-3) as white solid after concentration. ESI+MS [M+H]+ C8H8N2O2 calc'd 165.1, found 165.1.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O>[N+:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: c1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccccc1

Procedure:
When the nitric acid has reacted completely with benzene under adiabatic conditions in the reactor (1) to give nitrobenzene and water, the reaction mixture (S4) thereby heated to about 135° C. (see the examples) is fed to a phase separator in the form of a decanter (2), in which the reaction mixture is separated into a phase of crude nitrobenzene (S5) and spent acid (S6). The spent acid (S6) is partially concentrated in a first evaporator (3) operated at 260 mbar. Also shown is a false air stream (S16), which is drawn into the first evaporator (3) by the vacuum therein. The vapour stream (S12) produced in the first evaporator (3), comprising water, sulfuric acid, nitrobenzene, benzene and aliphatic organic compounds, which are contained as impurities in the benzene stream (S1) for reaction, are condensed in a condenser (8) to a first liquid discharge stream (S13). The unevaporated, liquid discharge stream of the first evaporator (S7) is fed to the second evaporator (4), which is operated at a pressure of 74 mbar, and thereby concentrated to a concentration of 70% by mass sulfuric acid (S8). Also shown is a second false air stream (S15), which is drawn into the second evaporator (3) by the vacuum therein. For further use, the re-concentrated sulfuric acid (S8) is accordingly stored in a sulfuric acid tank (5). In the second evaporation of the spent acid there is obtained a vapour stream (S9) consisting substantially of water as well as residues of sulfuric acid, nitrobenzene and benzene, which is condensed in a condenser (6).
Reaction SMILES: [C:1]([C:4]1[C:5]([N+:13]([O-])=O)=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH2:9])=[O:8])(=[O:3])[NH2:2]>C(O)C.[Pd]>[NH2:13][C:5]1[C:6]([C:7](=[O:8])[NH2:9])=[CH:10][CH:11]=[CH:12][C:4]=1[C:1]([NH2:2])=[O:3]
Reactant: NC(=O)c1cccc(C(N)=O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: NC(=O)c1cccc(C(N)=O)c1N
Reaction time: 5 h
Yield: 50 %

Procedure:
3-Carbamoyl-2-nitrobenzamide (0.6 g, 0.0029 mol) was dissolved in ethanol (50 ml) and the solution stirred with 5% palladium on charcoal catalyst (0.1 g) under a hydrogen atmosphere at 50 p.s.i. (3.45 bar) and 50° C. for 5 hours. The catalyst was removed by filtration, the solvent evaporated under vacuum and the residue crystallized from water to give the title compound as a grey solid (0.26 g, 50%), m.p.284°-288° C. Found: C,53.49; H,5.00; N,23.31. C8H9N3O2 requires C,53.62; H,5.06; N,23.45%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:12][C:13](=O)[CH2:14][Cl:15])[N:8]=[CH:7][C:6]([C:17]#[N:18])=[C:5]2[NH:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=1>C(O)(=O)C>[Cl:15][CH2:14][C:13]1[N:12]=[C:11]2[CH2:10][C:9]3[N:8]=[CH:7][C:6]([C:17]#[N:18])=[C:5]([NH:19][C:20]4[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=4)[C:4]=3[CH:3]=[C:2]2[N:1]=1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(NC(=O)CCl)c(N)cc23)cc(OC)c1OC
Solvent: CC(=O)O
Product: COc1cc(Nc2c(C#N)cnc3c2C=C2N=C(CCl)N=C2C3)cc(OC)c1OC
Temperature: 25 °C

Procedure:
A of 0.11 g (0.25 mmol) sample of product from Example 46 in 3.0 mL of glacial acetic acid is heated at 100° C. for 15 minutes, then cooled to room temperature. Following evaporation of the solvent in vacuo, the residue is suspended in water and neutralized with solid sodium carbonate. The solid is collected by filtration, washed with water and dried to yield 0.1 g of 2-(chloromethyl)-8-(3,4,5-trimethoxyanilino)imidazo[4,5-g]quinoline-7-carbonitrile as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:21][C:22]1[CH:23]=[C:24]([N:37]2[CH2:41][C@H:40]([CH2:42][NH:43][C:44](=[O:46])[CH3:45])[O:39][C:38]2=[O:47])[CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1.CCO.C([O-])([O-])=O.[K+].[K+]>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].C1(C)C=CC=CC=1>[C:44]([NH:43][CH2:42][C@@H:40]1[O:39][C:38](=[O:47])[N:37]([C:24]2[CH:25]=[CH:26][C:27]([C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]4)=[N:6][CH:7]=3)=[C:22]([F:21])[CH:23]=2)[CH2:41]1)(=[O:46])[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cn2)CC1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)C(=O)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)c(F)c2)C(=O)O1
Temperature: 90 °C
Yield: 69 %

Procedure:
A mixture of tert-Butyl 4-(5-bromo-2-pyridinyl)-1-piperazinecarboxylate (0.203 g, 0.593 mmol) and N-({(5S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (0.270 g, 0.714 mmol) in dmf (4 mL), EtOH (1.5 mL), toluene (2.5 mL) and K2CO3 (1 mL, 2 M, 2 mmol) was purged with nitrogen. PdCl2(dppf) (24 mg, 0.03 mmol) was added and the mixture was heated to 90° C. under nitrogen for 1 h, then partitioned between EtOAc and water. Column chromatography (EtOAc) gave the titled compound (0.210 g, 69%) as a white solid. APCI MS m/z 514 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 8.32 (bs, 1H), 8.27 (t, J=5.9 Hz, 1H), 7.75 (ddd, J=8.9, 2.4, 1.7 Hz, 1H), 7.53-7.60 (m, 2H), 7.38 (dd, J=8.6, 2.2 Hz, 1H), 6.94 (d, J=8.9 Hz, 1H), 4.72-4.79 (m, 1H), 4.15 (t, J=9.1 Hz, 1H), 3.77 (dd, J=9.2, 6.5 Hz, 1H), 3.52-3.57 (m, 4H), 3.40-3.46 (m, 6H), 1.84 (s, 3H), 1.43 (s, 9H).