Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[N:16]=[C:15]2[NH:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[C:31]([Cl:36])[CH:30]=1)(C(C)(C)C)(C)C.ClC(OC(Cl)C)=O>CO>[Cl:36][C:31]1[CH:30]=[C:29]([NH:28][C:15]2[C:14]3[C:19](=[CH:20][CH:21]=[C:12]([CH2:11][CH2:10][CH2:9][OH:8])[CH:13]=3)[N:18]=[C:17]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[N:16]=2)[CH:34]=[CH:33][C:32]=1[F:35]
Reactant: CC(C)(C)[Si](C)(C)OCCCc1ccc2nc(-c3cccnc3)nc(Nc3ccc(F)c(Cl)c3)c2c1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Product: OCCCc1ccc2nc(-c3cccnc3)nc(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a suspension of 6-(3-(tert-butyldimethylsilyloxy)propyl)-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine (0.35 g, 0.67 mmol) in MeOH (10 mL) was added 1-chloroethyl chloroformate (7.2 μl, 0.067 mmol). The mixture was stirred overnight at room temperature. Methanol was removed in vacuo. Sat. NaHCO3 aqueous (10 mL) and CH2Cl2 (10 mL) were added to the residue and stirred for a while. The resultant solid was collected by filtration and dried to give 0.25 g of 3-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)propan-1-ol as light yellow solid (91%). MS i/z=409 (M+1) (Method D) (retention time=1.71 min), 1H NMR (300 MHz, DMSO) δ 10.01 (s, 1H), 9.51 (s, 1H), 8.66 (m, 2H), 8.37 (s, 1H), 8.29-8.20 (m, 1H), 7.94-7.67 (m, 3H), 7.63-7.43 (m, 2H), 4.60 (t, J=5.0 Hz, 1H), 3.56-3.35 (m, 2H), 2.94-2.69 (m, 2H), 2.15-1.56 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]([C:19]3[C:20]([NH2:33])=[N:21][CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=4)[CH:24]=3)=[N:17][N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)(Cl)Cl.C(OCC)C>[CH3:32][O:31][C:27]1[CH:26]=[C:25]([C:23]2[CH:24]=[C:19]([C:16]3[O:15][C:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[N:18][N:17]=3)[C:20]([NH2:33])=[N:21][CH:22]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: COc1cccc(-c2cnc(N)c(-c3nnc(C4CCN(C(=O)OC(C)(C)C)CC4)o3)c2)c1
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COc1cccc(-c2cnc(N)c(-c3nnc(C4CCNCC4)o3)c2)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 4-{5-[2-amino-5-(3-methoxy-phenyl)-pyridin-3-yl]-[1,3,4]oxadiazol-2-yl}-piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.44 mmol) in chloroform (10 mL) was added 2M HCl in diethyl ether (10 mL) at 0° C., and the reaction mixture was stirred for 4 h at 0° C. After completion of the reaction, solvents in reaction mixture were evaporated under vacuum to get crude product. Crude product was purified by washing with ethyl acetate and hexane to afford the title compound as a pale yellow powder.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1.[N-:35]=[N+:36]=[N-:37].[Na+]>CN(C=O)C>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)([C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)[OH:20])[CH:8]=3)[N:3]3[N:35]=[N:36][N:37]=[C:2]3[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(C(O)(c2ccc3nc(Cl)nc(-c4cccc(Cl)c4)c3c2)c2cncn2C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(O)(c2ccc3c(c2)c(-c2cccc(Cl)c2)nc2nnnn23)c2cncn2C)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
A mixture of intermediate 15 (0.0224 mol) and sodium azide (0.067 mol) in DMF (120 ml) was stirred at 90° C. for 2 hours, brought to room temperature, poured out into ice water and stirred. The precipitate was filtered, washed with water and taken up in DCM. The organic layer was washed with water, separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (15-40 μm) (eluent: toluene/iPrOH/NH4OH 90/10/1). The pure fractions were collected and the solvent was evaporated, yielding 9 g (80%) of 5-(3-chlorophenyl)-α-(4-methoxyphenyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-methanol (intermediate 16), mp 200° C.
Reaction SMILES: [F:1][C:2]1[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])=[CH:28][CH:27]=[C:26]([F:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14](I)[N:13](S(C3C=CC=CC=3)(=O)=O)[C:10]2=[N:11][CH:12]=1)=[O:5].[CH3:38][NH:39][CH3:40]>O.O1CCOCC1>[CH3:38][N:39]([CH3:40])[C:14]1[NH:13][C:10]2=[N:11][CH:12]=[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:26]([F:37])=[CH:27][CH:28]=[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:32])=[O:33])[C:2]=3[F:1])[CH:8]=[C:9]2[CH:15]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)cc(I)n3S(=O)(=O)c2ccccc2)c1F
Reactant: CNC
Solvent: O
Solvent: C1COCCO1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(N(C)C)cc3c2)c1F
Temperature: 100 °C
Yield: 18 %

Procedure:
2,6-Difluoro-N-(2-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.050 g, 0.076 mmol) and 7.9M dimethylamine in water (0.240 mL) were combined in 1,4-dioxane (0.500 mL). The solution was heated at 100° C. for 18 hours in a sealed vessel. The reaction mixture was concentrated and purified via reverse phase chromatography to give N-(2-(dimethylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (5.9 mg, 18% yield) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 11.00 (s, 1H), 10.54 (s, 1H), 8.32 (s, 2H), 8.01 (d, 1H), 7.81 (d, 1H), 7.40 (m, 1H), 7.05 (m, 1H), 5.28 (s, 1H), 2.91 (s, 6H), 1.73 (m, 2H), 0.97 (m, 3H). m/z (API-pos) 438.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]=1[F:17])[O:6][CH2:7][CH3:8])[CH3:2].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.N1C=CC=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][C:12]([O:16][C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)=[CH:11][C:10]=1[F:17])[O:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCOC(=O)C(OCC)c1c(F)cc(O)cc1F
Reactant: COc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(OCC)c1c(F)cc(Oc2ccc(OC)cc2)cc1F
Yield: 64.6 %

Procedure:
(RS)-(2,6-Difluoro-4-hydroxy-phenyl)-ethoxy-acetic acid ethyl ester (500 mg) was dissolved in CH2Cl2 (20 ml). Cu(OAc)2 (349 mg), 4-methoxyphenylboronic acid (876 mg) and MS4 Å were added followed by pyridine (760 mg). The mixture was stirred over night before filtration and evaporation of the solvent. CC (Hept/CH2Cl2 1:4) afforded 455 mg (65%) of (RS)-[2,6-difluoro-4-(4-methoxy-phenoxy)-phenyl]-ethoxy-acetic acid ethyl ester. Yellow oil.
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH2:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH:14](I)[CH2:13]1)[CH3:11].Cl[C:20]1[S:24][N:23]=[C:22]([S:25][CH3:26])[N:21]=1>[Zn].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCCC1>[CH2:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:20]2[S:24][N:23]=[C:22]([S:25][CH3:26])[N:21]=2)[CH2:13]1)[CH3:11]
Reactant: CSc1nsc(Cl)n1
Reactant: CCC1CCCC(I)C1
Agent: [Fe+2]
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CCC1CCCC(c2nc(SC)ns2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 47.1 %

Procedure:
439 mg of zinc powder and 63 mg of 1,2-dibromoethane was added into 7 ml of tetrahydrofurane under nitrogen atmosphere and the mixture was refluxed for 1 minute. After cooling to room temperature, 36 mg of trimethylsilyl chloride and 3.0 g of 3-ethylcyclohexyl iodide were added to the mixture, and the mixture was stirred for 6 hours at room temperature. Further, 561 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole and 137 mg of {1,1′-bis(diphenylphosphino)ferrocene} dichloro palladium(II) dichloromethane complex were added in the mixture, and the reaction mixture was refluxed for 17 hours. The reaction mixture was concentrated, and the residue subjected to silica gel column chromatography to give 384 mg of 5-(3-ethylcyclohexyl)-3-methylthio-1,2,4-thiadiazole.
Reaction SMILES: C([Li])CCC.CC(C)=O.C(=O)=O.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH:21]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH3:31])[NH:24][C:23]([CH2:32][O:33][CH2:34][C:35]#[CH:36])=[C:22]1[C:37]([O:39][CH2:40][CH3:41])=[O:38].[CH:42](=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CCCCCC.O1CCCC1>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH:21]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH3:31])[NH:24][C:23]([CH2:32][O:33][CH2:34][C:35]#[C:36][CH:42]([OH:49])[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[C:22]1[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: O=Cc1ccccc1
Reactant: C#CCOCC1=C(C(=O)OCC)C(c2cccc(Cl)c2Cl)C(C(=O)OC)=C(C)N1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(COCC#CC(O)c2ccccc2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reaction time: 2 h
Yield: 21.9 %

Procedure:
A 1.6M solution of n-butyllithium in hexane (3.4 ml) was added dropwise over 15 minutes to a stirred, cooled (acetone/cardice bath) solution of 1-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}prop-2-yne (1.10 g) in tetrahydrofuran (25 ml) and the mixture stirred at -70° for 2 hours. The mixture was then allowed to warm up to between -35° and -40°, stirred at that temperature for 2 hours, treated dropwise with a solution of benzaldehyde (0.16 g) in tetrahydrofuran (5 ml) over 5 minutes and then stirred at between -10° and -15° for one hour and at room temperature for 14 hours. The reaction mixture was partitioned between ethyl acetate and water and the organic layer washed with water, dried over Na2SO4 and evaporated. The residue was triturated with diethyl ether and the resulting solid collected, washed with diethyl ether and dried to give the title compound (0.18 g), m.p. 160°-164°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][C:15]([C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[C:14]3[NH:26][C@H:27]2[CH2:32][CH2:31][C@H:30]([NH:33]C(=O)OC(C)(C)C)[CH2:29][CH2:28]2)[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[OH:8].C(O)(C(F)(F)F)=O>>[NH2:33][C@H:30]1[CH2:31][CH2:32][C@H:27]([NH:26][C:14]2[C:13]3[C:18](=[CH:19][CH:20]=[C:11]([C:4]4[CH:5]=[C:6]([O:9][CH3:10])[C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=4)[CH:12]=3)[N:17]=[CH:16][C:15]=2[C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])[CH2:28][CH2:29]1
Reactant: COc1cc(-c2ccc3ncc(C(=O)C(C)C)c(N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c3c2)cc(Cl)c1O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2ccc3ncc(C(=O)C(C)C)c(N[C@H]4CC[C@H](N)CC4)c3c2)cc(Cl)c1O

Procedure:
Following general procedure A-2, tert-butyl (trans-4-((6-(3-chloro-4-hydroxy-5-methoxyphenyl)-3-isobutyrylquinolin-4-yl)amino)cyclohexyl)carbamate (0.10 mmol) was reacted with TFA (2 mL) to afford the desired product (16.6 mg, 35% over 2 steps) as a yellow solid. 1H NMR (500 MHz, MeOD) δ 8.96 (s, 1H), 8.34 (d, J=2.1 Hz, 2H), 8.03 (dd, J=8.6, 2.1 Hz, 1H), 7.90 (d, J=8.6 Hz, 1H), 7.28 (d, J=2.2 Hz, 1H), 7.20 (d, J=2.2 Hz, 1H), 4.22-4.13 (m, 1H), 3.98 (s, 3H), 3.81-3.71 (m, 2H), 3.03-2.94 (m, 1H), 2.38-2.32 (d, J=12.6 Hz, 2H), 2.13-2.06 (m, 2H), 1.73-1.61 (q, J=12.5 Hz, 2H), 1.50-1.38 (m, 2H), 1.24 (d, J=6.7 Hz, 6H). ESI MS m/z 468 [C26H30ClN3O3+H]+; HPLC>99% (AUC), tR=11.34 min.
Reaction SMILES: [NH2:1][O:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([OH:14])[C:10](=[CH:12][CH:13]=1)[OH:11])(=[O:6])=[O:5].[NH2:15][C:16]1[S:17][CH:18]=[C:19]([C:21](=O)[C:22]([NH:24][C@@H:25]2[C:32](=[O:33])[N:31]3[C@@H:26]2[S:27][CH2:28][C:29]([CH2:37][S:38][C:39]2[CH:44]=[C:43]([CH3:45])[N:42]4[N:46]=[CH:47][C:48]([C:49]([OH:51])=[O:50])=[C:41]4[N:40]=2)=[C:30]3[C:34]([OH:36])=[O:35])=[O:23])[N:20]=1>>[NH2:15][C:16]1[S:17][CH:18]=[C:19](/[C:21](=[N:1]/[O:2][CH2:3][S:4]([C:7]2[CH:13]=[CH:12][C:10]([OH:11])=[C:9]([OH:14])[CH:8]=2)(=[O:5])=[O:6])/[C:22]([NH:24][C@@H:25]2[C:32](=[O:33])[N:31]3[C@@H:26]2[S:27][CH2:28][C:29]([CH2:37][S:38][C:39]2[CH:44]=[C:43]([CH3:45])[N:42]4[N:46]=[CH:47][C:48]([C:49]([OH:51])=[O:50])=[C:41]4[N:40]=2)=[C:30]3[C:34]([OH:36])=[O:35])=[O:23])[N:20]=1
Reactant: NOCS(=O)(=O)c1ccc(O)c(O)c1
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=O)c4csc(N)n4)[C@H]3SC2)nc2c(C(=O)O)cnn12
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\OCS(=O)(=O)c4ccc(O)c(O)c4)c4csc(N)n4)[C@H]3SC2)nc2c(C(=O)O)cnn12

Procedure:
307 mg of 4-[[(aminooxy)methyl]sulphonyl]pyrocatechol were reacted with 575 mg of (6R,7R)-7-(2-amino-4-thiazoleglyoxylamido)-3-[[(3-carboxy-7-methylpyrazolo[1,5-a]pyrimidin-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in an analogous manner to the procedure described in Examples 11 or 7. There was obtained (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(3-carboxy-7-methylpyrazolo[1,5-a]pyrimidin-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([C:18]([OH:20])=O)[CH:12]=[CH:13][CH:14]=2)[CH:9]1[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[S:62]1[C:66]2[CH:67]=[CH:68][CH:69]=[CH:70][C:65]=2[N:64]=[C:63]1[NH2:71]>ClCCl.C(OCC)(=O)C>[S:62]1[C:66]2[CH:67]=[CH:68][CH:69]=[CH:70][C:65]=2[N:64]=[C:63]1[NH:71][C:18]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]([CH3:21])[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:17][CH2:16]2)=[O:20]
Reactant: CC1c2c(cccc2C(=O)O)CCN1C(=O)OC(C)(C)C
Reactant: Nc1nc2ccccc2s1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1c2c(cccc2C(=O)Nc2nc3ccccc3s2)CCN1C(=O)OC(C)(C)C

Procedure:
A mixture of EXAMPLE 43A (400 mg), PyBOP (benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, 714 mg), triethylamine (0.383 mL) and benzo[d]thiazol-2-amine (247 mg) in dichloromethane (10 mL) was stirred overnight at room temperature. The mixture was diluted with ethyl acetate (100 mL), washed with brine (30 mL×3), dried over Na2SO4, filtered, concentrated and purified by flash chromatography (silica gel, petroleum ether/ethyl acetate=1/1).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si](C(C)(C)C)(C)C)[C@H:9]1[CH2:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[C:25]([Cl:31])[C:24]=1[CH3:32])=O)(C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O.C1CCN2C(=NCCC2)CC1>C1COCC1.CCOC(C)=O.O>[Cl:31][C:25]1[C:24]([CH3:32])=[C:23]([N:22]2[CH2:21][C@@H:9]3[C@H:10]([OH:13])[CH2:11][CH2:12][N:8]3[C:6]2=[O:5])[CH:28]=[CH:27][C:26]=1[C:29]#[N:30]
Reactant: Cc1c(NC[C@@H]2[C@H](O[Si](C)(C)C(C)(C)C)CCN2C(=O)OC(C)(C)C)ccc(C#N)c1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Cc1c(N2C[C@@H]3[C@H](O)CCN3C2=O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 5.7 %

Procedure:
To a solution of (2R,3R)-3-(tert-Butyldimethylsilanyloxy)-2-[(3-chloro-4-cyano-2-methylphenylamino)methyl]pyrrolidine-1-carboxylic acid tert-butyl ester (51E) (22 mg, 0.06 mmol) dissolved in THF (1 mL) was added 1,1′-carbonyldiimidazole (9.40 mg, 0.06 mmol) and the mixture was stirred at rt for 3 days, and then brought to reflux for 1 h. An aliquot (˜half of the reaction mixture) was treated with DBU (10 μL, 0.07 mmol) and the reaction mixture was heated at reflux overnight. The reaction was then diluted with EtOAc and water, and the layers were separated. The organic layer was washed with brine, concentrated under reduced pressure, and purified via preparative HPLC (Luna C-18, 21.2×100 mm, eluting with 60-100% solvent B (A=90% H2O-10% MeOH-0.1% TFA and B=10% H2O-90% MeOH-0.1% TFA) over 12 min; Flow rate at 20 mL/min. UV detection at 220 nm). The major peak was collected, concentrated and treated with TFA (2 mL) overnight. The reaction was concentrated and purified via preparative HPLC (Luna C-18, 21.2×100 mm, eluting with 40-100% solvent B (A=90% H2O-10% MeOH-0.1% TFA and B=10% H2O-90% MeOH-0.1% TFA) over 10 min; Flow rate at 20 mL/min. UV detection at 220 nm) to provide the title compound (1 mg). LC/MS m/z 292 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:18])[C:15]([OH:17])=O.S(Cl)(Cl)=O.ClC1C=C2C(=CC=1)NC=C2CCNC(=O)C(Cl)=O.C(N(CC)CC)C.[CH:48]1([C:54]([NH:56][NH2:57])=O)[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[O:17][C:54]([CH:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)=[N:56][N:57]=1)=[O:18]
Reactant: O=C(O)C(=O)NCCc1c[nH]c2ccc(Cl)cc12
Reactant: NNC(=O)C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(Cl)C(=O)NCCc1c[nH]c2ccc(Cl)cc12
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1nnc(C2CCCCC2)o1
Temperature: 80 °C
Reaction time: 3 h
Yield: 1.5 %

Procedure:
To a suspension of 2-(2-(5-chloro-1H-indol-3-yl)ethylamino)-2-oxoacetic acid (0.920 mg; 3.45 mmol) in chloroform (50 mL) was added thionyl chloride (2.51 mL; 34.50 mmol) and the mixture was stirred at 80° C. for 3 h and was then evaporated to dryness. The resulting 2-(2-(5-chloro-1H-indol-3-yl)ethylamino)-2-oxoacetyl chloride (0.480 g; 1.68 mmol) was dissolved in dichloromethane (12 mL) and a mixture of triethylamine (0.945 mL; 6.73 mmol) and cyclohexanecarboxylic acid hydrazide (0.232 g; 1.60 mmol) in dichloromethane (8 mL) was added at 0° C. The mixture was stirred at room temperature for 2 h and p-toluenesulfonyl chloride (0.324 g, 1.68 mmol) was added. The resulting mixture was stirred overnight at room temperature, diluted with dichloromethane, washed with an aqueous solution of sodium carbonate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluent: 12 to 100% ethyl acetate in heptane) to give 0.0088 g (1.40%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-cyclohexyl-1,3,4-oxadiazole-2-carboxamide as a white solid.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=2[CH:14]([CH3:16])[CH3:15])[C:5](=[O:17])[CH2:4][S:3]1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.ClCCl>[CH:14]([C:8]1[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=1[N:6]1[C:5](=[O:17])[CH2:4][S:3]/[C:2]/1=[N:1]\[C:19](=[O:20])[O:21][C:22]1[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=1)([CH3:15])[CH3:16]
Reactant: Cc1ccc(C(C)C)c(N2C(=N)SCC2=O)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.9 %

Procedure:
A round-bottomed flask was charged with 2-imino-3-(2-isopropyl-5-methylphenyl)thiazolidin-4-one (CA49) (1.30 g, 5.23 mmol), 4-Nitrophenyl chloroformate (1.06 g, 5.23 mmol) and cesium carbonate (1.71 g, 5.23 mmol) were dissolved in acetonitrile (13 mL). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction was diluted with dichloromethane and adsorbed onto silica gel. Purification by flash column chromatography using 0-100% ethyl acetate/hexanes as eluent provided the title compound as a dark red solid (1.88 g, 86%): 1H NMR (400 MHz, CDCl3) δ 8.31-8.18 (m, 2H), 7.39-7.27 (m, 4H), 6.92-6.83 (m, 1H), 4.14-4.00 (m, 2H), 2.61 (p, J=6.9 Hz, 1H), 2.36 (d, J=0.7 Hz, 3H), 1.30-1.10 (m, 6H); ESIMS m/z 414 ([M+H]+).
Reaction SMILES: Cl.O1CCOCC1.[NH2:8][C:9]1[C:14]2[N:15]=[C:16]([CH2:38][CH2:39][CH3:40])[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]([O:30]C(OC(C)(C)C)=O)[C:23](=[O:29])OC(C)(C)C)[C:13]=2[C:12]([CH3:41])=[C:11]([CH3:42])[N:10]=1.C(N(CC)CC)C.[C:50]1([N:56]=C=O)[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>ClCCl.C(=O)(O)[O-].[Na+].CO>[NH2:8][C:9]1[C:14]2[N:15]=[C:16]([CH2:38][CH2:39][CH3:40])[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]([OH:30])[C:23]([NH:56][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:29])[C:13]=2[C:12]([CH3:41])=[C:11]([CH3:42])[N:10]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCCc1nc2c(N)nc(C)c(C)c2n1CCCCN(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nc2c(N)nc(C)c(C)c2n1CCCCN(O)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.7 %

Procedure:
A solution of 4N hydrochloric acid in dioxane (2.5 mL, 10.2 mmol, 20 eq) was added to a solution of tert-butyl 4-(4-amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl[(tert-butoxycarbonyl)oxy]carbamate (250 mg, 0.51 mmol), prepared as described in Parts A-F of Example 14, and stirred for 1 hour at ambient temperature. Methanol (2 mL) was added to the reaction mixture, which was stirred overnight. The reaction mixture was concentrated under reduced pressure and the material was concentrated from methanol and chloroform and dried. The material was suspended in dichloromethane (5 mL) and triethylamine (0.71 mL, 5.1 mmol) and cooled to −5° C. Phenyl isocyanate (0.056 mL, 0.51 mmol) was added dropwise and the reaction mixture was slowly allowed to warm to ambient temperature. After two hours, the reaction mixture was diluted with dichloromethane (10 mL) and saturated aqueous sodium bicarbonate (5 mL) and stirred vigorously and the phases were separated. The aqueous layer was extracted with dichloromethane (2×10 mL) and the combined organics were washed with saturated aqueous sodium bicarbonate (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to produce a white solid. The material was purified by HPFC (eluting with 5-30% CMA in chloroform), recrystallized from acetonitrile, triturated with ethyl acetate and dried at 80° C. under high vacuum to afford 60 mg of 1-[4-(4-amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridine-1-yl)butyl]-1-hydroxy-3-phenyl-urea as a white powder, mp 159.0-160.5° C. Anal. Calcd for C22H30N6O2 C, 64.37; H, 7.37; N, 20.47. Found: C, 64.01; H, 7.20; N, 20.27.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][CH2:9][N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12][C:11]1=[O:27].[N:28](OC(C)(C)C)=[O:29]>C1(C)C=CC=CC=1>[CH3:7][O:8][CH2:9][N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH:12]([NH:28][OH:29])[C:11]1=[O:27]
Reactant: COCN1C(=O)CCN(c2ccccc2)c2ccccc21
Reactant: CC(C)(C)ON=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COCN1C(=O)C(NO)CN(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.6 %

Procedure:
Potassium tert-butoxide (57.8 g) was added to 1-methoxymethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (29.1 g) in absolute toluene (1 litter) at 0° C. The resultant mixture was stirred for 30 minutes at 0° C., and tert-butyl nitrite (31.9 g) was added thereto, followed by stirring for 18 hours at room temperature. Ice-water was added to the reaction mixture for separation of layers, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=25:1), to thereby obtain 22.8 g of the title compound as a light brown oily substance (yield: 71.1%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[F:15][C:16]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:17]=1[NH2:18]>>[F:15][C:16]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:17]=1[NH:18][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Nc1ccc(F)cc1F
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(F)cc1F

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2,4-difluoroaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.