Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)=[CH:4][CH:3]=1.[Cl:27]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(OCC)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:20])=[O:21])=[N:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:26])([F:24])[F:25])[C:9]=2[Cl:27])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)cc2)cn1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(Cl)c2-c2ccc(Br)cc2)cn1
Reaction time: 18 h
Yield: 62.6 %

Procedure:
To a solution of 5-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide (350 mg, 0.783 mmol) in N,N-dimethylformamide (12 ml) was added N-chlorosuccinimide (1.05 g, 7.83 mmol) at room temperature. After the mixture was stirred for 18 hr, 1.05 g of N-chlorosuccinimide was added. The resulting mixture was stirred for further 36 hr. 20 ml of saturated aqueous sodium thiosulfate and 50 ml of diethyl ether were added and the two-phase-mixture was stirred for 0.5 hr. The separated organic layer was washed with water (20 ml×3) and dried over magnesium sulfate. Removal of solvent gave a pale yellow gum, which was chromatographed on a column of silica gel (50 g) eluting with ethyl acetate/hexane (1:3) to afford 236 mg (63%) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:13]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:41]=[CH:40][C:24]2[NH:25][C:26]([C@@H:28]([NH2:39])[CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[N:27][C:23]=2[CH:22]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])[N:5]=[CH:4][N:3]=[C:2]2[NH:39][C@H:28]([C:26]1[NH:25][C:24]2[CH:40]=[CH:41][C:21]([Cl:20])=[CH:22][C:23]=2[N:27]=1)[CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33]
Reactant: CC(C)(C)OC(=O)CCC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(c1cc2ncnc(Cl)c2cc1Cl)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCC[C@H](Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 2d from 4,6-dichloro-7-(pyrrolidin-1-yl-carbonyl)-quinazoline, (S)-1-(5-chloro-1H-benzimidazol-2-yl)-4-(tert.-butyloxycarbonyl)-butylamine and triethylamine in N,N-dimethylformamide.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[C:23]2[N:27]([C@H:28]3[CH2:32][CH2:31][NH:30][CH2:29]3)[CH:26]=[N:25][N:24]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].N1C=CC=CC=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C1COCC1>[C:2]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[C:23]2[N:27]([C@H:28]3[CH2:32][CH2:31][N:30]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:29]3)[CH:26]=[N:25][N:24]=2)(=[O:13])=[O:14])=[CH:8][CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-c2nncn2[C@H]2CCNC2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-c2nncn2[C@H]2CCN(S(C)(=O)=O)C2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
To 4-tert-butyl-N-[4-chloro-2-((S)-4-pyrrolidin-3-yl-4H-[1,2,4]triazol-3-yl)phenyl]-benzenesulfonamide hydrochloride (0.25 g, 0.505 mmol) in THF (8 mL) was added pyridine (0.60 mL, 7.4 mmol). The resultant solution was stirred for 20 minutes at room temperature. The reaction mixture was subsequently cooled to 0° C., methanesulfonyl chloride (0.595 mL, 7.6 mmol) was added, and the mixture was stirred overnight at room temperature. The following day, the volatiles were evaporated and the resultant residue was adsorbed onto silica gel and purified by automated normal-phase chromatography (using 50→100% EtOAc in hexanes) to obtain the title compound (0.183 g) in 67.5% yield: MS (ES) M+H expected 538.0, found 538.1.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:13])[CH2:5][CH2:6][O:7]2.[CH3:14][Mg]Br.O>C(OCC)C>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([CH3:14])([OH:13])[CH2:5][CH2:6][O:7]2
Reactant: C[Mg]Br
Reactant: O=C1CCOc2cc(F)cc(F)c21
Solvent: CCOCC
Solvent: O
Product: CC1(O)CCOc2cc(F)cc(F)c21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.00 g (10.86 mmol) of the compound from Example 170A were dissolved in 40 ml of diethyl ether at 0° C., and 5.4 ml (16.29 mmol) of a 3N solution of methylmagnesium bromide in diethyl ether were slowly added dropwise. Stirring at 0° C. for 1 h was followed by warming to RT, addition of water and diethyl ether to the reaction solution and separation of the phases. The aqueous phase was extracted with diethyl ether, and the combined organic phases were dried over sodium sulfate and filtered, and the solvents were removed in vacuo. The crude product was purified by flash chromatography on silica gel (mobile phase: dichloromethane). 2.03 g (93% of theory) of the title compound were obtained.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:9]2[C:10](=[O:25])[N:11]([CH3:24])[CH2:12][C:13]3[N:14]([CH:15]=[N:16][C:17]=3[C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:8]=2[CH:7]=[CH:6][CH:5]=1.[CH3:26]I.O>CS(C)=O>[Cl:3][C:4]1[C:9]2[C:10](=[O:25])[N:11]([CH3:24])[CH2:12][C:13]3[N:14]([CH:15]=[N:16][C:17]=3[C:18]#[C:19][C:20]([O:23][CH3:26])([CH3:22])[CH3:21])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: CN1Cc2c(C#CC(C)(C)O)ncn2-c2cccc(Cl)c2C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COC(C)(C)C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Reaction time: 0.75 h

Procedure:
1.20 g (18.6 mmol) of freshly powdered potassium hydroxide was stirred at room temperature for 5 minutes in 15 ml of dimethyl sulfoxide. 1.65 g (5 mmol) of 7-chloro-4,5-dihydro-3-(3-hydroxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one and 1.42 g (10 mmol) of methyl iodide were then added thereto in succession, whereby the temperature rises to 35°. The reaction mixture was stirred for 45 minutes and then poured into 50 ml of water. The mixture was extracted five times with methylene chloride, the combined organic phases were dried over magnesium sulphate and evaporated. After crystallization from diisopropyl ether there was obtained 7-chloro-4,5-dihydro-3-(3-methoxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 172°-174°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[N:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[N:23]=3)[C:13]=2[C:14]([OH:16])=[O:15])[N:4]=1.[H-].[Na+].Cl[CH2:35][S:36][CH2:37]Cl>CN(C)C=O>[CH3:29][O:28][C:26]1[CH:25]=[C:24]([O:30][CH3:31])[N:23]=[C:22]([O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:12]([O:11][C:5]3[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=3)[C:13]=2[C:14]([O:16][CH2:35][S:36][C:37]2[CH:19]=[CH:20][CH:12]=[CH:13][CH:14]=2)=[O:15])[N:27]=1
Reactant: COc1cc(OC)nc(Oc2cccc(Oc3nc(OC)cc(OC)n3)c2C(=O)O)n1
Reactant: ClCSCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Oc2cccc(Oc3nc(OC)cc(OC)n3)c2C(=O)OCSc2ccccc2)n1
Yield: 126.7 %

Procedure:
1.7 g (4.0 mmol) of 2,6-bis[(4,6-dimethoxypyrimidin-2-yl) oxy]benzoic acid, 0.2 g of 60% sodium hydride and 0.72 g (4.4 mmol) of chloromethylsulfide were reacted in N,N-dimethylformamide, treated and purified in the same manner as in Example 1 to obtain 1.4 g of a white crystal having a melting point of from 89° to 93° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1([C:18]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=O)=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)(=O)C.CO>[C:12]1([C:18]2[C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:1][C:2]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[N+:9]([O-:11])=[O:10])[N:8]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc2nc(-c3ccccc3)c(-c3ccccc3)nc12
Reaction time: 2 h

Procedure:
1.53 g (10 mmol) of 2,3-diaminonitrobenzene and 2.00 g (9.6 mmol) of benzil were placed in a four-necked flask, and were dissolved by adding a 1:1 mixed solvent of acetic acid/methanol thereto. Thereafter, reaction was allowed at 70° C. for 2 hr. After the reaction, the solvent was removed, and the reaction product was extracted on a silica gel column (ethyl acetate:hexane=1:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=2)[C@@H:12]([N:22]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:23]2[N:24]=[N:25][NH:26][N:27]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:43]([O:47][CH2:48][CH2:49]O)([CH3:46])([CH3:45])[CH3:44].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=2)[C@@H:12]([N:22]([CH2:28][C:29]2[CH:30]=[C:31]([C:39]([F:40])([F:41])[F:42])[CH:32]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:34]=2)[C:23]2[N:24]=[N:25][N:26]([CH2:49][CH2:48][O:47][C:43]([CH3:46])([CH3:45])[CH3:44])[N:27]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)c2cc3c(cc21)COC3
Reactant: CC(C)(C)OCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OCCn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCN(C(=O)OC(C)(C)C)c3cc4c(cc32)COC4)n1
Reaction time: 12 h

Procedure:
To a solution of (S)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester (Example 73, Step 6) (0.167 mmol) in dichloromethane (20 mL), add 2-tert-butoxy-ethanol (0.835 mmol) and triphenylphosphine (0.501 mmol). To this solution, add diethyl azodicarboxylate (0.501 mmol) dropwise at room temperature. After stirring for 12 h, remove the solvent under vacuum. Chromatograph the intermediate over silica gel, eluting with ethyl acetate/hexane (2-35%) to afford the title compound as an oil. MS (ES+): 699 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[CH:18]=[C:17]([O:19]C)[N:16]=[C:15]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[C:35]5[C:30](=[N:31][CH:32]=[CH:33][CH:34]=5)[NH:29][C:28]4=[O:36])[CH2:23][CH2:22]3)[CH:14]=1)=[O:12])[CH2:6][CH2:5]2.Cl.N1C=CC=CC=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[CH:14]=[C:15]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[C:35]5[C:30](=[N:31][CH:32]=[CH:33][CH:34]=5)[NH:29][C:28]4=[O:36])[CH2:23][CH2:22]3)[NH:16][C:17](=[O:19])[CH:18]=1)=[O:12])[CH2:6][CH2:5]2
Reactant: COc1cc(C(=O)N2CCc3cc(F)ccc32)cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)[nH]c(=O)c1)N1CCc2cc(F)ccc21
Reaction time: 0.12 h

Procedure:
A well stirred mixture of 20 mg (0.041 mmol) 1-[4′-(5-fluoro-2,3-dihydroindole-1-carbonyl)-6′-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 100 mg (0.865 mmol) pyridine hydrochloride was kept in a melt for 7 min using a hot air blower. After the reaction mixture had cooled it was dissolved in DMF and purified by preparative HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [NH2:1][C:2]([C:4]1[NH:8][CH:7]=[N:6][C:5]=1[NH:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:12]=1)=[O:3].C(N=[C:37]=[S:38])(=O)C1C=CC=CC=1>C(Cl)Cl>[Cl:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:12]=[C:11]2[CH2:10][N:9]1[C:5]2[N:6]=[CH:7][NH:8][C:4]=2[C:2](=[O:3])[NH:1][C:37]1=[S:38]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1cc(CNc2nc[nH]c2C(N)=O)c2cc(Cl)ccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1cc(Cn2c(=S)[nH]c(=O)c3[nH]cnc32)c2cc(Cl)ccc21
Temperature: 80 °C
Yield: 44.5 %

Procedure:
A solution of tert-butyl 3-({[5-(aminocarbonyl)-1H-imidazol-4-yl]amino}methyl)-5-chloro-1H-indole-1-carboxylate (0.30 g, 0.78 mmol, obtained from Example 10(b)) and benzoyl isothiocyanate (0.13 mL, 0.94 mmol) in CH2Cl2 (5 mL) was stirred for 2 h and then evaporated. Ammonia (7 M in MeOH, 3 mL) was added to the residue and the mixture was heated to 80° C. for 2 h and then evaporated. Purification by flash chromatography using MeOH (2%) in CHCl3 gave the title compound (0.15 g, 50%). 1H1NMR (DMSO-d6) δ ppm 13.92 (1H), 12.57 (1H), 8.23 (1H), 8.12 (1H), 7.99 (1H), 7.81 (1H), 7.37 (1H), 5.81 (2H), 1.61 (9H); MS (ESI) m/z 430 (M−1).
Reaction SMILES: Br[C:2]1([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]1=[O:18].[OH2:26]>[N+]([O-])([O-])=O.[Ag+]>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:2]2([OH:26])[C:10](=[O:11])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:3]2=[O:18])=[CH:24][CH:23]=1
Reactant: O=C1c2cccc(-c3ccccc3)c2C(=O)C1(Br)c1ccc(Cl)cc1
Reactant: O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Product: O=C1c2cccc(-c3ccccc3)c2C(=O)C1(O)c1ccc(Cl)cc1

Procedure:
A mixture of 2-bromo-2-(p-chlorophenyl)-4-phenylindane-1,3-dione (0.3 g), silver nitrate (0.15 g) ethanol (3 ml) and water (3 ml) was heated under reflux for 2 hours. After cooling, the precipitated solid was filtered off. The solvent was removed from the filtrate under reduced pressure and the residual solid was chromatographed in silica. Recrystallisation from ethanol-water of the fraction eluted with ethyl acetate afforded 2-(p-chlorophenyl)-2-hydroxy-4-phenylindane-1,3-dione, m.p. 161-163.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:38])[C:22]([N:24]([CH:35]([CH3:37])[CH3:36])[CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)=[O:23])[C:17]1=[O:39])(=[O:14])=[O:13])[CH:6]=[CH:5]2.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:27][CH2:26][CH2:25][N:24]([CH:35]([CH3:37])[CH3:36])[C:22](=[O:23])[C@@H:21]([N:18]1[CH2:19][CH2:20][C@H:16]([NH:15][S:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=3)[CH:8]=2)(=[O:13])=[O:14])[C:17]1=[O:39])[CH3:38]
Reactant: CC(C)N(CCNC(=O)OC(C)(C)C)C(=O)[C@H](C)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(CCN)C(=O)[C@H](C)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 71.3 %

Procedure:
tert-Butyl 2-[[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl](isopropyl)amino]ethylcarbamate (0.21 g) was dissolved in DCM (4 ml), and trifluoroacetic acid (4 ml) was added. The mixture was stirred at room temperature for 2.5 h and then concentrated under reduced pressure. The residue was partitioned between saturated sodium bicarbonate solution and DCM, and the organic layer was separated, dried (over magnesium sulphate) and concentrated under reduced pressure. The residue was purified using SPE (silica, eluting with DCM, diethyl ether, ethyl acetate, methanol and methanol:10% aqueous ammonia) to give the title compound (0.124 g) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.[H-].[Na+].[CH3:12][CH2:13][O:14]C(C)=O>C1COCC1>[O:14]=[C:13]([CH3:12])[CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:8]#[N:9]
Reactant: CCOC(C)=O
Reactant: N#CCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)C(C#N)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(Pyridin-3-yl)acetonitrile (7.00 g, 59.3 mmol) was dissolved in THF (100 ml). NaH (60% in oil) (5.93 g, 148 mmol) was slowly added and the reaction mixture was stirred at RT for 1 hour (continuous gentle gas evolution). EtOAc (1 ml) was added and the mixture was stirred until an exothermic reaction occurred. EtOAc (7 mL) was then added slowly to maintain gentle heating. The reaction was stirred at RT for 2 hours and then approximately 75% of the THF was removed in vacuo. The resulting mixture was partitioned between Et2O and water and the aqueous phase was washed with Et2O (2×50 mL). The aqueous phase was then acidified with 1M HCl and the product was extracted into EtOAc. A significant amount of solid gradually formed between the two layers. This material was filtered off and dried.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:15][C:16]1[N:23]=[CH:22][CH:21]=[C:20](Br)[C:17]=1[C:18]#[N:19]>CN(C=O)C>[Br:15][C:16]1[C:17]([C:18]#[N:19])=[C:20]([N:12]2[CH2:11][CH2:10][CH:9]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:14][CH2:13]2)[CH:21]=[CH:22][N:23]=1
Reactant: N#Cc1c(Br)ccnc1Br
Reactant: c1ccc(C2CCNCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N2CCC(c3ccccc3)CC2)ccnc1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.4 %

Procedure:
To a suspension of NaH (0.146 g, 3.818 mmol, 60%) in DMF (20 ml) cooled at 0° C. was added 4-phenylpiperidine (0.616 g, 3.818 mmol). The resulting mixture was stirred for 5 min., then compound D1 (1 g, 3.016 mmol) was added. The resulting reaction mixture was stirred for 1 h. The reaction mixture was then quenched with NH4Cl (aqueous sat. solution) and extracted with Et2O. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH gradient as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D6 (0.985 g, 75%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:24][O:25][CH2:26][CH3:27])[N:20]([CH2:21][CH2:22][CH3:23])[C:16]=2[C:15]2[CH:14]=[C:13]([OH:28])[CH:12]=[CH:11][C:10]=2[N:9]=1.[N:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.O>CN(C=O)C>[N:29]1([C:35]([O:28][C:13]2[CH:12]=[CH:11][C:10]3[N:9]=[C:8]([NH2:7])[C:17]4[N:18]=[C:19]([CH2:24][O:25][CH2:26][CH3:27])[N:20]([CH2:21][CH2:22][CH3:23])[C:16]=4[C:15]=3[CH:14]=2)=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: CCCn1c(COCC)nc2c(N)nc3ccc(O)cc3c21
Reactant: O=C(Cl)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OC(=O)N4CCOCC4)cc3c21
Yield: 88.3 %

Procedure:
Cesium carbonate (1.62 g, 5.00 mmol) was added to a solution of 4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol (500 mg, 1.66 mmol, prepared in Parts A and B of Example 566) in anhydrous DMF (30 mL). The reaction was stirred for ten minutes, and 4-morpholinecarbonyl chloride (275 mg, 1.83 g) was then added. The reaction was stirred overnight at ambient temperature and poured into deionized water (300 mL). The resulting mixture was stirred for one hour and then extracted with chloroform (3×100 mL). The combined organic fractions were concentrated under reduced pressure, and the resulting solid was purified by chromatography on a HORIZON HPFC system (silica cartridge, eluting with a gradient of 0-20% CMA in chloroform). The resulting solid was recrystallized from acetonitrile and dried under vacuum to yield 606 mg of 4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl morpholine-4-carboxylate as a white, crystalline solid, mp 193-196° C. Anal. calcd for C21H27N5O4: C, 61.00; H, 6.58; N, 16.94. Found: C, 61.01; H, 6.51; N, 17.21.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]([OH:15])=O)[CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl.[CH3:17][NH:18][O:19][CH3:20].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[CH3:20][O:19][N:18]([CH3:17])[C:13]([C:8]1[CH:9]=[N:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)=[O:15]
Reactant: COc1ccc2cc(C(=O)O)cnc2c1
Reactant: CNOC
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2cc(C(=O)N(C)OC)cnc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of the intermediate from step D (1.5 mmol) and N,O-dimethyhydroxylamine hydrochloride (219 mg, 2.25 mmol), in dichloromethane (20 mL) was added triethyl amine (1.04 mL, 7.5 mmol) followed by bromo(trispyrrolidin-1yl)phosphonium hexafluorophosphate (840 mg, 1.8 mmol). After stirring the reaction mixture at room temperature for 3 hours, it was quenched by the addition of 1N HCl (10 mL). The resulting mixture was extracted with DCM. The organic layer was washed with saturated NaHCO3 solution, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 70% ethyl acetate-hexanes. 1H NMR (500 MHz, CDCl3): 9.15 (d, J=1.8 Hz, 1H), 8.5 (d, J=1.8 Hz, 1H), 8.0 (s, 1H), 7.7 (d, J=9.0 Hz, 1H), 7.43 (d, J=2.2 Hz, 1H), 7.24 (dd, J=2.5, 9.0 Hz, 1H), 3.96 (s, 3H), 3.57 (s, 3H), 3.43 (s, 3H). LC-MS: 1.6 min; (M+H)=247.1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].I[C:31]1[CH:32]=[N:33][N:34]([CH:36]2[CH2:41][CH2:40][C:39](=[O:42])[CH2:38][CH2:37]2)[CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:31]3[CH:32]=[N:33][N:34]([CH:36]4[CH2:37][CH2:38][C:39](=[O:42])[CH2:40][CH2:41]4)[CH:35]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11]
Reactant: O=C1CCC(n2cc(I)cn2)CC1
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CCC(=O)CC4)c3)cc12
Temperature: 90 °C

Procedure:
A 20 ml sealable vial was charged with 3-[1-(2,6-Dichloro-3-fluorophenyl)ethyl]-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (80.0 mg, 0.156 mmol), 4-(4-Iodopyrazol-1-yl)cyclohexanone (52.5 mg, 0.172 mmol), Pd(PPh3)4 (12.0 mg, 0.0103 mmol), potassium carbonate (71.8 mg, 0.514 mmol), and 4:1 dioxane:water (5 mL). The cap was sealed and the vial was evacuated and backfilled with nitrogen (3×). After that, the vial was heated at 90° C. for 2 h. The reaction mixture was partitioned between EtOAc/H2O (15 ml/10 ml). The aqueous phase was extracted with EtOAc (10 ml). The combined organic extracts were washed with water (10 ml) and brine (10 ml), dried over MgSO4, filtered, and concentrated in vacuo to give a brown oil that was purified by prep. TLC eluting with 4% MeOH/DCM to give the title compound. 1H NMR (400 MHz, CDCl3): δ=1.88 (d, J=7.2 Hz, 3H), 2.31-2.68 (m, 8 H), 4.64 (tt, J=11.8, 4.0 Hz, 1 H), 5.28 (q, J=7.2 Hz, 1 H), 7.01 (dd, J=8.0 & 8.8 Hz, 1 H), 7.30 (s, 1 H), 7.32 (brs, 1 H), 7.48 (s, 1 H), 7.60 (d, J=0.8 Hz, 1 H), 7.66 (d, J=0.8 Hz, 1 H), 8.41 (brs, 1 H), 9.77 (brs, 1 H). MS (ES+): m/z=471.16/473.11 (100/68) [MH+]. HPLC: tR=3.39 min (polar—5 min, ZQ3).