Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C(O)C.[NH2:6][C:7]1[C:8](=[O:28])[N:9]([CH2:23][C:24]([O:26]C)=[O:25])[C:10]([CH3:22])=[CH:11][C:12]=1[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14]>ClCCl>[NH2:6][C:7]1[C:8](=[O:28])[N:9]([CH2:23][C:24]([OH:26])=[O:25])[C:10]([CH3:22])=[CH:11][C:12]=1[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: COC(=O)Cn1c(C)cc(S(=O)(=O)c2ccccc2)c(N)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(S(=O)(=O)c2ccccc2)c(N)c(=O)n1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.7 ml of a 1 N aqueous sodium hydroxide solution and 5.7 ml of ethanol are added to 1.6 g (4.76 mmol) of methyl 3-amino-6-methyl-2-oxo-4-(phenylsulphonyl)-1,2-dihydropyridine-1-acetate. 1.5 ml of dichloromethane are then introduced and the mixture is kept stirred for 2 hours at room temperature. The reaction medium is concentrated under vacuum and 8 ml of water and 5.8 ml of a 1 N aqueous hydrochloric acid solution are added. The precipitate is filtered, it is rinsed with water and it is dried under vacuum.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.[C:17]1([S:23]([CH:26]2[CH2:30][CH2:29][NH:28][CH2:27]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:28]2[CH2:29][CH2:30][CH:26]([S:23]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)(=[O:25])=[O:24])[CH2:27]2)=[O:15])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccccc1)C1CCNC1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: Cl
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(S(=O)(=O)c3ccccc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-(benzenesulfonyl)pyrrolidine hydrochloride (12.7 mg, 0.051 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (11.5 mg). Calcd for C21H20N2O4S: 396.1144, found 396.1142.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:12][C:13]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:14]=1[C:15]#[N:16]>>[C:15]([C:14]1[CH:17]=[C:18]([CH:19]=[CH:20][C:13]=1[F:12])[O:21][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5])#[N:16]
Reactant: N#Cc1cc(O)ccc1F
Reactant: N#Cc1cc(C=O)ccc1F
Product: N#Cc1cc(Oc2ccc(C=O)cc2C#N)ccc1F

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 2-fluoro-5-hydroxybenzonitrile.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([F:21])[CH:14]=2)[N:9]2[CH:22]=[CH:23][CH:24]=[C:8]2[C:7]1=[O:25]>C(Cl)Cl.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>[F:21][C:15]1[CH:14]=[C:13]([CH2:12][C:10]2[N:9]3[CH:22]=[CH:23][CH:24]=[C:8]3[C:7](=[O:25])[NH:6][CH:11]=2)[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: COc1ccc(Cn2cc(Cc3ccc(C#N)c(F)c3)n3cccc3c2=O)c(OC)c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(Cc2c[nH]c(=O)c3cccn23)cc1F
Temperature: 120 °C

Procedure:
A solution of A3 (1 eq) in a mixture of DCM and TFA (2:1) was heated in a microwave oven at 120° C. for 10 min. The reaction mixture was diluted with DCM and toluene and concentrated under reduced pressure. The resulting crude was diluted with DCM and washed with sat. aq. NaHCO3 solution, dried (Na2SO4) and concentrated under reduced pressure. The resulting crude was purified by Biotage system eluting with EtOAc/petrol ether to obtain the desired compound. MS (ES) C15H10FN3O requires: 267, found: 268 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 10.51 (1H, d, J=5.3 Hz), 7.97 (1H, dd, J=6.3, 2.0 Hz), 7.79-7.72 (1H, m), 7.47 (1H, t, J=9.0 Hz), 7.34-7.30 (1H, m), 6.92-6.88 (1H, m), 6.54-6.49 (2H, m), 4.08 (2H, s).
Reaction SMILES: C([NH:8][CH:9]([CH3:23])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]=1)(OC(C)(C)C)=O.[ClH:24]>C(O)C>[ClH:24].[CH2:21]([O:20][C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH2:10][CH:9]([NH2:8])[CH3:23])[CH:16]=[CH:15][CH:14]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)Nc1cccc(CC(C)NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Nc1cccc(CC(C)N)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-Boc-1-methyl-2-(3-ethoxycarbonylaminophenyl)ethylamine (1.173 g, crude) was dissolved in ethanol (5.0 ml), to which was then added hydrochloric acid (5 ml), followed by stirring at room temperature for 1.5 hours. Then, hydrochloric acid (2.5 ml) was further added thereto, followed by stirring at room temperature for 2 hours. The solvent was evaporated, to give the title compound (1.148 g, crude) as a yellow oil. It was used in the next reaction without carrying out a further purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=O.S(Cl)(Cl)=O.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[O:7]=[C:5]([C:17]1[CH:18]=[CH:19][C:14]([Br:13])=[CH:15][CH:16]=1)[CH2:4][CH2:3][CH:2]([CH3:1])[CH3:8]
Reactant: CC(C)CCC(=O)O
Reactant: Brc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: CC(C)CCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 82 h

Procedure:
A mixture of 25 g (.215 mol) of 4-methyl valeric acid and 29.35 g (.247 mol) of thionyl chloride was heated at reflux for 1.5 hour. The excess thionyl chloride was removed under reduced pressure using a cryogenic trap. The residue was taken up with 120 g (0.764 mol) of bromobenzene (Compound 27) and the mixture was cooled in an ice-bath and then treated with 23 g (0.172 mol) of anhydrous aluminum chloride through a powder addition funnel. The mixture was stirred at room temperature for 82 h and then quenched by the addition of 50 ml of an ice/water mixture, followed by 30 ml of conc. HCl. The organic layer was separated and the aqueous layer extracted with 2×50 ml of ether. The organic extracts were combined and washed successively with water and saturated NaCl solution and then dried (MgSO4) The solvent was then removed in-vacuo and the residue purified by distillation (~80 degrees C./0.01 mm) to give the title compound as a colorless solid. PMR (CDCl3) & 0.94 (6 H, d, J 6.0 Hz), 1.53 (3H, m), 2.85-2.97 (2H, m)., 7.60 (2H, d, J 8.4 Hz), 7.83 (2H, d, J 8.4 Hz).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][NH:6][C:7]1[C:12]2[N:13]([CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)[C:14](=[O:17])[CH2:15][O:16][C:11]=2[CH:10]=[CH:9][CH:8]=1)C.CO.[OH-].[Na+]>C1COCC1>[CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[CH2:18][N:13]1[C:12]2[C:7]([NH:6][CH2:5][C:4]([OH:29])=[O:3])=[CH:8][CH:9]=[CH:10][C:11]=2[O:16][CH2:15][C:14]1=[O:17]
Reactant: CCOC(=O)CNc1cccc2c1N(Cc1ccc3ccccc3c1)C(=O)CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CNc1cccc2c1N(Cc1ccc3ccccc3c1)C(=O)CO2

Procedure:
A mixture of (4-naphthalen-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-ylamino)-acetic acid ethyl ester, I-63 (105 mg), methanol (3.0 mL), THF (2.0 mL) and 2.0 M NaOH (0.5 mL) was stirred at room temperature for 18 h. Methanol was evaporated and the residue was taken water (3.0 mL) and acidified to pH 1 with 2.0 M HCl resulting in the precipitation of a white solid. Solid was extracted with chloroform (10 mL×2), and the combined extracts were dried (brine, anhydrous sodium sulfate), concentrated and dried on high vacuum to afford (4-naphthalen-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-ylamino)-acetic acid, I-64 (102 mg).
Reaction SMILES: [H-].[Na+].[C:3]([NH:12][C@@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])(=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:21](Br)[CH:22]=[CH2:23].Cl>CCCCCC.C1COCC1>[CH2:23]([N:12]([C@@H:13]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:14])[C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:22]=[CH2:21]
Reactant: CCCCCCCC(=O)N[C@H](C)c1ccccc1
Reactant: C=CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCN(C(=O)CCCCCCC)[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 326 %

Procedure:
Sodium hydride (60%) (0.65 g, 16.3 mmol) was washed with three 20-ml portions of hexane and then suspended in 5 ml of THF. Hereto were added a solution of 2.00 g (8.1 mmol) of (R)-N-octanoyl-1-phenylethylamine in 15 ml of THF, and 1.96 g (16.3 mmol) of allyl bromide, and the reaction was allowed to proceed at room temperature for 1 hour and, then, at 70° C. for 2 hours. The reaction mixture was cooled to room temperature and added dropwise to 20 ml of ice-cooled 1 M hydrochloric acid to thereby terminate the reaction. The resulting mixture was extracted with 30 ml of hexane. The organic phase was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was then distilled off. The desired product was purified on a silica gel column. Thus was obtained 7.59 g (94%) of the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]([NH:12][C:13]([C@@H]3C4(Cl)C(Cl)([Cl:22])C(Cl)(C(Cl)=C4Cl)[C@@H]3C(O)=O)=[O:14])[CH:10]=[CH:11][C:5]=2[N:4]=1.NC1C=CC2N=C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)N(C(OC(C)(C)C)=O)C=2C=1.[C:63]1(=[O:77])[C:72]2[C:67]3[C:68](=[CH:73][CH:74]=[CH:75][C:66]=3C(=O)[O:64]1)[CH:69]=[CH:70][CH:71]=2>>[ClH:22].[NH2:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]([NH:12][C:13]([C:66]3[CH:75]=[CH:74][CH:73]=[C:68]4[C:67]=3[C:72]([C:63]([OH:77])=[O:64])=[CH:71][CH:70]=[CH:69]4)=[O:14])[CH:10]=[CH:11][C:5]=2[N:4]=1
Reactant: Nc1nc2ccc(NC(=O)[C@H]3[C@@H](C(=O)O)C4(Cl)C(Cl)=C(Cl)C3(Cl)C4(Cl)Cl)cc2[nH]1
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Agent: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc2ccc(N)cc2n1C(=O)OC(C)(C)C
Agent: Cl
Product: Nc1nc2ccc(NC(=O)c3cccc4cccc(C(=O)O)c34)cc2[nH]1
Yield: 96 %

Procedure:
Following the same procedure to synthesize (2S,3R)-3-(2-amino-1H-benzo[d]imidazol-6-ylcarbamoyl)-1,4,5,6,7,7-hexachlorobicyclo[2.2.1]hept-5-ene-2-carboxylic acid hydrochloride (10), tert-butyl 6-amino-2-(bis(tert-butoxycarbonyl)amino)-1H-benzo[d]imidazole-1-carboxylate (0.082 g, 183 mmol) was reacted with benzo[de]isochromene-1,3-dione (0.036 g, 0.183 mmol) to give the title compound (0.067 g, 96% yield) as a white solid. 1H NMR (400 MHz, DMSO) δ 11.43-11.21 (bs, 1H), δ 8.75 (s, 2H), δ 8.56 (q, 2H), δ 7.92 (t, 1H), δ 7.47 (s, 2H), δ 7.42 (d, 2H), δ 7.21 (d, 1H) ppm; 13C NMR (100 MHz, DMSO) δ 161.4, 151.9, 136.1, 133.2, 132.1, 130.9, 130.5, 129.4, 129.8, 129.3, 119.7, 119.3, 112.8, 106.9, 94.6 ppm; HRMS (ESI) Calcd for C19H14N4O3 (M+) 346.1066. Found 346.1061.
Reaction SMILES: [CH3:1][N:2]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[C:24]([CH3:32])[CH:23]=2)=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:3]1[CH2:7][O:6][CH2:5][CH:4]1[C:8]([OH:10])=O.[NH2:33][OH:34]>>[OH:34][NH:33][C:8]([C@H:4]1[C@@H:3]([N:2]([CH3:1])[S:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:24]([CH3:32])[CH:23]=3)=[CH:18][CH:19]=2)(=[O:12])=[O:13])[CH2:7][O:6][CH2:5]1)=[O:10]
Reactant: NO
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N(C)C3COCC3C(=O)O)cc2)c2ccccc2n1
Product: Cc1cc(COc2ccc(S(=O)(=O)N(C)[C@H]3COC[C@H]3C(=O)NO)cc2)c2ccccc2n1
Yield: 21 %

Procedure:
According to the procedure of Example 24, Step 3, 4-{methyl-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl]-amino}-tetrahydro-furan-3-carboxylic acid (0.160 g, 0.35 mmol) and hydroxylamine gave (3S,4R)-4-{methyl-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl]-amino}-tetrahydro-furan-3-carboxylic acid hydroxyamide as an amorphous white solid (0.035 g, 21%) after purification using Biotage Flash 40S chromatography, eluting with 5% methanol in ethyl acetate. MS: 472 (M+H)+
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[C:9](=[O:11])[CH3:10].CCN(CC)CC.[S:19]1[C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]1[O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1>ClCCCl.CCOC(C)=O>[S:19]1[C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]1[O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:6]2[CH2:7][CH:2]3[CH2:8][CH:5]2[CH2:4][N:3]3[C:9](=[O:11])[CH3:10])=[CH:31][CH:30]=1
Reactant: CC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: O=Cc1ccc(Oc2nc3ncccc3s2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(=O)N1CC2CC1CN2Cc1ccc(Oc2nc3ncccc3s2)cc1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 88.1 %

Procedure:
To a 1-L round-bottom, 3-necked flask equipped with magnetic stirring, dynamic nitrogen inlet, and thermocouple probe were added 1-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]ethanone hydrochloride (53.3 g, 0.302 mol), DCE (250 mL), and Et3N (100 mL, 1.006 mol). The flask was warmed to 50° C. and aged for 20 min. An additional 100 mL of DCE was added to facilitate stirring. The solution was cooled to 40° C. and the solution was then added via cannula to a 2-L round-bottom, 3-necked flask equipped with overhead mechanical stirring, dynamic nitrogen inlet, and thermocouple probe containing 4-(thiazolo[4,5-b]pyridin-2-yloxy)-benzaldehyde (51.6 grams, 0.201 mol) dissolved in DCE (100 mL). The 1-L round-bottom flask was rinsed with DCE (100 mL). The rinse solvent was added to the reaction mixture. The resultant deep purple solution was aged at rt for 2.5 h. After such time, the sodium triacetoxyborohydride (72.5 g, 0.342) was added in 4 equal portions over a four-hour period. Once addition was complete, the resultant solution was aged at rt overnight. The reaction was quenched by the slow addition of water (1 L) over a 10-minute period. After 30 additional minutes of stirring, the solution was filtered to remove a fine rag layer of precipitate. The layers were separated and the aqueous layer was extracted with DCE (1×500 mL). The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated to yield crude product as a thick brown oil. The crude product was suspended in EtOAc (500 mL), warmed to 70° C., and cooled slowly to rt. The resultant slurry was filtered and the filtrate was concentrated to yield 1-{5-[4-(thiazolo[4,5-b]pyridin-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-ethanone (67.2 g, 0.177 mol) as a brown glass. MS (ESI): mass calcd. for C20H20N4O2S, 380.13; m/z found, 381.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([O:23]C)[CH:20]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[CH:18]=2)=[C:13]([F:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[Al+3].[Cl-].[Cl-].[Cl-].C(S)C.O>C(Cl)Cl>[F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([OH:23])[CH:20]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[CH:18]=2)=[C:13]([F:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(OC)cc(-c3cccc(F)c3)c2)c1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCS
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(O)cc(-c3cccc(F)c3)c2)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of ethyl 2-[2,4-difluoro-3-[[3-(3-fluorophenyl)-5-methoxy-phenyl]methylamino]phenoxy]acetate (400 mg, 0.9 mmol, 1.0 eq) and AlCl3 (718 mg, 5.4 mmol, 6.0 eq) in DCM (10 mL) at 0° C. was added ethanethiol (315 mg, 5.4 mmol, 6.0 eq) under N2. The reaction mixture was stirred at 0° C. for 30 min. The resulting mixture was poured into water and extracted with EtOAc. The organic extract was washed with brine, dried (Na2SO4), filtered, evaporated in vacuo and the crude residue obtained purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:4) to give the title compound as an oil (260 mg, 67%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[NH:11][N:10]=2)[CH:5]=[C:4]([Cl:17])[N:3]=1.C(N(C(C)C)CC)(C)C.[C:27]1([C:33]2[CH:37]=[C:36]([CH2:38][NH2:39])[O:35][N:34]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)CCC>[Cl:17][C:4]1[N:3]=[C:2]([NH:39][CH2:38][C:36]2[O:35][N:34]=[C:33]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:37]=2)[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[NH:11][N:10]=2)[CH:5]=1
Reactant: NCc1cc(-c2ccccc2)no1
Reactant: CC(C)c1cc(Nc2cc(Cl)nc(Cl)n2)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)c1cc(Nc2cc(Cl)nc(NCc3cc(-c4ccccc4)no3)n2)n[nH]1
Temperature: 90 °C
Reaction time: 30 h
Yield: 44.6 %

Procedure:
To a solution of 2,6-dichloropyrimidin-4-yl-(5-isopropyl-1H-pyrazol-3-yl)-amine (19.44 g, 71.7 mmol) in 1-butanol (200 mL) was added diisopropylethylamine (23.7 mL, 143 mmol) and 3-phenylisoxazol-5-ylmethylamine (15.0 g, 86.1 mmol). The mixture was stirred at 90° C. for 30 h, then concentrated on a rotary evaporator. The residue was taken up in 100 mL of methanol and boiled until the volume reached around 50 mL. The solution was allowed to cool to room temperature and then placed in the refrigerator overnight. The solid that formed was collected by filtration, while the filtrate was concentrated on a rotary evaporator, heated to boiling in methanol and cooled overnight in the refrigerator. This solid was collected and the filtrate was subjected to methanol recrystallization a third time. The three solids were combined to give the desired product (13.1 g, 45%) as a white solid.
Reaction SMILES: O1CCCCC1[O:7][CH:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:9][CH2:10][CH2:11][N:12]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([CH3:28])[C:23]([O:25]CC)=[O:24])[S:13]([CH3:16])(=[O:15])=[O:14].C(O)C.[OH-].[Na+]>Cl.O>[OH:7][CH:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:9][CH2:10][CH2:11][N:12]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([CH3:28])[C:23]([OH:25])=[O:24])[S:13]([CH3:16])(=[O:14])=[O:15]
Reactant: CCCCCC(CCCN(CCCCCC(C)C(=O)OCC)S(C)(=O)=O)OC1CCCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCC(O)CCCN(CCCCCC(C)C(=O)O)S(C)(=O)=O
Reaction time: 4.5 h

Procedure:
A soluton is prepared from ethyl 7-{N-[4-(2-tetrahydropyranyloxy)nonyl]methanesulfonamido}-2-methylheptanoate (4.9 g., 0.01 mole), ethanol (50 ml.), and 4 drops of hydrochloric acid (conc.), and kept at ambient temperature for 4.5 hours. Then to the reaction is added a solution of sodium hydroxide (0.72 g., 0.018 mole) in water (10 ml.) and the reaction is kept at ambient temperature for an additional 20 hours. Most of the ethanol is removed in vacuo and the residue dissolved in water (100 ml.). The solution is extracted once with ether (75 ml.). then acidified with hydrochloric acid (dil.). The oil that separates is extracted into ether, the ether is washed with brine, dried over sodium sulfate, then removed under vacuum to give 7-[N-(4-hydroxynonyl)methanesulfonamido]-2-methylheptanoic acid as a yellow liquid.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.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]>[C:16]1([C:2]2[S:3][C:4]3[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1ccc2nc(Br)sc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2nc(-c3ccccc3)sc2c1
Yield: 73.9 %

Procedure:
A mixture of ethyl 2-bromo-benzothiazole-6-carboxylate 20d (300 mg, 1.05 mmol), phenylboronic acid (192 mg, 1.57 mmol), K2CO3 (188 mg, 1.36 mmol) and Pd(dppf)Cl2.CH2Cl2 (43 mg, 0.05 mmol) in dioxane (2 mL) and H2O (0.4 mL) was heated at 120° C. for 25 min in a microwave reactor. The reaction mixture was diluted with CH2Cl2, washed with H2O, dried over Na2SO4, and concentrated. Purification by flash column chromatography (silica gel, 15% EtOAc/heptane) gave compound 20e (220 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1([CH2:21][CH3:22])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8](=O)[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19].CO.Cl.[CH3:27][S:28]([NH:31][NH2:32])(=[O:30])=[O:29]>O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1([CH2:21][CH3:22])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8](=[N:32][NH:31][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3=O
Reactant: CS(=O)(=O)NN
Agent: Cl
Solvent: CO
Solvent: O
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3=NNS(C)(=O)=O
Reaction time: 0.02 h

Procedure:
To the ester of Example 4, Step B (0.5 g, 1.6 mmol) was added 10 ml MeOH, 0.4 ml 1N HCl and 0.37 ml H2O. The mixture was stirred one minute followed by addition of CH3SO2NHNH2 all at once. After overnight stirring, the MeOH was evaporated and additional water was added. This aqueous phase was twice extracted with CH2Cl2. The organic phase was concentrated to a crude solid and purified by flash chromatography using CH2Cl2 --EtOAc 95-5 as eluent. The product 0.33 g, was obtained as a solid m.p. 80°-82° C.
Reaction SMILES: [CH3:1][C:2]([NH:11][C:12](=[O:41])[CH2:13][N:14]1[C:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[CH:17][C:16]([C:27]2[N:28]=[N:29][N:30](CC3C=CC(OC)=CC=3)[CH:31]=2)=[N:15]1)([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1>C(O)(C(F)(F)F)=O>[CH3:10][C:2]([NH:11][C:12](=[O:41])[CH2:13][N:14]1[C:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[CH:17][C:16]([C:27]2[N:28]=[N:29][NH:30][CH:31]=2)=[N:15]1)([CH3:1])[CH2:3][N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1
Reactant: COc1ccc(Cn2cc(-c3cc(Cc4ccc(F)cc4)n(CC(=O)NC(C)(C)CN4CCOCC4)n3)nn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CN1CCOCC1)NC(=O)Cn1nc(-c2c[nH]nn2)cc1Cc1ccc(F)cc1
Yield: 37.3 %

Procedure:
A solution of N-(1,1-dimethyl-2-morpholin-4-ylethyl)-2-{5-(4-fluorobenzyl)-3-[1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl]-1H-pyrazol-1-yl}acetamide (1.3 g, 2.31 mmol) in TFA (30 mL) was refluxed overnight. The mixture was concentrated in vacuo and the residue was treated with water (30 mL) and CH2Cl2 (40 mL). The mixture was adjusted to pH 8-9 with Et3N. The organic layer was separated, dried over Na2SO4 and concentrated. The residue was purified via prep. HPLC to yield the title compound (380 mg, 38%) as yellow syrup. 1H NMR (400 MHz, MeOD) δ ppm 8.003 (s, 1H), 7.322 (m, 2 H), 7.100 (m 2 H), 6.399 (s, 1 H), 4.916 (m, 3 H), 4.089 (s, 2 H), 3.899-3.189 (m, 9 H), 1.472 (s, 6 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.C(O)C.C(OCC)(=O)C.[Sn](Cl)Cl>[Pt]=O.[Pd].[Fe].[Zn].C(O)(=O)C.C1COCC1.CO>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=[N+]([O-])c1cnc2ccccc2c1
Agent: O=[Pt]
Agent: [Fe]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cnc2ccccc2c1

Procedure:
The 3-nitroquinoline derivative of the formula (c) is then catalytically reduced in an inert solvent such as ethanol, ethyl acetate, methanol or THF, using platinum oxide or palladium/carbon, or reduced by iron or zinc and acetic acid or tin (II) chloride, to give the 3-aminoquinoline derivative of the formula (d).