Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]1[N:17]=[C:18]([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]2[OH:30])=[O:22])[S:19][CH:20]=1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C.O>[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]1[N:17]=[C:18]([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]2=[O:30])=[O:22])[S:19][CH:20]=1
Reactant: O=C(NC1CCCCC1O)c1nc(-c2ccco2)cs1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC1CCCCC1=O)c1nc(-c2ccco2)cs1
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
Oxalyl chloride (0.776 mL, 1.55 mol) and dimethyl sulfoxide (0.240 mL, 3.38 mmol) were dissolved in dichloromethane (3 mL), and the mixture was stirred at −60° C. for 10 minutes. To the solution was added 4-(2-furyl)-N-(2-hydroxycyclohexyl)thiazole-2-carboxamide (413 mg, 1.41 mmol) obtained in Step 1 and the mixture was stirred for 15 minutes. Triethylamine (0.983 mL, 7.05 mmol) was added to the mixture, and the mixture was stirred at room temperature for 10 minutes, then water and ethyl acetate were added thereto and the mixture was extracted. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give 4-(2-furyl)-N-(2-oxocyclohexyl)thiazole-2-carboxamide (339 mg, 83%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]3[CH2:15][CH2:14]3)=[C:11]([C:16]([OH:18])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]3[CH2:14][CH2:15]3)=[C:11]([C:16]([NH:31][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:18])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnn(-c2ccc(Br)cc2)c1C1CC1
Reactant: NC1CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)c1cnn(-c2ccc(Br)cc2)c1C1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-(4-bromophenyl)-5-cyclopropyl-pyrazole-4-carboxylic acid (Intermediate #30) (237 mg, 0.77 mmol) was suspended in DCM (5 mL). One drop of DMF was added and then oxalyl chloride (200 μL, 2.32 mmol) was added slowly. The reaction mixture was stirred at ambient temperature for 4 h and then evaporated under reduced pressure. The residue was to dissolved in DCM (5 mL) and added to a solution of cyclohexylamine (97 μL, 0.85 mmol) and DIPEA (403 μL, 2.32 mmol) in DCM (5 mL). The mixture was stirred at ambient for 24 h and then water, (10 mL) was added and the mixture passed through a phase separating filter. The product was recovered from the filtrate by flash column chromatography (SiO2, elution gradient 0-100% EtOAc in isohexane). Pure fractions were combined and evaporated to give 1-(4-bromophenyl)-N-cyclohexyl-5-cyclopropyl-pyrazole-4-carboxamide as white solid. (277 mg, 92%)
Reaction SMILES: Cl.O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[S:40])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:26][CH:25]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(OCC)(=O)C>[N:18]1([C:21](=[S:40])[O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:31][C:32](=[O:39])[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:28][CH:29]=2)[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=S)OCc2ccc(OCC(=O)c3ccccc3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(COc1ccc(COC(=S)N2CCNCC2)cc1)c1ccccc1
Yield: 78.8 %

Procedure:
a solution of HCl in dioxane (4 M; 380 uL, 10 eq) was added to a solution of 4-(2-oxo-2-phenylethoxy)benzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate (72.1 mg) in ethyl acetate (2 mL) and the resultant mixture was shaken at ambient temperature for 16 h. The solvent was removed in vacuo and the resultant crude material was suspended in dichloromethane (4 mL) and shaken with MP—CO3 (1 g, 17 eq) at ambient temperature for 1 h. Purification by ion-exchange chromatography [SCX-2 (500 mg); DCM, MeOH, NH3—MeOH] afforded the desired product (44.7 mg, 79%) as a colourless oil: NMR δH(400 MHz; CDCl3) 2.82–2.86 (4H, m), 3.41–3.63 (4H, br s), 4.12 (2H, s), 5.23 (2H, s), 6.84–6.90 (2H, m), 7.24–7.29 (2H, m), 7.46–7.52 (2H, m) and 7.58–7.64 (1H, m); HPLC (XTERRA, 50/80, 235 nm) 97.7% (2.05 min).
Reaction SMILES: FC1C=C(O)C=CC=1.BrCCCCCCCCCO.[F:20][C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=1)[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34].FC1C=C(C=CC=1)OCCCCCCCCC(O)=O.Cl.Cl.[CH2:59]([O:66][C:67](=[O:75])[CH2:68][C@@H:69]([NH2:74])[CH2:70][N:71]([CH3:73])[CH3:72])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>>[CH2:59]([O:66][C:67](=[O:75])[CH2:68][C@@H:69]([NH:74][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][O:24][C:23]1[CH:35]=[CH:36][CH:37]=[C:21]([F:20])[CH:22]=1)[CH2:70][N:71]([CH3:72])[CH3:73])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: OCCCCCCCCCOc1cccc(F)c1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: Cl
Agent: O=C(O)CCCCCCCCOc1cccc(F)c1
Agent: OCCCCCCCCCBr
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCOc1cccc(F)c1

Procedure:
The title compound, m/e=397.4 ([M+H]+), was produced in analogy with example 18, steps 1 to 4. Thus, 3-fluorophenol was alkylated in step 1 with 9-bromo-1-nonanol, leading to 9-(3-fluoro-phenoxy)-nonan-1-ol, which was oxidized in step 2 to 9-(3-fluoro-phenoxy)-nonanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-[9-(3-fluoro-phenoxy)-nonanoylamino]-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.[Br:24][C:25]1[CH:26]=[N:27][C:28](Cl)=[N:29][CH:30]=1.CCCCCC>CCO>[Br:24][C:25]1[CH:26]=[N:27][C:28]([N:7]2[CH2:8][CH2:9][C:4]([S:3][CH3:2])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:5][CH2:6]2)=[N:29][CH:30]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCOC(=O)C1(SC)CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(SC)CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.2 %

Procedure:
To a solution of ethyl 4-(methylthio)piperidine-4-carboxylate hydrochloride (0.17 g, 0.75 mmol) in EtOH (10.0 mL) was added DIPEA (0.60 mL, 3.75 mmol) at rt and the mixture stirred at rt for 10 min followed by addition of 5-bromo-2-chloropyrimidine (0.18 g, 0.90 mmol). The reaction was heated up to 70° C. for 1 h. After completion of reaction (by TLC), solvent was evaporated and the crude residue purified over 100-200 M silica-gel using 3.0% EtOAc:hexane to obtain the desired product as a white solid (0.16 g, 60% yield). 1H NMR (DMSO-d6): δ 1.18 (t, J=7.20 Hz, 3H), 1.70 (m, 2H), 2.04 (s, 3H), 2.14 (m, 2H), 3.50 (m, 2H), 4.00 (m, 2H), 4.20 (q, J=7.20 Hz, 2H), and 8.46 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=O)=[O:22])[C:16]=1[CH3:32])[C:5](=[O:11])[NH:6]2.Cl.C(N=C=NCCCN(C)C)C.O[C:46]1[C:54]2[N:53]=N[NH:51][C:50]=2[CH:49]=[CH:48][CH:47]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:51][C:50]3[CH:49]=[CH:48][CH:47]=[CH:46][C:54]=3[NH2:53])=[O:31])=[O:22])[C:16]=1[CH3:32])[C:5](=[O:11])[NH:6]2
Reactant: Cc1cccc2c1C(=NN=Cc1[nH]c(C)c(C(=O)NCCCCCC(=O)O)c1C)C(=O)N2
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cccc2c1C(=NN=Cc1[nH]c(C)c(C(=O)NCCCCCC(=O)Nc3ccccc3N)c1C)C(=O)N2
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.9 %

Procedure:
6-(5-(((4-methyl-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)-hexanoic acid (437 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (427 mg, 81% yield) as a red solid. LC-MS (m/z) 528 (M+1).
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:4]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:5](=[O:27])[O:6][C:7]=1[P+](C1CC=CCC=1)(C1CC=CCC=1)C1CC=CCC=1.[CH:34]([C:36]1[CH2:37][S:38][C@@H:39]2[C@H:59]([NH:60][C:61](=[O:69])[CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C:58](=[O:70])[N:40]2[C:41]=1[C:42]([O:44][CH:45]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])=O>ClCCl.C(=O)([O-])O.[Na+]>[CH3:2][C:3]1=[C:4]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:5](=[O:27])[O:6]/[C:7]/1=[CH:34]/[C:36]1[CH2:37][S:38][C@@H:39]2[C@H:59]([NH:60][C:61](=[O:69])[CH2:62][C:63]3[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=3)[C:58](=[O:70])[N:40]2[C:41]=1[C:42]([O:44][CH:45]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43]
Reactant: O=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Reactant: CC1=C([P+](C2=CCC=CC2)(C2=CCC=CC2)C2=CCC=CC2)OC(=O)C1c1ccccc1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1=C(c2ccccc2)C(=O)O/C1=C/C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1

Procedure:
2,5-Dihydro-4-methyl-2-oxo-3-phenylfuran-5-yl-triphenylphosphonium bromide (2.21 g) and diphenylmethyl 3-formyl-7β-phenylacetamidoceph-3-em-4-carboxylate (2 g) in dichloromethane (30 mls) and saturated aqueous sodium hydrogen carbonate (30 mls) were stirred vigorously atroom temperature for ca 20 mins. T.l.c. analysis showed all the starting material had been consumed. The organic layer was separated and washed with dilute hydrochloric acid, brine and then dried. After removal of solvent, the residue was flash chromatographed on silica gel eluting with 40% ethyl acetate/hexane. After trituration with ether, the title compound was obtained as a pale yellow crystalline compound, (0.643 g, 25%), m.p. 180°-183° C. (decomp.) ethyl acetate/hexane. (Found: C, 71.93; H, 5.10; N, 4.17; S, 4.54.%. C40H32N2O6S requires C, 71.84; H, 4.82; N, 4.19; S, 4.79%); νmax (CH2Cl2) 1785, 1760, 1715, 1680, 1490 and 1365cm - ; δH (CDCl3) 1.99 (3H,s), 3.44 (2H,ABq, J18.7Hz), 3.67 (2H,ABq,J16.1Hz), 5.02 (1H,d,J4.9Hz), 5.93 (1H,dd,J4.9,8.9Hz), 6.08(1H,d,J8.9Hz), 6.28(1H,s), 6.97 (1H,s) and 7.1-7.5 (20H,m); [mass spectrum: +ve ion (3-NOBA, Na+) MNa+, 691].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20](=[O:23])[NH:21][CH3:22])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:24]([OH:26])=[O:25])=[CH:5][CH:4]=1.[CH:27]1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20](=[O:23])[NH:21][CH3:22])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:5][CH:4]=1
Reactant: On1nnc2ccccc21
Reactant: CNC(=O)c1ccc2ncc(C(=O)O)c(Nc3ccc(OC)cc3)c2c1
Agent: CN(C)c1ccncc1
Solvent: CO
Product: CNC(=O)c1ccc2ncc(C(=O)OC)c(Nc3ccc(OC)cc3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.6 %

Procedure:
To a suspension of 0.1 g of 4-[(4-methoxyphenyl)amino]-6-(methylcarbamoyl)-quinoline-3-carboxylic acid in dichloromethane EDC.HCl (1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride, 0.161 g), HOBt (N-hydroxybenzotriazole, 0.042 g), DMAP (4-dimethylaminopyridine, 0.17 g) and 20 mL of methanol were added and the reaction mixture was stirred at room temperature for 3 h. After aqueous work up, the reaction mixture was extracted, concentrated and dried over anhydrous sodium sulfate to afford the crude product which was later purified by column chromatography to afford 0.062 g (60%) of methyl 4-[(4-methoxyphenyl)amino]-6-(methylcarbamoyl)quinoline-3-carboxylate. 1H NMR (300 MHz, CDCl3) δ 11.51 (s, 1H, —NH—), 9.12 (s, 1H, aromatic), 8.38-8.15 (m, 2H, aromatic), 8.10 (s, 1H, aromatic), 7.23 (d, 2H, J=9 Hz, aromatic), 7.02 (d, 2H, J=9 Hz, aromatic), 4.02 (s, 3H, —OCH3), 3.90 (s, 3H, —OCH3), 2.92 (s, 3H, —NCH3); LC-MS (m/z) 365.9 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][F:15])[CH:8]=[CH:7][N:6]=1)=[O:4].O.[OH-].[Li+]>C1COCC1.O.CO>[F:15][CH2:14][CH2:13][CH2:12][CH2:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=1
Reactant: COC(=O)c1cc(CCCCF)ccn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(CCCCF)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a mixture of 4-(4-fluoro-butyl)-pyridine-2-carboxylic acid methyl ester (0.24 g) in THF (3 mL) and water (1 mL) was added lithium hydroxide monohydrate (71.3 mg, 1.7 mmol, 1.5 equiv). The mixture was stirred at rt overnight and diluted with methanol (20 mL). Then H+ resin was added and the mixture was shaken for 10 minutes. The resin was washed with methanol (1×), 1:1 acetonitrile/water (1×), and acetonitrile (1×). The product was eluted with 5% TEA in methanol (4×) and acetonitrile (1×). The combined organic solvents were evaporated and co-evaporated with toluene to provide 4-(4-Fluoro-butyl)-pyridine-2-carboxylic acid (0.22 g, 65%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH:21][C:22]([NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[F:32])=[O:23])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15](O)=[O:16])[S:14][C:7]=12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:66][N:67]1[CH2:72][CH2:71][N:70]([CH2:73][CH2:74][CH2:75][NH2:76])[CH2:69][CH2:68]1>C(#N)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH:21][C:22]([NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[F:32])=[O:23])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([NH:76][CH2:75][CH2:74][CH2:73][N:70]3[CH2:69][CH2:68][N:67]([CH3:66])[CH2:72][CH2:71]3)=[O:16])[S:14][C:7]=12
Reactant: CN1CCN(CCCN)CC1
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)O)sc34)cc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCN5CCN(C)CC5)sc34)cc2F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (100 mg, 0.22 mmol), HATU (90 mg, 0.24 mmol) and N,N-diisopropylethylamine (55 mg, 0.43 mmol) in anhydrous acetonitrile (10 ml) was stirred at room temperature for 30 minutes, followed by addition of 3-(4-methylpiperazin-1-yl)propan-1-amine (40 mg, 0.25 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(4-methylpiperazin-1-yl)propyl]thieno[3,2-b]pyridine-2-carboxamide as brown solid. Yield: 110 mg, 84%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.[Br:18]N1C(=O)CCC1=O.O>C(#N)C.CN(C)C=O>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([Br:18])[CH:12]=3)[NH:7][C:6]=2[N:14]=1
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: NC(=O)c1cc2c(nc1N)[nH]c1ccc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
To a solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 35 mg, 0.15 mmol) in acetonitrile (1 mL) and N,N-dimethylformamide (1 mL), was added N-bromosuccinimide (37 mg, 0.209 mmol) in one portion at −10° C. The mixture was warmed to room temperature and stirred for one hour. Water was added and the mixture was extracted with methylene chloride (3×20 mL). Extracts were combined, dried over sodium sulfate, filtered and concentrated to afford the crude product which was subsequently purified by HPLC (Phenomenex Luna 15 μm C18, aqueous HCOOH/CH3CN) to yield 2-amino-6-bromo-9H-pyrido[2,3-b]indole-3-carboxamide (34, 20 mg, 40%) as yellow solid. NH4OAc standard conditions. DAD Retention Time =6.12 min. M+H=307. 1H NMR (300 MHz, MeOD): δ 8.65 (d, J=6.9 Hz, 1H), 8.03 (d, J=4.9 Hz, 1H), 7.43-7.37 (m, 1H), 7.33-7.27 (m, 1H).
Reaction SMILES: C(O)=[O:2].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:29])[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]#N)=[CH:23][CH:22]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1>[Ni].O>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:29])[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH:27]=[O:2])=[CH:23][CH:22]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: O=CO
Reactant: N#Cc1ccc(CCC(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)cc1
Agent: [Ni]
Solvent: O
Product: O=Cc1ccc(CCC(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)cc1

Procedure:
100 mL of formic acid is added to a reaction mixture of 3 g of Raney nickel moistened with water and 14.22 g (39.41 mmol) of N-(4′-chlorobiphenyl-4-yl)-3-(4-cyanophenyl)propionamide and refluxed for 20 hours. Then the catalyst is suction filtered and the filtrate is diluted with plenty of water. The precipitated N-(4′-chlorobiphenyl-4-yl)-3-(4-formylphenyl)propionamide is suction filtered and dissolved in ethyl acetate. The organic phase is washed first of all with 2 molar sodium hydroxide solution, then with water and finally with saturated sodium chloride solution, dried over sodium sulfate and activated charcoal, and freed from solvent by rotary evaporation. Yield: 11.7 g (57% of theory); C22H18ClNO2 (M=363.84); calc.: molecular ion peak (M+H)+: 364/66 (Cl); found: molecular ion peak (M+H)+: 364/66 (Cl); Rf value: 0.5 (silica gel, cyclohexane/ethyl acetate (1:1)).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:42][CH:41]=1)[C:10]([O:12][C@H:13]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[C:26]([O:34][CH2:35][CH:36]2[CH2:38][CH2:37]2)[CH:25]=1)[CH2:14][C:15]1[C:20]([Cl:21])=[CH:19][N+:18]([O-:22])=[CH:17][C:16]=1[Cl:23])=[O:11])=O)(C)(C)C.Cl>CCOC(C)=O>[ClH:21].[NH2:8][C@@H:9]([CH2:39][C:40]1[CH:41]=[CH:42][C:43]([O:46][S:47]([CH3:50])(=[O:48])=[O:49])=[CH:44][CH:45]=1)[C:10]([O:12][C@H:13]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[C:26]([O:34][CH2:35][CH:36]2[CH2:38][CH2:37]2)[CH:25]=1)[CH2:14][C:15]1[C:16]([Cl:23])=[CH:17][N+:18]([O-:22])=[CH:19][C:20]=1[Cl:21])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OS(C)(=O)=O)cc1)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Oc1ccc(C[C@H](N)C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 152.1 %

Procedure:
4-((S)-2((S)-2-(tert-butoxycarbonylamino)-3-(4-(methylsulfonyloxy)-phenyl)propanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-ethyl)-3,5-dichloropyridine 1-oxide (100 mg, 0.13 mmol) was dissolved in EtOAc (2 ml), and then HCl 7M in EtOAc (2 ml) was added. The mixture was stirred at RT for 3 hours, then was washed with WATER (2×). The crude was purified by preparative reverse-phase HPLC to give 69 mg (80%) of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[CH:14]=1)=[C:11]([CH3:16])[CH:10]=[C:9]([Br:17])[CH:8]=2)=[O:4].[OH-].[Na+].[CH]Cl>O>[Br:17][C:9]1[CH:8]=[C:7]2[C:12]([C:13](=[O:15])[CH:14]=[C:5]([C:3]([OH:4])=[O:2])[NH:6]2)=[C:11]([CH3:16])[CH:10]=1
Reactant: COC(=O)c1cc(=O)c2c(C)cc(Br)cc2[nH]1
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(Br)cc2[nH]c(C(=O)O)cc(=O)c12
Yield: 91.9 %

Procedure:
A solution of methyl-7-bromo-5-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (0.40 g) in water (10 ml) containing sodium hydroxide (0.22 g) was refluxed for 10 minutes, then acidified with cHCl. The precipitate was collected and recrystallised from H2O/EtOH/NaOH on addition of cHCl to give 7-bromo-5-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (0.35 g), mp 299° C. (dec.). m/e 283, 281 (M+); δ (360 MHz, NaOD-D2O) 2.86 (3H, s, CH3), 6.85 (1H, s, 3-H), 7.22 (1H, d, 6-H) and 7.83 (1H. d, 8-H).
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:28][CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([N:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:20]5[C:15](=[N:16][CH:17]=[N:18][C:19]=5[NH2:21])[N:14]([CH3:22])[N:13]=4)=[CH:9][CH:10]=3)[CH2:5][CH2:4]2)=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1nc(-c2ccc3c(c2)CCN3C(=O)Cc2cccc(Cl)c2)c2c(N)ncnc21
Temperature: 25 °C

Procedure:
In a 20 mL vial with cap, to the solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2HCl (70 mg, 0.206 mmol), (3-chlorophenyl)acetic acid (35.2 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0.144 mL, 0.825 mmol). The mixture was stirred at rt for over night. LCMS showed reaction was completed. The reaction was poured into water, off-white solid formed. The solid was filtered to give the title compound as an off-white solid. The final product has about 0.5 equivalent of DMF. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.28 (s, 2H), 3.94 (s, 5H), 4.26 (t, J=8.59 Hz, 2H), 7.28 (d, J=7.33 Hz, 1H), 7.35-7.41 (m, 3H), 7.44 (d, J=9.85 Hz, 1H), 7.52 (s, 1H), 8.18 (d, J=8.34 Hz, 1H), 8.25 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[C:6]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:3]1=[O:24].[C:25]([O:29][C:30]([NH:32][C@H:33]([CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]([CH2:47][CH3:48])[CH:39]=1)[C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[CH2:47]([N:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:38]([CH2:37][C@@H:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:28])([CH3:27])[CH3:26])[C:34](=[O:35])[NH:1][CH:2]2[CH2:11][C:10]3[C:5](=[C:6]([N:12]4[CH2:16][CH2:15][CH2:14][C:13]4=[O:17])[CH:7]=[CH:8][CH:9]=3)[N:4]([CH2:18][C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[C:3]2=[O:24])=[CH:39]1)[CH3:48]
Reactant: NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Reactant: CCn1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Product: CCn1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC2Cc3cccc(N4CCCC4=O)c3N(Cc3ccsc3)C2=O)c2ccccc21
Yield: 73.7 %

Procedure:
The procedure of Example 14(a) was repeated, except that (−)-3-amino-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-3,4-dihydroquinolin-2(1H)-one (200 mg) and (R)-2-(tert-butoxycarbonylamino)-3-(1-ethyl-1H-indol-3-yl)propanoic acid (234 mg) synthesized in Referential Example 1(b) were used, whereby the title compound (283 mg) was yielded.