Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[F:17][C:18]1[CH:19]=[C:20]([C:24]2[C:32]3[C:31](=[O:33])[NH:30][C:29]([C:34]([O:36]CC)=O)=[N:28][C:27]=3[S:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:82]2[CH:86]=[N:85][C:84]([O:87][CH2:88][CH2:89][O:90][C:91]3[CH:92]=[C:93]([CH2:97][NH2:98])[CH:94]=[CH:95][CH:96]=3)=[N:83]2)C=CC=CC=1>>[F:17][C:18]1[CH:19]=[C:20]([C:24]2[C:32]3[C:31](=[O:33])[NH:30][C:29]([C:34]([NH:98][CH2:97][C:93]4[CH:94]=[CH:95][CH:96]=[C:91]([O:90][CH2:89][CH2:88][O:87][C:84]5[N:85]=[CH:86][NH:82][N:83]=5)[CH:92]=4)=[O:36])=[N:28][C:27]=3[S:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1nc2scc(-c3cccc(F)c3)c2c(=O)[nH]1
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: O=C(NCc1cccc(OCCOc2nc[nH]n2)c1)c1nc2scc(-c3cccc(F)c3)c2c(=O)[nH]1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 5-(3-fluorophenyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 72 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (131.0 mg, 55%).
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]=2[S:4][CH:3]=1.[O:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1.CCO.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[O:19]1[CH:23]=[CH:22][C:21]([C:2]2[C:11]3[O:10][CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]=3[S:4][CH:3]=2)=[CH:20]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)csc2C1
Reactant: OB(O)c1ccoc1
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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOc2c(-c3ccoc3)csc2C1
Temperature: 95 °C
Reaction time: 12 h
Yield: 88.4 %

Procedure:
A mixture of tert-butyl 8-bromo-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (60.0 mg), 3-furanboronic acid (26.1 mg), EtOH (0.1 ml), 2N aqueous sodium carbonate solution (1 mL), tetrakis(triphenylphosphine)palladium (25 mg) and toluene (2 mL) was stirred at 95° C. for 12 hr under a nitrogen atmosphere, and the reaction mixture was poured into water. The mixture was extracted with ethyl acetate and the extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent gradient; 0→33% ethyl acetate/hexane) to give the title compound (51.0 mg, 88.1%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:23]=[CH:24][CH:25]=2)[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[O:11])=[CH:4][CH:3]=1.[S-:28][C:29]#[N:30].[K+].BrBr>C(O)(=O)C>[NH2:30][C:29]1[S:28][C:27]2[CH:26]=[C:5]([O:6][C:7]3[CH:8]=[C:9]([CH:23]=[CH:24][CH:25]=3)[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=3)=[O:11])[CH:4]=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1ccc(Oc2cccc(C(=O)Nc3ccc(C(F)(F)F)cc3)c2)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(Oc3cccc(C(=O)Nc4ccc(C(F)(F)F)cc4)c3)cc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
To a solution (50 mL) of 3-(4-aminophenoxy)-N-[4-(trifluoromethyl)phenyl]benzamide (3.72 g, 10.0 mmol) in acetic acid was added potassium thiocyanate (3.89 g, 40.0 mmol), and the mixture was stirred at room temperature for 30 min. To the obtained transparent solution was added dropwise bromine (2.40 g, 15.0 mmol) under ice-cooling, and the reaction mixture was stirred at room temperature for 18 hr. The precipitated yellow powder was filtered off through celite, and the filtrate was concentrated under reduced pressure. To the residue was added 0.1N aqueous sodium hydroxide solution and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1:1), and triturated with diethyl ether to give the title compound (2.93 g, 68%) as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([SH:4])[CH3:3].Cl[C:6]1[C:7]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:8]=2[S:9][C:10]=1[C:11]([NH2:13])=[O:12].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C=O)C.C(OCC)(=O)C>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:8]2[S:9][C:10]([C:11]([NH2:13])=[O:12])=[C:6]([S:4][CH:2]([CH3:3])[CH3:1])[C:7]=2[CH:17]=1
Reactant: CC(C)S
Reactant: COc1ccc2sc(C(N)=O)c(Cl)c2c1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2sc(C(N)=O)c(SC(C)C)c2c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
2-Propanethiol (1.1 mL, 12.4 mmol) is added to a suspension of 3-chloro-5-methoxybenzo[b]thiophene-2-carboxamide (3.00 g, 12.4 mmol) in 24 mL of DMF. Diazabicycloundecene (DBU) (1.8 mL, 12.4 mmol) is added and the mixture is warmed to 80° C. After 6 hours, additional amounts of 2-propanethiol (110 μL) and of DBU (180 μL) are added. Heating is continued for 1 hour. The reaction mixture is allowed to cool and then is diluted with ethyl acetate and washed with 1N NaOH, 1N HCl, water, and brine. The organic layer is dried over MgSO4. Filtration followed by concentration in vacuo and recrystallization from ethyl acetate:hexane gives 5-methoxy-3-[(1-methylethyl)thio]benzo[b]thiophene-2-carboxamide in 80% yield. An analytical sample is obtained by a second recrystallization from ethyl acetate:hexane; mp=143°-143.5° C.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[N:16]1([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][N:28]=2)[CH:24]=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][N:2]([CH:10]1[CH2:11][CH2:12][N:13]([CH2:24][C:23]2[CH:26]=[CH:27][N:28]=[C:21]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:22]=2)[CH2:14][CH2:15]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: O=Cc1ccnc(N2CCCC2)c1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(C(=O)OC(C)(C)C)C1CCN(Cc2ccnc(N3CCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64 %

Procedure:
tert-Butyl methyl(piperidin-4-yl)carbamate (2.333 mmol, 1 eq) and 2-(pyrrolidin-1-yl)-isonicotinaldehyde (2.66 mmol, 1.14 eq) were dissolved in dichloromethane (15 ml), and acetic acid (5.459 mmol, 2.34 eq) and sodium triacetoxyborohydride (3.266 mmol, 1.4 eq) were added. The reaction mixture was stirred for 48 h at RT. When the reaction was complete (TLC monitoring), sat. sodium hydrogen carbonate solution was added to the reaction mixture and the phases were separated. The aqueous phase was extracted with dichloromethane (2×30 ml). The combined organic phases were washed with sat. NaCl solution, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, ethyl acetate:cyclohexane 2:1). Yield: 64%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:14]2[CH:19]=[CH:18][C:17]([C:20](=O)[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22]N(C)C)=[CH:16][CH:15]=2)[CH2:11][C:10]([OH:13])([CH3:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:34]1([C:40]2[CH:41]=[C:42]([NH2:45])[NH:43][N:44]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(O)(=O)C.C(O)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:22][N:43]4[N:44]=[C:40]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[CH:41]=[C:42]4[N:45]=3)=[CH:18][CH:19]=2)[CH2:9][C:10]([OH:13])([CH3:12])[CH2:11]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Reactant: CN(C)C=C(C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CC(C)(O)C2)cc1)c1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCO
Product: CC1(O)CC(NC(=O)OC(C)(C)C)(c2ccc(-c3nc4cc(-c5ccccc5)nn4cc3-c3ccccc3)cc2)C1

Procedure:
A mixture of 2 (450 mg, 1 mmol) and 5-Phenyl-2H-pyrazol-3-ylamine (160 mg, 1 mmol) in acetic acid (2 mL) and ethanol (4 mL) was heated under reflux for 4 hours. After cooling, the mixture was diluted with 30 mL of DCM, the combined organic phase was washed with NaHCO3 aq. and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromoatography to give 10-1.
Reaction SMILES: [CH2:1]1[C:13]2[C:12]3[CH:11]=[C:10]([C:14]([NH:16][CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[O:15])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3][NH:2]1.[F:30][C:31]([F:41])([F:40])[C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)C>[F:30][C:31]([F:40])([F:41])[C:32]1[CH:39]=[CH:38][C:35]([CH2:36][N:2]2[CH2:3][CH2:4][C:5]3[NH:6][C:7]4[CH:8]=[CH:9][C:10]([C:14]([NH:16][CH:17]5[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]5)=[O:15])=[CH:11][C:12]=4[C:13]=3[CH2:1]2)=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc3[nH]c4c(c3c2)CNCC4)CC1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc3[nH]c4c(c3c2)CN(Cc2ccc(C(F)(F)F)cc2)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of tert-butyl 4-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate (11.63 g, 29.2 mmol) and 4-(trifluoromethyl)benzaldehyde (4.8 mL, 6.12 g, 35.1 mmol) in DCM (200 mL), sodium triacetoxyborohydride (12.4 g, 8.5 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight and then poured into saturated sodium bicarbonate solution (300 mL). The layers were separated, and the aqueous layer was extracted with DCM (3×100 mL). The combined organic layers were washed with brine (2×50 mL), dried (MgSO4), filtered and concentrated to give an off-white solid. Trituration with ethyl ether provided tert-butyl 4-(2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate (9 in Scheme 1(c)) as a white solid (13.60 g, 84%). 1H NMR (DMSO-d6, 300 MHZ) 11.03 (br s, 1H), 8.01 (d, J=7.7 Hz, 1H), 7.83 (s, 1H), 7.71 (d, J=8.3 Hz, 2H), 7.62 (d, J=7.7 Hz, 2H), 7.55 (d, J=8.8 Hz, 1H), 7.26 (d, J=8.5 Hz, 1H), 4.22-3.83 (m, 5H), 3.62 (s, 2H), 2.90-2.77 (br s, 6H), 1.82-1.70 (m, 2H), 1.55-1.30 (m, 11H) ppm; MS (ES) 557 (M+H)
Reaction SMILES: [O:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:2]1.CCN(C(C)C)C(C)C.[NH2:20][C:21]1[C:30]([C:31]([NH:33][C:34]2[CH:35]=[N:36][CH:37]=[C:38]([F:49])[C:39]=2[N:40]2[CH2:45][CH2:44][CH:43]([C:46](O)=[O:47])[CH2:42][CH2:41]2)=[O:32])=[C:24]2[N:25]=[CH:26][C:27]([F:29])=[CH:28][N:23]2[N:22]=1.F[B-](F)(F)F.ClC1C=CC2N=NN(OC(=[N+](C)C)N(C)C)C=2C=1>C1COCC1.O>[NH2:20][C:21]1[C:30]([C:31]([NH:33][C:34]2[CH:35]=[N:36][CH:37]=[C:38]([F:49])[C:39]=2[N:40]2[CH2:45][CH2:44][CH:43]([C:46]([N:8]3[CH2:9][CH2:10][N:5]([CH:3]4[CH2:4][O:1][CH2:2]4)[CH2:6][CH2:7]3)=[O:47])[CH2:42][CH2:41]2)=[O:32])=[C:24]2[N:25]=[CH:26][C:27]([F:29])=[CH:28][N:23]2[N:22]=1
Reactant: C1CN(C2COC2)CCN1
Reactant: Nc1nn2cc(F)cnc2c1C(=O)Nc1cncc(F)c1N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: Nc1nn2cc(F)cnc2c1C(=O)Nc1cncc(F)c1N1CCC(C(=O)N2CCN(C3COC3)CC2)CC1
Yield: 86.2 %

Procedure:
To a solution of 1-(oxetan-3-yl)piperazine (525 mg, 3.69 mmol) in THF (12 ml) was added DIPEA (1.72 ml, 9.91 mmol), followed by 1-(3-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)-5-fluoropyridin-4-yl)piperidine-4-carboxylic acid (hydrochloride salt, 1.5 g, 3.3 mmol). [(6-chlorobenzotriazol-1-yl)oxy-(dimethylamino)methylene]-dimethyl-ammonium tetrafluoroborate (TCTU, 1.29 g, 3.64 mmol) was added and the mixture stirred under nitrogen until reaction completion (determined by HPLC analysis). The mixture was cooled and water (24 ml) was added dropwise. The mixture was allowed to warm to ambient and stirred for 3 hrs, then filtered. The filter cake was washed with (3×3 ml). The damp cake was dried under vacuum (with a nitrogen bleed) at 40° C. The product was obtained as a yellow solid (1.54 g, 86%); 1H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.67 (s, 1H), 9.48 (dd, 1H), 9.26 (dd, 1H), 8.26 (d, 1H), 6.79 (s, 2H), 4.55 (t, 2H), 4.47 (t, 2H), 4.34 (t, 0.7H), 3.61 (dt, 4H), 3.48-3.41 (m, 2.5H), 3.22-3.17 (m, 2H), 3.05-3.03 (m, 2H), 3.99-2.93 (m, 1H), 2.28 (dt, 4H), 2.17-2.10 (m, 2H), 1.74 (d, 2H), 1.07 (t, 2H); 19F NMR (500 MHz, DMSO-d6) δ −152.8, −136.1; MS (ES+) 542.3.
Reaction SMILES: [Cl-].[NH4+].C(O)(C)C.[N+:7]([C:10]1[CH:23]=[CH:22][C:13]([C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])=[CH:12][CH:11]=1)([O-])=O>O>[NH2:7][C:10]1[CH:11]=[CH:12][C:13]([C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])=[CH:22][CH:23]=1
Reactant: CCOC(=O)CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: CCOC(=O)CC(=O)c1ccc(N)cc1
Temperature: 5 °C
Yield: 83.1 %

Procedure:
A mixture of 224 g of reduced iron, 13.4 g of ammonium chloride, 1,000 ml of isopropyl alcohol, and 200 ml of water was prepared, and then 237 g of ethyl p-nitrobenzoylacetate was added thereto in small amounts at temperatures ranging between 50° and 70° C. They were reacted at 70° C. for 1 hour and then the reaction solution was filtered. Then, 1,000 ml of water was added to the filtrate and cooled to 5° C., and crystals precipitated were collected by filtration to yield 172 g of yellow ethyl p-aminobenzoylacetate crystals, m.p., 82°-4° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9]1[N:10]=[C:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:12](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1>CCOCC>[C:2]1([NH:1][C:9]2[N:10]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: ClC1=NC(Cl)(c2ccccc2)C(c2ccccc2)=N1
Solvent: CCOCC
Product: c1ccc(NC2=NC(Nc3ccccc3)(c3ccccc3)C(c3ccccc3)=N2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 43.1 %

Procedure:
11.2 g (0.12 mol) of aniline are added dropwise, whilst stirring, to 8.7 g (0.03 mol) of 2,4-dichloro-4,5-diphenyl-4H-imidazole in 150 ml of ether. The mixture was then stirred for 20 hours at room temperature. The precipitate produced was filtered off and dried. After adding methylene chloride, the solution was repeatedly washed with water and then dried over sodium sulphate, and the solvent was distilled off. The oily residue crystallised on addition of a little ether. The product obtained was recrystallised from benzene/petroleum ether. 5.2 g (44% of theory) of 2,4-diphenylamino-4,5-diphenyl-4H-imidazole of melting point 153° - 156° C were obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:71][N:72]([CH3:79])[CH:73]1[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]1>CN1C(=O)CCC1>[CH3:71][N:72]([CH3:79])[CH:73]1[CH2:78][CH2:77][N:76]([C:32]([C:31]2[CH:35]=[CH:36][C:28]([NH:27][C:26]([NH:25][C:22]3[CH:21]=[CH:20][C:19]([C:9]4[N:10]=[C:11]([N:13]5[CH2:18][CH2:17][O:16][CH2:15][CH2:14]5)[N:12]=[C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[N:8]=4)=[CH:24][CH:23]=3)=[O:37])=[CH:29][CH:30]=2)=[O:33])[CH2:75][CH2:74]1
Reactant: CN(C)C1CCNCC1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(C(=O)c2ccc(NC(=O)Nc3ccc(-c4nc(N5CCOCC5)nc(N5CCOCC5)n4)cc3)cc2)CC1
Yield: 50.2 %

Procedure:
To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with N,N-dimethylpiperidin-4-amine (51 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product (30.6 mg, 52% yield); MS (ESI) m/z=616.7
Reaction SMILES: [F:1][C:2]1[C:3]([NH:25][C:26]2[CH:31]=[CH:30][C:29](I)=[CH:28][C:27]=2[F:33])=[C:4]([CH:12]=[C:13]([CH:16]=[N:17][O:18][CH2:19][CH2:20][C:21](=[O:24])[NH:22][CH3:23])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[C:34](C1C=CC(NC2C(F)=C(F)C(C=NOCCO)=CC=2C(NOCCO)=O)=C(F)C=1)#[CH:35].C(C1C=CC(NC2C(F)=C(F)C(/C=N/OCCO)=CC=2C(NOCCO)=O)=C(F)C=1)#C>>[C:34]([C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:3]2[C:2]([F:1])=[C:14]([F:15])[C:13](/[CH:16]=[N:17]/[O:18][CH2:19][CH2:20][C:21](=[O:24])[NH:22][CH3:23])=[CH:12][C:4]=2[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6])=[C:27]([F:33])[CH:28]=1)#[CH:35]
Reactant: CNC(=O)CCON=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: C#Cc1ccc(Nc2c(C(=O)NOCCO)cc(C=NOCCO)c(F)c2F)c(F)c1
Agent: C#Cc1ccc(Nc2c(C(=O)NOCCO)cc(/C=N/OCCO)c(F)c2F)c(F)c1
Product: C#Cc1ccc(Nc2c(C(=O)NOCCO)cc(/C=N/OCCC(=O)NC)c(F)c2F)c(F)c1

Procedure:
This compound was synthesized from 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylcarbamoyl-ethoxyimino)-methyl]-benzamide (Example 14, Compound 14), and the actual reaction was carried out according to the method for manufacturing 2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyimino)-methyl]-benzamide (Example 2, Compound 2).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[CH:10]=2)=[CH:6][CH:5]=[C:4]([N+:28]([O-])=O)[N:3]=1>CO.[Pd]>[CH3:1][C:2]1[N:3]=[C:4]([NH2:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:10]=1
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(-c2ccc(C3CCN(C)CC3)cc2)c1
Agent: [Pd]
Solvent: CO
Product: Cc1nc(N)ccc1Oc1ccnc(-c2ccc(C3CCN(C)CC3)cc2)c1
Yield: 87.1 %

Procedure:
A solution of 2-methyl-3-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)-6-nitropyridine (0.553 g, 1.367 mmol) in MeOH (20 mL) was treated with 10% Pd/C (50% wet, 0.146 g, 0.137 mmol) and hydrogenated (1 atm) overnight. The solids were removed via filtration, washed with MeOH and the filtrate was concentrated to dryness to afford 6-methyl-5-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-amine (446 mg, 87%). MS (ESI) m/z: 375.2 (M+H+).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11]([N:27]4[CH2:26][CH2:25][NH:24][CH:23]([CH3:22])[CH2:28]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC1CNCCN1
Solvent: CC#N
Product: Cc1c(F)c(N2CCNC(C)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 74.9 %

Procedure:
A suspension of 0.80 g (2.69 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 1.08 g (10.8 mmol) of 2-methylpiperazine, and 20 mL of acetonitrile was refluxed for 3 hours, then cooled in an ice bath. The precipitate was collected, washed with water and acetonitrile, and dried in vacuo to give 0.76 g of the title compound, mp 187°-188° C.
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:30]([O:32][C:33](=[O:62])[CH:34]([C:55]1[CH:56]=[C:57]([CH3:61])[CH:58]=[CH:59][CH:60]=1)[CH2:35][C:36]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][C:44](Br)=[CH:43][CH:42]=2)[N:38]([C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=2)[N:37]=1)[CH3:31].[CH2:63]([NH2:66])[CH:64]=[CH2:65]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH2:30]([O:32][C:33](=[O:62])[CH:34]([C:55]1[CH:56]=[C:57]([CH3:61])[CH:58]=[CH:59][CH:60]=1)[CH2:35][C:36]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][C:44]([NH:66][CH2:63][CH:64]=[CH2:65])=[CH:43][CH:42]=2)[N:38]([C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=2)[N:37]=1)[CH3:31]
Reactant: C=CCN
Reactant: CCOC(=O)C(Cc1cc(-c2ccc(Br)cc2)n(-c2ccc(C)cc2)n1)c1cccc(C)c1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCNc1ccc(-c2cc(CC(C(=O)OCC)c3cccc(C)c3)nn2-c2ccc(C)cc2)cc1
Temperature: 110 °C
Reaction time: 12 h
Yield: 46.9 %

Procedure:
To a mixture of Pd2(dibenzylideneacetone)3 (4 mg, 0.004 mmol, 1 mol %), 2-(di-tert-butylphosphino)biphenyl (6 mg, 0.02 mmol, 5 mol %) and K3PO4 (130 mg, 0.61 mmol, 1.5 equiv) was added a solution of 3-[5-(4-bromo-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid ethyl ester (Example 77, Step C; 200 mg, 0.4 mmol) in toluene (0.6 mL) followed by allylamine (0.030 mL, 0.48 mmol, 1.2 equiv). The resulting mixture was stirred at 110° C. for 12 h and then cooled to room temperature. Ethyl acetate (2 mL) and water (3 mL) were added, and the resulting aqueous layer was back-extracted with EtOAc (3×2 mL). The combined organic layers were washed with brine (3 mL), and then dried (MgSO4). The solvent was evaporated under reduced pressure, and the residue was purified by chromatography (silica gel, 25% ethyl acetate/hexanes) to afford the desired compound (90 mg, 47%). HPLC: Rt=3.19 (Method B). MS (ESI): mass calculated for C31H33N3O2, 479.26; m/z found, 480.3 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.29 (s, 1H), 7.27-7.04 (m, 7H), 6.96 (d, J=8.5 Hz, 2H), 6.49 (d, J=8.5 Hz, 2H), 6.07 (s, 1H), 5.96-5.89 (m, 1H), 5.29-5.25 (m, 1H), 5.18-5.16 (m, 1H), 4.20-4.14 (m, 1H), 4.10-4.02 (m, 2H), 3.76-3.75 (m, 2H), 3.52-3.45 (m, 1H), 3.08 (dd, J=14.5, 6.0 Hz, 1H), 2.34 (s, 6H), 1.19 (t, J=7.1 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10](Cl)(=[O:12])=[O:11])=[C:5]([CH3:14])[C:4]=1[CH3:15].[CH3:16][NH:17][CH2:18][CH2:19][C:20]#[N:21].C(N(CC)CC)C.C(OCC)(=O)C>C1COCC1>[C:20]([CH2:19][CH2:18][N:17]([CH3:16])[S:10]([C:6]1[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:15])[C:5]=1[CH3:14])(=[O:12])=[O:11])#[N:21]
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Reactant: CNCCC#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(C)c(S(=O)(=O)N(C)CCC#N)c(C)c1C
Reaction time: 16 h

Procedure:
4-Methoxy-2,3,6-trimethylbenzenesulfonyl chloride (5.00 g, 20 mmol) was added at room temperature to a solution of 3-methylaminopropionitrile (1.50 g, 18.3 mmol) and triethylamine (5.50 g, 55 mmol) in THF (30 ml), and stirring was carried out for 16 h. Ethyl acetate (50 ml) was then added to the reaction mixture, and washing with sodium hydrogen carbonate solution (3×50 ml) was carried out. The organic phase was dried over sodium sulfate and concentrated in vacuo.