Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NN.[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:11]1[CH2:21][CH2:20][C@@H:19]([N:22]2C(=O)C3C(=CC=CC=3)C2=O)[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C@H:12]1[NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37]>CO>[NH2:22][C@H:19]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C@@H:12]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C@H:11]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([F:10])[C:4]=2[F:3])[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2cccnc2[C@H](N2C(=O)c3ccccc3C2=O)CC[C@H]1c1cccc(F)c1F
Agent: NN
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1c2cccnc2[C@H](N)CC[C@H]1c1cccc(F)c1F
Yield: 51.2 %

Procedure:
A mixture of hydrazine (1 mL, 31.9 mmol) and tert-butyl (5S,6S,9R)-6-(2,3-difluorophenyl)-9-(1,3-dioxoisoindolin-2-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-ylcarbamate (0.428 g, 0.823 mmol) in methanol (5 mL) was heated using an oil bath (70° C.) for 4 h. LCMS showed no starting material remaining. The solvent was removed via vacuum and the crude residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, dried (sodium sulfate), filtered and concentrated. Flash chromatography using methanol in methylene chloride from 0 to 10% gave the desired product (164 mg, 51%): MS(ESI)[M+H+]=390.19; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.46 (1H, d, J=4.0 Hz), 7.63 (1H, d, J=7.5 Hz), 7.18 (1H, dd, J=7.7, 4.9 Hz), 6.92-7.08 (3H, m), 5.24 (1H, t, J=8.8 Hz), 4.50 (1H, dd, J=9.3, 2.5 Hz), 3.18 (1H, br. s.), 2.83 (2H, br. s.), 2.04-2.24 (3H, m), 1.57 (1H, d, J=9.0 Hz), 1.31 (9H, s), 0.68-0.92 (1H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:19])[CH:7]1[CH:12]([C:13]2=[O:18])[CH2:11][CH:10]=[CH:9][CH2:8]1)([O-])=O.N1C=CC=CC=1.S>O>[NH2:1][C:4]1[C:5]2[C:6](=[O:19])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:18])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)C2CC=CCC12
Agent: S
Solvent: O
Solvent: c1ccncc1
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 5.0 parts of 5-nitro-1,4,4a,9a-tetrahydroanthraquinone with 50 parts of pyridine was stirred at 90°C for 2 hours with introducing thereinto 0.8 parts/hour of gaseous hydrogen sulfide. The reaction mixture was then cooled to 25°C and added with 50 parts of water to precipitate crystals. The crystals were recovered by filtration, washed with water and dried under reduced pressure to obtain 3.9 parts of 1-aminoanthraquinone.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18]([CH3:25])([CH3:24])[C:19](=[O:23])[NH:20]2)=[CH:16][C:15]=1[NH:26][CH3:27]>O1CCOCC1>[CH3:27][N:26]1[C:15]2[CH:16]=[C:17]3[C:18]([CH3:24])([CH3:25])[C:19](=[O:23])[NH:20][C:21]3=[CH:22][C:14]=2[N:13]=[C:1]1[OH:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CNc1cc2c(cc1N)NC(=O)C2(C)C
Solvent: C1COCCO1
Product: Cn1c(O)nc2cc3c(cc21)C(C)(C)C(=O)N3
Temperature: 25 °C

Procedure:
9.8 g. 1,1'-Carbonyldiimidazole are added to 6.1 g. 6-amino-5-methylamino-3,3-dimethylindolin-2-one in 250 ml. dioxan and the reaction mixture is heated under reflux for 2 hours. The solution is evaporated to dryness in a vacuum and the reddish oil remaining behind is boiled under reflux for 2 hours with 20% aqueous hydrochloric acid. The mixture is cooled to ambient temperature and neutralised with aqueous ammonia solution, while cooling with ice. The precipitate is filtered off with suction and recrystallised from methanol. There are obtained 2.0 g. of the title compound; m.p. 364°-367° C.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:31][CH3:32])=[C:7]([NH:19][C:20](=[O:30])[C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=2)[CH:8]=[C:9]([C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:36]>C1COCC1>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]([N:19]([C:7]2[CH:8]=[C:9]([C:11]3[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:10]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[C:6]=2[O:31][CH3:32])[CH3:36])=[O:30])=[CH:22][CH:23]=1
Reactant: CI
Reactant: COc1ncccc1-c1cc(NC(=O)c2ccc([N+](=O)[O-])cc2)c(OC)c(C(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ncccc1-c1cc(N(C)C(=O)c2ccc(N)cc2)c(OC)c(C(C)(C)C)c1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
steps 1 & 2—To a solution of 102 (0.24 g, 0.55 mmol) in THF (5 mL) was added sodium hydride (0.033 g, 0.83 mmol). The mixture was stirred at RT until the evolution of gas subsided, and iodomethane (0.069 mL, 1.1 mmol) was added. The resulting mixture was stirred for 3 h and then quenched with water and the mixture extracted with EtOAc. The solvent was evaporated, and the crude residue was dissolved in EtOAc/hexane (2:1, 10 mL) to which was added 10% Pd/C (0.025 g). A stream of hydrogen gas was bubbled through the solution for 20 min, and the resulting solution was stirred at RT for 3 h. The solution was filtered, the filtrate concentrated, and the crude residue purified by SiO2 chromatography eluting with EtOAc/hexane to afford 0.23 g (97%) of 4-amino-N-[3-tert-butyl-2-methoxy-5-(2-methoxypyridin-3-yl)phenyl]-N-methylbenzamide (140) as a white foam.
Reaction SMILES: [C:1]1([C@H:7]2[C@H:16]3[CH2:17][CH2:18][N:19]([C:20]([C@H:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]4[NH:28][C:29]([NH:31][CH2:32][CH2:33][C:34](O)=[O:35])=[O:30])=[O:21])[C@H:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+].C([N:41](CC)CC)C.C(OP(C#N)(=O)OCC)C.C(=O)([O-])O.[Na+]>CN(C=O)C.O>[C:1]1([C@H:7]2[C@H:16]3[CH2:17][CH2:18][N:19]([C:20]([C@H:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]4[NH:28][C:29]([NH:31][CH2:32][CH2:33][C:34]([NH2:41])=[O:35])=[O:30])=[O:21])[C@H:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCNC(=O)N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Reactant: CCN(CC)CC
Agent: CCOP(=O)(C#N)OCC
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)CCNC(=O)N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Temperature: 25 °C
Yield: 68.7 %

Procedure:
The compound (0.171 g, 0.348 mmol) synthesized in Example 157, ammonium chloride (0.0261 g, 0.488 mmol), triethylamine (0.0685 ml, 0.488 mmol) and diethylcyanophosphonate (0.07 ml, 0.418 mmol) were stirred in DMF (5 ml) under ice-cooling for 1 hr and at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried (over anhydrous MgSO4), and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using basic silica gel (30 g) and eluted with ethyl acetate-methanol (1:0-4:1, v/v) to give the title compound (0.117 g, 69%) as an amorphous form from the object fraction.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([N:9]2C(=O)C(C)(C)[N:11]([CH2:17][CH2:18][CH2:19][C:20](O)=O)[C:10]2=O)=[CH:5][C:4]=1C(F)(F)F)#N.[C:28](O)(C)(C)[CH3:29].C(Cl)Cl>CN(C)C1C=CN=CC=1.CC(C)=O>[CH:17]1([N:11]=[C:10]=[N:9][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:8][CH2:7]2)[CH2:18][CH2:19][CH2:20][CH2:29][CH2:28]1
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1CCCC(=O)O
Reactant: CC(C)(C)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
By carrying out the esterification of the product of Example 62, with terbutanol in the presence of dicyclohexylcarbodiimide and 4-dimethylamino-pyridine as in Example 60, the expected product melting at 96°-97° C. with a Rf=0.32 (eluant: methylene chloride--acetone (98-2)) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:19][O:20][CH2:21][CH2:22][NH2:23]>C(O)CCC>[NH2:1][C:2]1[N:10]=[C:9]([NH:23][CH2:22][CH2:21][O:20][CH3:19])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: COCCN
Solvent: CCCCO
Product: COCCNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Yield: 72 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (10 mg, 0.385 mmol) and 2-methoxyethylamine in 2 ml of butanol were heated at 120° C. for 9 hours in autoclave. The reaction mixture was concentrated in vacuo to dryness and to the residue was added water. The mixture was extracted with chloroform and the organic layer was dried on sodium sulfate and concentrated in vacuo to dryness. The residue was purified with silica gel chromatography (3% methanol/chloroform) to give the subject compound (83 mg, yield 72%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:12])[CH3:11].[CH2:14]([S:18][C:19]([CH3:23])([CH3:22])[CH:20]=O)/[CH:15]=[CH:16]/[CH3:17]>>[CH2:14]([S:18][C:19]([CH3:23])([CH3:22])[CH2:20][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:11])[CH3:12])/[CH:15]=[CH:16]/[CH3:17]
Reactant: C/C=C/CSC(C)(C)C=O
Reactant: CC(C)(S)CNc1ccccc1N
Product: C/C=C/CSC(C)(C)CNc1ccccc1NCC(C)(C)S
Yield: 88.3 %

Procedure:
2-Amino-1-(2-mercapto-2-methylpropylamino)benzene (0.36 g, 1.84×10-3 mol) and 0.58 g (3.67×10-3 mol, 200 M %) 2-(trans-2-butenylthio)-2-methylpropanal were reacted by the procedures in Example 2 to give 0.55 g (88% yield) 1-[2-(trans-2-butenylthio)-2-methylpropylamino]-2-(2-mercapto-2-methylpropylamino)benzene as an oil after purification by radial chromatography on a 4 mm silica plate eluting with 100% hexane.
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=O)[CH3:2]>ClCCl.[Pd]>[O:4]1[CH2:5][CH2:6][CH:2]([CH2:5][CH2:6][CH2:2][CH2:1][OH:4])[CH2:1]1
Reactant: CCOC(C)=O
Agent: [Pd]
Solvent: ClCCl
Product: OCCCCC1CCOC1

Procedure:
All batches of the material were combined, loaded in dichloromethane and purified on silica (100 g) using a 0-25% gradient of ethyl acetate-cyclohexane over 40 mins using a Flashmaster II. The appropriate fractions were combined and evaporated in vacuo, a solution of the residue (3.42 g, 14.9 mmol) and 10% palladium on carbon (684 mg) in ethyl acetate (100 ml) was hydrogenated at atmospheric pressure and room temperature for 24 hours. The catalyst was filtered through Celite and the filtrate concentrated in vacuo to give the title compound as a yellow oil (2.22 g).
Reaction SMILES: [F:1][C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C2[O:36]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1.O1CN1>C1(C)C=CC=CC=1.C1COCC1>[F:1][C:2]1[CH2:7][CH2:6][C:5]([OH:36])([C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[CH2:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: O=C(OCc1ccccc1)C1CC=C(F)CC1
Agent: C1NO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)C1(O)CC=C(F)CC1
Temperature: -78 °C

Procedure:
A mixture of benzyl 4-fluorocyclohex-3-ene-1-carboxylate (1.77 g, 7.56 mmol) and 38 mL of THF was stirred vigorously and cooled to −78° C. To the reaction mixture was added dropwise over 15 minutes a solution of 0.5 M potassium bis(trimethylsilyl)amide in toluene (2.56 g, 12.8 mmol. The reaction mixture was allowed to stir vigorously for 1 hour. In a separate flask, 3-phenyl-2-(phenyl-sulfonyl)oxaziridine (2.17 g, 8.31 mmol) was dissolved in 2 mL of THF. The oxaziridine solution was then added to the reaction mixture dropwise. The reaction mixture was allowed to stir for 2 hours more and quenched with a saturated aqueous ammonium chloride solution. The biphasic reaction was separated and the aqueous layer was extracted three times with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered, concentrated and purified by chromatography on silica gel, eluting with 0-15% EtOAc in hexanes, to give benzyl 4-fluoro-1-hydroxycyclohex-3-ene-1-carboxylate as an oil.
Reaction SMILES: [CH:1]1([C:5]([NH:7][C:8]2[CH:9]=[C:10]([CH:15]3[C:24]([CH3:26])([CH3:25])[CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:27]([O:29]C)=[O:28])[CH:21]=4)[NH:16]3)[CH:11]=[CH:12][C:13]=2[F:14])=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([C:5]([NH:7][C:8]2[CH:9]=[C:10]([CH:15]3[C:24]([CH3:26])([CH3:25])[CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:27]([OH:29])=[O:28])[CH:21]=4)[NH:16]3)[CH:11]=[CH:12][C:13]=2[F:14])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(NC(=O)C3CCC3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(F)c(NC(=O)C2CCC2)c1
Yield: 80 %

Procedure:
A mixture of methyl 2-(3-(cyclobutanecarboxamido)-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (0.26 mmol, 1.0 eq.) and 4.5 mL sodium hydroxide (1 mol/L) in 3 mL methanol was stirred at reflux for 1-2 h. LC-MS indicated that the starting material was consumed completely. The methanol was removed by reduced pressure. The residue was acidified pH to 5-6 with 1 M hydrochloric acid. A lot of precipitates were formed and collected by filtration to afford 2-(3-(cyclobutanecarboxamido)-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid; Yield: 80%; MS (ESI+APCI) M+1=397.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([N:14]=[N+]=[N-])[CH2:10][C@H:9]1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[CH2:10][C@H:9]1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CSc1ccc(S(=O)(=O)C[C@@H]2C[C@H](N=[N+]=[N-])CC[C@@H]2NC(=O)OC(C)(C)C)cc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: CSc1ccc(S(=O)(=O)C[C@@H]2C[C@H](N)CC[C@@H]2NC(=O)OC(C)(C)C)cc1
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
±(1S*,2R*,4R*)-[4-Azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-carbamic acid tert-butyl ester (from example 55d), (100 mg) was dissolved in MeOH (1 ml) prior to the addition of 5% Pd/BaSO4 (120 mg). A hydrogen balloon was added and the solution was stirred for 1.5 h. The palladium was filtered off and the solution was concentrated to give ±(1S*,2R*,4R*)-[4-amino-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-carbamic acid tert-butyl ester (94 mg). MS found: (M+H)+=415.2.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=3)[CH:7]=[CH:6][C:5]=2[N:4]2[CH2:27][CH2:28][C@H:29]([CH2:30][C:31]([OH:33])=[O:32])[C:3]=12.C1COCC1.[OH-].[K+:40]>CC(C)=O>[K+:40].[Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[C:15]([C:23]([F:24])([F:25])[F:26])[CH:14]=3)[CH:7]=[CH:6][C:5]=2[N:4]2[CH2:27][CH2:28][C@H:29]([CH2:30][C:31]([O-:33])=[O:32])[C:3]=12
Reactant: CC(C)Oc1ccc(COc2ccc3c(c2)c(Cl)c2n3CC[C@@H]2CC(=O)O)cc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(C)Oc1ccc(COc2ccc3c(c2)c(Cl)c2n3CC[C@@H]2CC(=O)[O-])cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 24 h

Procedure:
(R)-2-(9-Chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid (15 mg, 0.031 mmol) was dissolved in a suitable solvent (THF or acetone, 0.5 mL) and heated to 60° C. 2.08 M aqueous KOH (15 mL, 0.031 mmol) was added and the reaction mixture was cooled to 35° C. and stirred for 24 h. No solid product was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:24][C:25]2[C:34]3[C:29](=[C:30]([C:35]([NH2:37])=[O:36])[CH:31]=[CH:32][CH:33]=3)[N:28]=[C:27]([CH3:38])[N:26]=2)[CH2:9][N:10]([CH3:23])S(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(S)C=CC=CC=1>CC#N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:24][C:25]2[C:34]3[C:29](=[C:30]([C:35]([NH2:37])=[O:36])[CH:31]=[CH:32][CH:33]=3)[N:28]=[C:27]([CH3:38])[N:26]=2)[CH2:9][NH:10][CH3:23])=[CH:4][CH:3]=1
Reactant: Cc1nc(N[C@H](CN(C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c2ccc(F)cc2)c2cccc(C(N)=O)c2n1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [Cs+]
Solvent: CC#N
Product: CNC[C@@H](Nc1nc(C)nc2c(C(N)=O)cccc12)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43 %

Procedure:
Crude 4-[((1S)-1-(4-Fluorophenyl)-2-{methyl[(4-nitrophenyl)sulfonyl]amino}ethyl)-amino]-2-methylquinazoline-8-carboxamide (161 mg; 0.30 mmol) and Cs2CO3 (488 mg; 1.50 mmol) were suspended in CH3CN (7 ml), and stirred for 10 minutes at room temperature. Benzenethiol (0.12 ml; 1.20 mmol) was added via syringe and the solution was stirred vigorously at room temperature overnight. The reaction mixture was concentrated, dissolved in DMSO (3 ml), and purified via Reverse Phase chromatography (Yamazen, basic buffer) to provide 9 16? (46 mg; 43% yield) as the free base. LC-MS [354 (M+1)]
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=1.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([CH2:26][CH2:27][NH2:28])=[CH:18]1.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>CN(C=O)C>[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([CH2:26][CH2:27][NH:28][C:11]([C:8]2[CH:7]=[C:6]([CH2:5][C:4]3[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=3)[O:10][N:9]=2)=[O:13])=[CH:18]1
Reactant: NCCc1coc2ccccc12
Reactant: O=C(O)c1cc(Cc2cccc(F)c2)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1coc2ccccc12)c1cc(Cc2cccc(F)c2)on1
Yield: 8.5 %

Procedure:
A solution of the 5-(3-fluorobenzyl)isoxazole-3-carboxylic acid (0.057 g, 0.257 mmol), 2-(benzofuran-3-yl)ethanamine (0.042 g; 0.260 mmol), HATU (0.108 g; 0.285 mmol) and N,N-diisopropylethylamine (0.112 mL; 0.649 mmol) in DMF (3 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by preparative HPLC (method 2) to yield 0.008 g (9%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:28]1([C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:38]([C:37]3[CH:36]=[CH:35][C:34]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:41][CH:40]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Reactant: Cc1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)cs1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(N6CCOCC6)cc5)nc34)CC2)cs1
Temperature: 85 °C
Yield: 30.7 %

Procedure:
To a mixture of 5-bromo-4-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.041 g, 0.10 mmol), EtOH (2.6 mL) and DMF (0.35 mL), 4-morpholin-4-yl-benzaldehyde (0.021 g, 0.11 mmol) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.30 mL, 0.3 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM, and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 96:4) to give the title compound as a solid (0.017 g, 30%); 1H-NMR (500 Mz, DMSO-d6): δ 2.63-2.70 (m, 7H), 3.21-3.27 (m, 4H), 3.60-3.68 (m, 6H), 3.76 (m, 4H), 7.07 (d, J=9.0 Hz, 2H, ArH, C6H4), 7.31 (s, 1H, thiazole 5-H), 8.05 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.17 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.22 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 3.29 min—554/556 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 554.1345, calculated for C25H29BrN7OS (M+H)+: 554.1338.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH2:13][O:14][C:15]2[C:16](=[O:24])[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[NH:19][CH:20]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[C:26]1([CH2:25][O:24][C:16]2[C:15]([O:14][CH2:13][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:20][N:19]=[C:18]([C:21]([O:23][CH2:13][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:22])[CH:17]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
21.5 g (156 mmol) of potassium carbonate was added to a suspension of 29.4 g (120 mmol) of 1,4-dihydro-5-(phenylmethoxy)-4-oxo-2-pyridinecarboxylic acid in 350 ml of N,N-dimethylformamide (DMF) and stirred for 1 hour at room temperature. 31 ml (264 mmol) of benzylbromide was added and the mixture was heated at 100° C. under stirring for 25 hours. After cooling to room temperature, the DMF was distilled off in vacuo and the residue triturated with ethyl acetate with short heating to 60° C. 40 g of inorganic salts were filtered off, the filtrate was concentrated to ca. 75 ml and chromatographed on silica gel with ethyl acetate:petroleum ether 90:10 as eluent. Yield: 35.5 g; melting point 116.7° C.
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].[CH2:32]([N:39]1[CH2:44][CH2:43][O:42][CH:41]([C:45]2[CH:52]=[CH:51][C:48]([CH:49]=O)=[CH:47][CH:46]=2)[CH2:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:32]([N:39]1[CH2:44][CH2:43][O:42][CH:41]([C:45]2[CH:46]=[CH:47][C:48]([CH:49]=[CH:5][C:4]3[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:3]=3[Cl:2])=[CH:51][CH:52]=2)[CH2:40]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Clc1cccc(Cl)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [H-]
Solvent: C1CCOC1
Product: Clc1cccc(Cl)c1C=Cc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
To a suspension of (2,6-dichloro-benzyl)-triphenyl-phosphonium bromide (2.06 g; 4.1 mmol) (See: A. Schmidpeter, H. Noeth, G. Jochem, H.-P. Schroedel, K. Karaghiosoff; Chem. Ber., 1995, 128, 379) in THF (25 mL) was added sodium hydride (60% dispersion in mineral oil) (215 mg; 4.5 mmol), at 0° C. After stirring for 1 hour, 4-(4-benzyl-morpholin-2-yl)-benzaldehyde (1.05 g; 3.7 mmol) was added, at 0° C. Subsequently, the resulting mixture was heated under reflux for 1 hour. After cooling to RT, 5% aqueous NaHCO3 was added and the mixture extracted with Et2O. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O:hexanes 1:1) to afford 4-benzyl-2-{4-[2-(2,6-dichloro-phenyl)-vinyl]-phenyl}-morpholine (1.15 g).