Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17]([C:19]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20]2)=[O:18])[C@H:14]([C:29]([O:31][CH3:32])=[O:30])[CH2:13]1)(=[O:11])=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+].[F:39][C:40]([F:45])([F:44])[C@H:41]([OH:43])[CH3:42]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:43][C@@H:41]([CH3:42])[C:40]([F:45])([F:44])[F:39])[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17]([C:19]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:20][CH2:21]2)=[O:18])[C@H:14]([C:29]([O:31][CH3:32])=[O:30])[CH2:13]1)(=[O:10])=[O:11]
Reactant: C[C@@H](O)C(F)(F)F
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(O[C@@H](C)C(F)(F)F)cc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
Under an atmosphere of argon, (2S,4R)-methyl 4-(2-chloro-4-fluorophenylsulfonyl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)pyrrolidine-2-carboxylate (200 mg, 331 μmol, Eq: 1.00, [prepared in analogy to General Procedure C, steps C1-C5, using 2-chloro-4-fluorothiophenol in step C2]) and cesium carbonate (194 mg, 595 μmol, Eq: 1.8) were combined with N,N-dimethylacetamide (2 ml) to give a colorless solution. (R)-1,1,1-trifluoropropan-2-ol (90.5 mg, 793 μmol, Eq: 2.4) was added. The reaction mixture was stirred over night at rt. The crude reaction mixture was concentrated in vacuo. The residue was poured into HCl (0.5 M, 5 ml) and extracted with ethyl acetate (5×20 ml). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 40% EtOAc in heptane) to yield the title compound as a white foam (178 mg, 67.1%, MS (m/e)=594.07 [M+H+])
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][CH2:14][C:15](=O)[C:7]1=[C:6]2[CH3:17].Cl.[NH2:19][OH:20]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][CH2:14][C:15](=[N:19][OH:20])[C:7]1=[C:6]2[CH3:17]
Reactant: COc1ccc2c(c1)c(C)c1n2CCCC1=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc2c(c1)c(C)c1n2CCCC1=NO
Yield: 94.2 %

Procedure:
6,7,8,9-Tetrahydro-2-methoxy-10-methylpyrido[1,2-a]indol-9-one, (9.16 g, 0.04 mol, described in Example 15, Step 2), was dissolved in pyridine (180 mL). Hydroxylamine hydrochloride (5.56 g, 0.08 mol) was added and the resulting solution refluxed for 90 minutes. The reaction mixture was concentrated in vacuo to ~15 mL, water (200 mL) was added and the product was extracted with ether (2×50 mL). The combined organic extracts were washed with water (100 mL), 5% hydrochloric acid (50 mL), 10% aqueous sodium bicarbonate (100 mL), then dried over MgSO4, filtered, and evaporated to afford the desired oxime 9.2 g (94%) m.p. 174°-6° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]2[CH2:16][CH:15]([CH2:17][NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[NH2:21])[O:14][C:6]2=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH:9]=[CH:8]2.[H][H]>O.[Pd]>[CH3:2][C:3]1[CH:4]=[C:5]2[CH2:16][CH:15]([CH2:17][NH:18][C:19](=[O:24])[C:20]([CH3:22])([CH3:23])[NH2:21])[O:14][C:6]2=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH2:9][CH2:8]2
Reactant: [H][H]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)C(C)(C)N)C2
Agent: [Pd]
Agent: Cl
Solvent: O
Product: Cc1cc2c(c3c1NC(=O)CC3)OC(CNC(=O)C(C)(C)N)C2
Yield: 82 %

Procedure:
A hydrochloric acid salt of 5-methyl-2-(α-methylalanyl)aminomethyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (1.15 g, 3.27 mmol) was dissolved in water (30 ml). To the obtained solution, 10% palladium-on-carbon (1.15 g) was added, followed by stirring at 80° C. for 3.5 hours in the atmosphere of hydrogen. The reaction mixture was filtered, and the filtrate was condensed under reduced pressure. The resultant residue was subjected to a recrystallization procedure using methanol--ether to obtain 851 mg of the title compound as colorless powdery crystals (73.5%).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:25][C:26]1[CH:27]=[C:28]([NH:33]N)[CH:29]=[CH:30][C:31]=1[F:32]>>[F:25][C:26]1[CH:27]=[C:28]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:29]=[CH:30][C:31]=1[F:32]
Reactant: NNc1ccc(F)c(F)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccc(F)c(F)c3)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and 3,4-difluoro-phenylhydrazine according to the method described for example 91. MS: M=429.2 (M+H)+
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C:17]1[CH:25]=[CH:24][C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=1)=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])=[O:4].[NH:26](C(OC(C)(C)C)=O)[C@@H:27]([C:32](O)=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:26][C@@H:27]([C:32]([NH:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[CH:24][CH:25]=1)=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])=[O:4])=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30]
Reactant: N=C(N)NCCC[C@H](NC(=O)CN)C(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](N)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 107.6 %

Procedure:
Following the procedures of Preparation Ic, a reaction mixture comprising (i) 910 mg (1.57 mmol) of H-Gly-L-Arg-pNA.2H-TFA, (ii) 363 mg (1.57 mmol) of Boc-D-Leu-OH, (iii) 1.2 ml of DIEA and (iv) 695 mg (1.57 mmol) of Bop is reacted in DMF and the reaction mixture is kept at RT for 2 h, with stirring. After evaporation to dryness under vacuum, the evaporation residue is chromatographed on silica gel using a CHCl3 /MeOH/AcOH gradient (20/3/1 to 10/3/1 v/v) as the eluent. The homogeneous fractions collected are pooled and the eluent is evaporated off. Lyophilization gives 785 mg (yield: 80%) of the expected product in pure form.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:26]([N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39])[C:27]#[CH:28].C(NCC)C>[Cu]I.CN(C)C=O>[NH:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[CH:8]([O:18][CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)[C:4]1[CH:3]=[C:2]([C:28]#[C:27][CH2:26][N:29]2[C:33](=[O:34])[C:32]3[C:31](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:30]2=[O:39])[CH:7]=[CH:6][CH:5]=1
Reactant: CN1CCC(OC(c2cccc(I)c2)c2nc3ccccc3[nH]2)CC1
Reactant: C#CCN1C(=O)c2ccccc2C1=O
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CN1CCC(OC(c2cccc(C#CCN3C(=O)c4ccccc4C3=O)c2)c2nc3ccccc3[nH]2)CC1
Reaction time: 24 h

Procedure:
A screw-cap tube is charged with 2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (200 mg), dichloro-bis(triphenylphosphine) palladium(II) (9.2 mg), copper(I) iodide (16.4 mg), N-propargylphthalimide (400 mg), diethylamine (310 μL) and N,N-dimethylformamide (2 mL). The tube is evacuated, filled with argon and sealed. After stirring at room-temperature for 24 h, the mixture is diluted with water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 98/2/0.2 to 95/5/0.5 to give 2-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)isoindole-1,3-dione.
Reaction SMILES: [C:1]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[CH:22].[OH2:29].[OH-].[Na+].OO>C1COCC1.C(OCC)(=O)C>[OH:29][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: O
Reactant: C#CCCCCCCCCCCCCCCCCCCCC(=O)OC(C)(C)C
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCCCCO
Reaction time: 1 h
Yield: 54 %

Procedure:
A solution of the acetylene (33) (0.4 g, 1.02 mmol) in dry THF (5 ml) at room temperature under nitrogen was treated with borane-dimethyl sulphide complex (1.04 ml of a 2M solution in THF, 2.08 mmol) and the resulting solution stirred for 1 hour, after which time no starting material was present on tlc. The reaction was then treated sequentially with water (2 ml), 2N aqueous sodium hydroxide (1 ml) and 30% hydrogen peroxide (1 ml). The resulting solution was left a further 15 minutes, then ethyl acetate added and the organic layer separated. The aqueous layer was re-extracted with ethyl acetate, the organic layers combined, dried (MgSO4) and evaporated. The crude product obtained in this manner was purified on silica (5 g). Elution with 10% ethyl acetate in petrol gave tert.-butyl 22-hydroxydocosanoate (34) as a white solid (0.23 g, 54%).
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1.[C:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[C:28]([N:31]1[CH2:36][CH2:35][N:34]([C:2]2[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]3[S:10][C:11]4[C:17]([N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=4[N:13]=3)=[O:7])=[CH:4][N:3]=2)[CH2:33][CH2:32]1)(=[O:30])[CH3:29]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(Cl)nc3)nc12
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(N4CCN(C(C)=O)CC4)nc3)nc12
Temperature: 120 °C
Yield: 31.6 %

Procedure:
A stirred suspension of 200 mg (0.49 mmol) 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide, 2.53 g (19.8 mmol) 1-acetylpiperazine and 290 mg (0.89 mmol) cesium carbonate in 4 ml NMP in a thick-walled glass pressure tube fitted with a teflon cap was heated at 120° C. for 24 h. The reaction mixture was then cooled to room temperature and poured onto water. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed with saturated brine, dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (0/99-4/96 methanol/dichlormoethane) followed by trituration in ether afforded 77 mg (31%) 6-(4-acetyl-piperazin-1-yl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide as a white crystalline solid. ES-MS m/e (%): 519 (M+Na+, 26), 417 (M+H+, 100).
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[N:13][N:14]([CH3:16])[N:15]=2)=[CH:7][CH:6]=1.[NH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:30]=[C:26]([C:27]([NH2:29])=[O:28])[C:25]([OH:31])=[CH:24][CH:23]=1>O1CCOCC1>[C:27]([C:26]1[CH:30]=[C:22]([CH:23]=[CH:24][C:25]=1[OH:31])[O:21][CH2:20][CH2:19][NH:18][CH2:17][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[N:13][N:14]([CH3:16])[N:15]=2)=[CH:7][CH:6]=1)(=[O:28])[NH2:29]
Reactant: NCCOc1ccc(O)c(C(N)=O)c1
Reactant: Cn1nnc(-c2ccc(OCC3CO3)cc2)n1
Solvent: C1COCCO1
Product: Cn1nnc(-c2ccc(OCC(O)CNCCOc3ccc(O)c(C(N)=O)c3)cc2)n1

Procedure:
Analogously to the procedure described in Example 12, by reacting 2.3 g of 5-[4-(2,3-epoxypropoxy)-phenyl]-2-methyl-2H-tetrazole with 1.5 g of 5-(2-aminoethoxy)-salicylamide there is obtained 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(2-methyl-2H-tetrazol-5-yl)-phenoxy]-2-propanol having a melting point of 174°-175° (from dioxan).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][O:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28])(=[O:20])=[O:19]>>[C:1]([O:5][C:6]([N:8]([O:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])[S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([CH3:17])(=[O:20])=[O:19])(=[O:29])=[O:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: COCCOC(=O)ONC(=O)OC(C)(C)C
Product: COCCOC(=O)ON(C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O

Procedure:
1-({[(tert-Butoxy)carbonyl]({[(2-methoxyethoxy)carbonyl]oxy})amino}-sulfonyl)-2-methanesulfonylbenzene (100) is prepared from 1-{[({[(tert-butoxy)carbonyl]amino}oxy) carbonyl]oxy}-2-methoxyethane and 2-methylsulfonyl benzenesulfonyl chloride according to Scheme 11. (0.59 g, 46%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.16-8.80 (2H, m), 7.54-8.02 (2H, m), 4.47-4.47 (2H, m), 3.66 (2H, d, 4.1 Hz), 3.41 (3H, s), 3.38 (3H, s), 1.42 (9H, s)
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([NH2:19])=[NH:18])=[CH:16][C:10]=3[N:9]=2)=[CH:6][C:5]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)=[CH:4][C:3]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][NH2:32])[C:26]=1[OH:33].C(N(CC)CC)C.[O-:41][C:42]#[N:43].[K+].Cl>CO>[OH:1][C:2]1[C:7]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([NH2:19])=[NH:18])=[CH:16][C:10]=3[N:9]=2)=[CH:6][C:5]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)=[CH:4][C:3]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][NH:32][C:42]([NH2:43])=[O:41])[C:26]=1[OH:33]
Reactant: N#C[O-]
Reactant: N=C(N)c1ccc2[nH]c(-c3cc(-c4nnn[nH]4)cc(-c4cccc(CN)c4O)c3O)nc2c1
Agent: Cl
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CO
Product: N=C(N)c1ccc2[nH]c(-c3cc(-c4nnn[nH]4)cc(-c4cccc(CNC(N)=O)c4O)c3O)nc2c1
Temperature: 50 °C
Reaction time: 72 h
Yield: 8.3 %

Procedure:
2-(2,2′-Dihydroxy-5-(1H-tetrazol-5-yl)-3′-aminomethylbiphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine (0.2 g 0.2 mmol), prepared as in Example 7, was dissolved in methanol (10 mL). The solution was treated with triethylamine (0.2 mL, 1.5 mmol) and then potassium cyanate (0.09 g, 1.1 mmol aqueous solution, 0.5 mL) was added in 3 portions over 1 hour. 1N hydrochloric acid (5 mL) was added and the mixture was stirred at 50° C. over 3 days. Drying afforded crude product, which was subjected to purification by reverse phase HPLC to give 2-(2,2′-dihydroxy-5-(1H-tetrazol-5-yl)-3′-ureidomethylbiphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine (0.008 g) as a brown solid. LCMS calcd. 484.47, obsrvd. (M+H) 485.1, (M−H) 483.1.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].BrBr.[C:10]1([O:16][CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(=O)C>[CH3:17][O:16][C:10]1[CH:15]=[CH:14][C:13]([CH:7]2[NH:1][C:2](=[O:3])[NH:4][C:5]2=[O:6])=[CH:12][CH:11]=1
Reactant: O=C1CNC(=O)N1
Reactant: COc1ccccc1
Agent: BrBr
Solvent: CC(=O)O
Product: COc1ccc(C2NC(=O)NC2=O)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
4.0 g (40 mmol) of hydantoin, 30 ml of acetic acid and 2.0 ml (40 mmol) of bromine were mixed at room temperature. The reaction mixture was then vigorously stirred at a temperature of 60° C. for 2 hours. After cooling the reaction mixture to room temperature, 8.64 g (80 mmol) of anisol was added to the reaction mixture and the reaction was further conducted at a temperature of 100° C. for 6 hours. The resulting precipitate was recovered by filtration, washed with water, and then dried to obtain 3.96 g (yield 48%) of 5-(p-methoxyphenyl)hydantoin.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([O:9]CC)=O)=[N:4][N:3]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>CO>[NH2:1][C:2]1[S:6][C:5]([C:7]([NH:15][CH:12]2[CH2:14][CH2:13]2)=[O:9])=[N:4][N:3]=1
Reactant: NC1CC1
Reactant: CCOC(=O)c1nnc(N)s1
Solvent: CO
Product: Nc1nnc(C(=O)NC2CC2)s1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 71.4 %

Procedure:
To a suspension of ethyl 5-amino-1,3,4-thiadiazole-2-carboxylate (2 g, 11.55 mmol) in methanol (15 mL) was added cyclopropylamine (1.5 mL, 21.65 mmol). The mixture was stirred at room temperature for 1 h and at 40° C. for 1.5 h. Additional cyclopropylamine (2 mL) was added. After 3 h at 40° C., 1 h at 50° C. and 20 min at 70° C., the mixture was concentrated to half the volume, diluted with water (2.5 mL), heated to boil to give a clear solution and cooled to room temperature. The solid was filtered, washed with cold methanol, and dried to give 5-amino-N-cyclopropyl-1,3,4-thiadiazole-2-carboxamide as yellow crystals (1.52 g, 72% yield). MS (ES+) m/z: 185 (M+H); LC retention time: 0.87 min (analytical HPLC Method A).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].[CH:32]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)=[O:33]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([CH:32]=[O:33])[CH:39]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Product: COC(=O)c1c(-c2cccc(C=O)c2)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1

Procedure:
The present compound was synthesized by a method similar to that in Example 272 and using 2-benzyl-6-chloro-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg) and 3-formylphenylboronic acid. Colorless crystals (140 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18].[OH-].[Na+]>>[N+:17]([C:3]1[C:2]([CH3:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2)([O-:19])=[O:18]
Reactant: Cc1ccc2ncccc2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc2ncccc2c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
2.45 mol of 6-methylquinoline were added to 1 l of concentrated sulfuric acid, and 2.94 mol of 65% strength nitric acid were added dropwise at from 0 to 10° C. The mixture was stirred for one hour, poured onto ice, adjusted to pH 2.5 using aqueous sodium hydroxide solution, filtered off with suction, washed with water and dried over magnesium sulfate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH2:10][C:11]([NH2:13])=[O:12])#[CH:2].Cl[C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)=[CH:28][CH:27]=2)[N:16]=1.F[B-](F)(F)F.CCN(CC)CC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:13][C:11](=[O:12])[CH2:10][C:4]1[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:19]1[C:20]([C:21]([F:22])([F:23])[F:24])=[CH:15][N:16]=[C:17]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][CH2:37]3)=[CH:28][CH:27]=2)[N:18]=1
Reactant: C#Cc1ccc(F)cc1CC(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(C#Cc4ccc(F)cc4CC(N)=O)n3)cc2)CC1
Temperature: 120 °C

Procedure:
A suspension of 2-(2-ethynyl-5-fluorophenyl)acetamide (A35) (0.114 g, 0.643 mmol), tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (K5) (0.267 g, 0.585 mmol), PdCl2(PPh3)2 (0.021 g, 0.029 mmol), t-Bu3PH.BF4 (8 mg, 0.03 mmol) and CuI (6 mg, 0.03 mmol) in anhydrous DMF (4 mL) was degassed with nitrogen for 10 minutes. Et3N (1 mL) was added and the resulting mixture was heated under microwave irradiation at 120° C. for 20 minutes. The volatiles were removed under reduced pressure, then the residue adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A36 as a yellow solid (0.198 g, 57%); 1H NMR (400 MHz, d6-DMSO) δ 10.41 (s, 1H), 8.81 (s, 1H), 7.69-7.62 (m, 3H), 7.47 (s, 1H), 7.31-7.19 (m, 4H), 7.07 (s, 1H), 4.05 (s, 2H), 3.72 (s, 2H), 2.80 (s, 2H), 2.69-2.59 (m, 1H), 1.74 (d, J=13.5 Hz, 2H), 1.55-1.44 (m, 2H), 1.42 (s, 9H). LCMS-A: rt 6.554 min; m/z 596 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:12]=[C:13]([C:30]3[CH:35]=[CH:34][C:33]([S:36][CH3:37])=[CH:32][CH:31]=3)[N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.I([O-])(=O)(=O)=[O:39].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[C:11]2[N:12]=[C:13]([C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH3:37])=[O:39])=[CH:32][CH:31]=3)[N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CSc1ccc(-c2nc3c(Cl)nc4ccccc4c3n2CCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)c1ccc(-c2nc3c(Cl)nc4ccccc4c3n2CCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 50 °C
Reaction time: 13 h
Yield: 72.4 %

Procedure:
To a suspension of 0.63 g of tert-butyl 4-[2-[4-chloro-2-(4-methylthio-phenyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl]-1-piperidinecarboxylate in 18 ml of 1,4-dioxane, a solution of 0.38 g of sodium periodate in 6 ml of water was added dropwise, and the mixture was stirred at 50° C. for 13 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography using 1,2-dichloroethane—methanol (10:1) as an eluting solvent to give 0.47 g of a colorless solid. Recrystallization from a mixture of isopropanol and water gave colorless crystals having the melting point of from 183 to 186° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[N:22]=[C:21]([N:24]2[C:28]4[CH:29]=[CH:30][C:31]([O:33][CH2:34][C:35]5([CH3:39])[CH2:38][O:37][CH2:36]5)=[CH:32][C:27]=4[N:26]=[CH:25]2)[CH:20]=[CH:19]3)[CH2:10][CH2:9]1)(C)(C)C.CC(C)([O-])C.[Na+].O>CC1CCCO1>[CH3:39][C:35]1([CH2:34][O:33][C:31]2[CH:30]=[CH:29][C:28]3[N:24]([C:21]4[CH:20]=[CH:19][C:18]5[C:23](=[C:14]([N:11]6[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]6)[CH:15]=[CH:16][CH:17]=5)[N:22]=4)[CH:25]=[N:26][C:27]=3[CH:32]=2)[CH2:38][O:37][CH2:36]1
Reactant: CC1(COc2ccc3c(c2)ncn3-c2ccc3cccc(N4CCC(NC(=O)OC(C)(C)C)CC4)c3n2)COC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: O
Product: CC1(COc2ccc3c(c2)ncn3-c2ccc3cccc(N4CCC(N)CC4)c3n2)COC1
Yield: 85.8 %

Procedure:
The compound, (1-{2-[5-(3-Methyl-oxetan-3-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-yl)-carbamic acid tert-butyl ester (2 g, 3.68 mmol, 1 equivalent), sodium t-butoxide (1.77 g, 18.4 mmol, 5 equivalents), 2-methyltetrahydrofuran (30 mL, 15 volumes), and water (66 mL, 1 equivalent) were added to a 100 mL round bottom flask. The mixture was heated to reflux and held at reflux for 24–30 hours. At reaction completion, the mixture was cooled to 20–30° C. The reaction was quenched into a 20% citric acid solution (10 volumes) and stirred at 20–30° C. for 30–60 minutes. The citrate salt precipitated out of solution during this time. A 50% sodium hydroxide solution (˜1 weight equivalent) was charged to basify the reaction mixture (pH 10–12). The layers were separated at 30–40° C. The aqueous layer was washed with ethyl acetate (10 volumes) and then the combined organics were concentrated to low volume. Ethyl acetate (14 mL, 7 volumes) was charged and the slurry was allowed to granulate for 10–20 hours. The solids were filtered and 1-{2-[5-(3-Methyl-oxetan-3-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine (1.4 g, 86% yield) was isolated.