Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2][NH2:3].C(#N)C.[C:10]1([CH2:16][C:17](Cl)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O>[C:10]1([CH2:16][C:17]([NH:3][NH:2][C:1]([O:5][CH3:6])=[O:4])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)NN
Reactant: O=C(Cl)Cc1ccccc1
Solvent: O
Solvent: CC#N
Product: COC(=O)NNC(=O)Cc1ccccc1
Reaction time: 15 h
Yield: 76.1 %

Procedure:
To a solution of 90.1 g. (1.0 mole) of methyl carbazate and 500 ml. of acetonitrile 154.6 g. (1.0 mole) of phenyl acetyl chloride are added. The reaction mixture is heated to boiling for 15 hours and clarified. The residual oil is poured into 500 ml. of water, whereby the oil soon solidifies. Thus 158.4 g. of the white desired compound are obtained, yield 76.1%, m.p.: 94°-95° C.
Reaction SMILES: I[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>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.C1(C)C=CC=CC=1>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:2]3[C:3]4[C:8]([C:9]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[C:10]5[C:15]=3[CH:14]=[CH:13][CH:12]=[CH:11]5)=[CH:7][CH:6]=[CH:5][CH:4]=4)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(-c2ccc(Br)cc2)cc1
Reactant: Ic1c2ccccc2c(-c2ccccc2)c2ccccc12
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: Cc1ccccc1
Product: Brc1ccc(-c2ccc(-c3c4ccccc4c(-c4ccccc4)c4ccccc34)cc2)cc1
Yield: 45 %

Procedure:
1.0 g (2.63 mmol) of 9-iodo-10-phenylanthracene, 542 mg (2.70 mmol) of 4-(4-bromophenyl)phenylboronic acid, 46 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium, 3 mL (6 mmol) of potassium carbonate solution (2.0 mol/L), and 10 mL of toluene were stirred for 9 hours at 80° C. After reaction, toluene was added, and it was filtered through florisil®, celite, and alumina. The filtrate was washed with water and saturated saline, and then dried with magnesium sulfate. After natural filtering, the filtrate was concentrated, and when recrystallization was performed with a mixture of chloroform and hexane, 562 mg of 9-[4-(4-bromophenyl)phenyl]-10-phenylanthracene (PBA) that was a target substance and was a light brown solid was obtained in a yield of 45% (Synthesis Scheme (e-2)).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9].N1C=CC=CC=1.[O:18](S(C(F)(F)F)(=O)=O)[S:19]([C:22]([F:25])([F:24])[F:23])(=O)=[O:20]>ClCCl>[CH3:7][C:5]1[S:4][C:3]([C:8]([O:10][CH3:11])=[O:9])=[C:2]([O:1][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:20])=[O:18])[CH:6]=1
Reactant: COC(=O)c1sc(C)cc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1sc(C)cc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C

Procedure:
Into a 100-mL round-bottom flask, was placed methyl 3-hydroxy-5-methylthiophene-2-carboxylate (1.04 g, 5.74 mmol), dichloromethane (7 mL), pyridine (1.44 mL, 17.81 mmol). This was followed by the addition of Tf2O (1.45 mL, 8.61 mmol) dropwise with stirring at 0° C. The resulting solution was stirred for 2.0 h at 0° C. in a water/ice bath. The reaction progress was monitored by GCMS. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×15 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×20 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:9). This resulted in 1.74 g (99%) of methyl 5-methyl-3-(((trifluoro methyl)sulfonyl)oxy)thiophene-2-carboxylate as yellow oil.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:21]([O:22]CC2C=CC(OC)=CC=2)[C@:20]([CH3:33])([OH:32])[C@@H:19]([CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[O:18][C@H:10]1[O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(Cl)Cl.O>[CH2:1]([O:8][C@@H:9]1[C@@H:21]([OH:22])[C@:20]([CH3:33])([OH:32])[C@@H:19]([CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[O:18][C@H:10]1[O:11][CH2:12][CH2:13][Si:14]([CH3:15])([CH3:17])[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CO[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCC[Si](C)(C)C)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@]2(C)O)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](OCC[Si](C)(C)C)[C@H](OCc2ccccc2)[C@@H](O)[C@]1(C)O
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To a stirred solution of 5.08 (7.2 g, 11.6 mmol) in CH2Cl2 (137 mL) and H2O (8 mL) at 0° C. was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (3.4 g, 15.0 mmol). The reaction mixture was stirred for 1 h then diluted with CH2Cl2 and sequentially washed with saturated aqueous NaHCO3, H2O, and brine. After concentration of the organic phase in vacuo, the crude residue was purified by silica gel chromatography (25% EtOAc/petroleum ether) to afford the title compound (4.5 g, 9.0 mmol, 78%). 1H NMR (500 MHz, CDCl3): δ ppm 7.39-7.32 (m, 4H, PhH), 7.29 (t, J=6.8 Hz, 1H, PhH), 4.95, 4.68 (ABq, J=11.2 Hz, 1H each, OCH2Ph), 4.42 (d, J=7.8 Hz, 1H, H-1), 4.01-3.94 (m, 1H, OCHHCH2SiMe3), 3.90-3.80 (m, 2H, H-6), 3.60 (d, J=9.8 Hz, 1H, H-3), 3.60-3.54 (m, 1H, OCHHCH2SiMe3), 3.51 (br s, 1H, OH), 3.41 (t, J=6.8 Hz, 1H, H-5), 3.16 (dd, J=9.8, 7.8 Hz, 1H, H-3), 2.48 (br s, 1H, OH), 1.25 (s, 3H, Me), 1.05-0.99 (m, 2H, OCH2CH2SiMe3), 0.90 (s, 9H, SiCMe3), 0.11, 0.11 (s, 3H each, SiME2), 0.02 (s, 9H, SiMe3); 13C NMR (125 MHz, CDCl3): δ ppm 138.73, 128.56, 128.03, 127.86, 103.70, 80.62, 78.29, 75.77, 74.63, 73.80, 67.81, 62.57, 25.91, 18.68, 18.21, 15.31, −1.31, −5.39, −5.52; HRMS calcd for C25HSONO6Si2 [M+NH4]+: 516.3177. found 516.3165.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]([F:31])([F:30])[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[CH:25]=O)[N:18]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[O:40][CH:41]=[C:42]([C:44]([CH3:48])([CH3:47])[CH2:45][NH2:46])[N:43]=2)=[CH:35][CH:34]=1>ClCCCl>[F:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]2[O:40][CH:41]=[C:42]([C:44]([CH3:48])([CH3:47])[CH2:45][NH:46][CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([C:19]4[N:18]=[C:17]([C:16]([F:31])([F:30])[F:15])[O:21][N:20]=4)[CH:23]=3)[N:43]=2)=[CH:37][CH:38]=1
Reactant: O=Cc1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(CNCc1cccc(-c2noc(C(F)(F)F)n2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 17.5 %

Procedure:
Sodiumtriacetoxy borohydride (197 mg, 0.9 mmol) was added to a solution of 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzaldehyde (150 mg, 0.62 mmol) and 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine (150 mg, 0.64 mmol) in dry DCE (2 mL) at 0° C. under nitrogen atmosphere and stirred at room temperature for 8 h (monitored by TLC, petroleum ether/EtOAc 6:4). Reaction mixture was carefully quenched with 10% NaHCO3 solution and the organic product was extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous Na2SO, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 10-15% EtOAc in petroleum ether) to get 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methyl-N-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)propan-1-amine (50 mg, yield 18%). 1H NMR (400 MHz, MeOD) δ 8.01 (m, 2H), 7.96-7.92 (m, 3H), 7.67 (s, 1H), 7.54-7.52 (m, 1H), 7.49-7.45 (m, 1H), 7.20-7.15 (m, 1H), 3.82 (s, 2H), 2.76 (s, 2H), 1.32 (s, 6H). MS (ESI) m/z: Calculated for C23H20F4N4O2: 460.15. found: 461.2 (M+H)+.
Reaction SMILES: C(O[C:4]([C:6]1[CH:10]=[N:9][N:8]2[CH2:11][CH2:12][NH:13][C:7]=12)=O)C.[H-].COCCO[Al+]OCCOC.[Na+].[H-].O1CCCC1>C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1>[CH3:4][C:6]1[CH:10]=[N:9][N:8]2[CH2:11][CH2:12][NH:13][C:7]=12
Reactant: CCOC(=O)c1cnn2c1NCC2
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: Cc1cnn2c1NCC2
Temperature: 25 °C
Yield: 60 %

Procedure:
To a solution of 2,3-dihydro-7-ethoxycarbonyl-1H-imidazo[1,2-b]pyrazole (5 g) in xylene (27 ml) was added dropwise 3.4M solution (27 ml) of sodium bis(2-methoxyethoxy)aluminum hydride in toluene under ice-cooling. The mixture was stirred at room temperature and then stirred at 140° C. for 3.5 hours. The reaction mixture was cooled at 5° C. and poured into a mixture of ice-water (100 ml) and tetrahydrofuran (100 ml). The insoluble material was filtered off and the filtrate was separated. The aqueous layer was extracted with tetrahydrofuran. The organic layer and extract were combined and dried over magnesium sulfate. The solvent was evaporated to give 2,3-dihydro-7-methyl-1H-imidazo[1,2-b]pyrazole (2.04 g).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Li]CCCC.[I:27]I.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[I:27][C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: II
Reactant: Brc1c2ccccc2c(-c2ccccc2)c2ccccc12
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Ic1c2ccccc2c(-c2ccccc2)c2ccccc12
Reaction time: 1 h
Yield: 83 %

Procedure:
3.33 g (10 mmol) of 9-bromo-10-phenylanthracene was dissolved in 80 ml of tetrahydrofuran (abbreviation: THF), and the temperature was lowered to −78° C. 7.5 ml (12.0 mmol) of n-BuLi (1.6M) was dropped into the reaction solution by a dropping funnel, and it was stirred for 1 hour. A solution in which 5 g (20.0 mmol) of iodine was dissolved in 20 ml of THF was dropped and stirred for 2 hours at −78° C. After reaction, a sodium thiosulfate water solution was added to stop the reaction. An organic layer was washed with a sodium thiosulfate water solution and a saturated saline and dried with magnesium sulfate. After the natural filtration, the filtrate was concentrated and the obtained solid was recrystallized by ethanol. Then, 3.1 g of a light-yellow solid of 9-iodo-10-phenylanthracene, which was the intended object, was obtained with a yield of 83% (synthetic scheme of (b-5)).
Reaction SMILES: [CH2:1]([CH:3]1[NH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[N:5]2[CH:14]=[CH:15][CH:16]=[C:4]12)[CH3:2].[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>>[CH2:1]([CH:3]1[N:12]([C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[N:5]2[CH:14]=[CH:15][CH:16]=[C:4]12)[CH3:2]
Reactant: CCC1Nc2cc(F)ccc2-n2cccc21
Reactant: COc1ccc(C(=O)Cl)cc1
Product: CCC1c2cccn2-c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1

Procedure:
4-Ethyl-7-fluoro-5-(4-methoxybenzoyl)-4,5-dihydropyrrolo[1,2-a]quinoxaline was prepared from the product of Example 17 and p-anisoyl chloride according to the procedure of Example 106, Step 2, mp 39-42° C. MS (ESI) m/z 351; Anal. Calcd for C21H19FN2O2: C, 71.99; H, 5.47; N, 7.99. Found: C, 70.90; H, 5.62; N, 7.65.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[S:6][C:7]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(OCC)(OCC)OCC.C([BH3-])#N.[N-]=C=O>COCCOC.CN(C)C(=O)C.C(O)(=O)C>[NH2:1][C:2]([NH:4][C:5]1[S:6][C:7]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][N:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)=[CH:17][CH:18]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: NC(=O)Nc1sc(-c2ccc(C=O)cc2)cc1C(N)=O
Reactant: CN1CCNCC1
Agent: [BH3-]C#N
Agent: [N-]=C=O
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: CN1CCN(Cc2ccc(-c3cc(C(N)=O)c(NC(N)=O)s3)cc2)CC1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 12.4 %

Procedure:
2-[(Aminocarbonyl)amino]-5-(4-formylphenyl)-3-thiophenecarboxamide (100 mg) was stirred in a mixture of 1,2-dimethoxyethane (10 ml) and N,N-dimethylacetamide (5 ml). 1-Methyl piperazine (0.16 g) was added, followed by triethyl orthoformate (5 ml) and acetic acid (0.5 ml). The reaction was stirred at 80° C. for 20 minutes, and then polymer-supported cyanoborohydride (0.45 g) was added. The reaction was stirred at 80° C. for a further 2 h, and then polymer-supported isocyanate (0.5 g) was added. The resins were removed by filtration, and the filtrate was then passed through a 5 g SCX column, washing with methanol (25 ml). The product was eluted using 1M methanolic ammonia (45 ml), and this solution was then evaporated to dryness under reduced pressure and the residue purified by chromatography on silica, eluting with dichloromethane/methanol (9:1), to give the product as an off-white solid (16 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1>COC(C)(C)C>[Br:15][C:11]1[CH:10]=[C:9]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:14]=[CH:13][CH:12]=1
Reactant: Brc1cccc(Br)c1
Reactant: CN1CCNCC1
Solvent: COC(C)(C)C
Product: CN1CCN(c2cccc(Br)c2)CC1

Procedure:
1-Methyl-piperazine (1 ml, 8.99 mmol) and 1,3-dibromo-benzene (3 ml, 24.82 mmol) are heated to 200° C. in a sealed tube under microwave irradiation for 300 min (150 W, 9 bar). The residue is diluted with tert-butyl methyl ether (50 ml) and extracted with 1M HCl. The aqueous layer is neutralized with sodium bicarbonate, and extracted with ethyl acetate (150 ml). The organic layer is separated and dried over MgSO4. The drying agent is filtered and the solvent is removed in vacuum; yield: 700 mg 1-(3-bromo-phenyl)-4-methyl-piperazine; HPLC/MS: 1.24 min, [M+H]=255.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[OH:21])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>>[N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCCCCCC(O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(CCCCCNc1c([N+](=O)[O-])cnc2ccccc12)c1ccccc1
Yield: 56.8 %

Procedure:
By the general method described in Step 6 of Example 1, 6-(3-nitroquinolin-4-ylamino)-1-phenylhexan-1-ol (4.0 g, 11 mmol) was oxidized with DMSO (1.28 g, 16.4 mmol), oxalyl chloride (1.53 g, 12.0 mmol), and triethylamine (3.32 g, 32.8 mmol) to provide 6-(3-nitroquinolin-4-ylamino)-1-phenylhexan-1-one (2.27 g) as light orange crystals after recrystallization from ethyl acetate.
Reaction SMILES: CO[C:3](=[O:14])[CH2:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:7].[CH3:15][NH2:16].[K+].[Br-]>C(O)C>[CH3:15][NH:16][C:3]([CH2:4][NH:5][C:6](=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][CH:9]=1)=[O:14]
Reactant: COC(=O)CNC(=O)c1cccnc1
Reactant: CN
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Product: CNC(=O)CNC(=O)c1cccnc1
Temperature: 55 °C

Procedure:
A suspension of [(pyridine-3-carbonyl)-amino]-acetic acid methyl ester (1.5 g, 7.7 mmol) and methylamine (33 wt % in absolute ethanol, 3.86 mL, 38.6 mmol) in ethanol (8 mL) was heated at 55° C. in a Parr reactor for 6 h. The mixture was cooled and then concentrated under reduced pressure to yield the product as a iridescent beige plates (1.41 g, 94%): 1H NMR (300 MHz, DMSO-d6) δ 9.05 (d, J=2.2 Hz, 1H), 9.00 (t, J=5.8 Hz, 1H), 8.77 (d, J=4.0 Hz, 1H), 8.23 (br d, J=8.1 Hz, 1H), 7.90 (q, J=4.1 Hz, 1H), 7.53 (dd, J=7.7, 4.7 Hz, 1H), 3.86 (d, J=5.8 Hz, 2H), 2.61 (d, J=4.4 Hz, 3H); IR (KBr) 3314, 1641 cm−1; ESIMS m/z 194 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[NH:8][C:7](=O)[N:6]=[CH:5]2.O.O=P(Cl)(Cl)[Cl:18]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[N:8]=[C:7]([Cl:18])[N:6]=[CH:5]2
Reactant: COc1cc(Br)cc2cnc(=O)[nH]c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1cc(Br)cc2cnc(Cl)nc12

Procedure:
6-bromo-8-methoxy-1H-quinazolin-2-one (2.62 g, 10.27 mmol) is suspended in 30 mL POCl3 and refluxed for 30 min. The reaction mixture is stirred into water, while the temperature never exceeds 15° C. The aqueous phase is extracted with DCM, the organic phase is dried and 6-bromo-2-chloro-8-methoxy-quinazoline (HPLC-MS: tRet.=1.88 min, MS(M+H)+=273/275/277; method FSUN) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12](OS(C(F)(F)F)(=O)=O)=[C:11]([CH:23]=[O:24])[CH:10]=1.[CH:25]1(B(O)O)[CH2:27][CH2:26]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Br-].[Na+]>O.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:25]2[CH2:27][CH2:26]2)=[C:11]([CH:23]=[O:24])[CH:10]=1
Reactant: O=Cc1cc(-c2ccc(Cl)cc2Cl)ccc1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1cc(-c2ccc(Cl)cc2Cl)ccc1C1CC1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
To a mixture of trifluoromethanesulfonic acid 2′,4′-dichloro-3-formylbiphenyl-4-yl ester (30.0 g, 0.075 mol), cyclopropyl boronic acid (8.50 g, 0.097 mol), potassium phosphate (56.30 g, 0.27 mol) and sodium bromide (7.7 g, 0.075 mol) is added toluene (300 ml) then distilled water (30 ml) under a nitrogen atmosphere. To this mixture is then added tetrakis(triphenylphosphine) palladium (9.30 g, 0.0081 mol) in one portion, and the mixture is then heated at 100° C. overnight. After cooling to room temperature the mixture is diluted with distilled water (500 ml) and ethyl acetate (500 ml), and the two layers are separated. The aqueous phase is extracted again with ethyl acetate (2×500 ml), then all organic fractions are combined, then washed with distilled water (1L) then brine (1L). After drying over magnesium sulfate the suspension is filtered and the filtrate is concentrated in vacuo. The crude product is purified by flash column chromatography on silica gel (2-10% ethyl acetate in hexanes as eluant), then additionally by flash column chromatography on basic alumina (10% ethyl acetate in hexane as eluant) to afford 2′,4′-dichloro-4-cyclopropylbiphenyl-3-carbaldehyde (11.7 g, 54%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[N:5]=[CH:4][C:3]=1[C:14]([NH2:16])=[O:15].[CH3:17][CH:18]1[CH2:23][CH2:22][CH:21]([CH2:24][C:25](O)=O)[CH2:20][CH2:19]1.C[Si](OP(=O)=O)(C)C>O>[CH3:17][CH:18]1[CH2:23][CH2:22][CH:21]([CH2:24][C:25]2[NH:16][C:14](=[O:15])[C:3]3[CH:4]=[N:5][N:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[CH3:13])[C:2]=3[N:1]=2)[CH2:20][CH2:19]1
Reactant: Cc1ccccc1-n1ncc(C(N)=O)c1N
Reactant: CC1CCC(CC(=O)O)CC1
Agent: C[Si](C)(C)OP(=O)=O
Solvent: O
Product: Cc1ccccc1-n1ncc2c(=O)[nH]c(CC3CCC(C)CC3)nc21
Temperature: 130 °C
Reaction time: 3 h

Procedure:
150 mg (0.69 mmol) of 5-amino-1-(2-methylphenyl)-1H-pyrazole-4-carboxamide (Example 23A) and 130 mg (0.83 mmol) of 2-(4-methylcyclohexyl)acetic acid are mixed with 0.3 ml of trimethylsilyl polyphosphate and stirred at 130° C. for 3 h. The hot reaction mixture is added to 20 ml of water and then extracted with dichloromethane (2×20 ml). The combined organic phases are washed with water (20 ml) and with saturated sodium chloride solution (20 ml) and dried over sodium sulphate. The solvent is distilled off under reduced pressure, and the crude product is purified by preparative HPLC (YMC Gel ODS-AQ S 5/15 μm; eluent. A: water, eluent B: acetonitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95% B). 182 g (78% of theory) of the product are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16](OS(C(F)(F)F)(=O)=O)[C:17]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[NH2:39][CH2:40][CH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>CN(C=O)C>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:39][CH2:40][CH:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[C:17]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(OS(=O)(=O)C(F)(F)F)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Reactant: NCC1CCOCC1
Solvent: CN(C)C=O
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(NCC4CCOCC4)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
tert-Butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (250 mg, 0.45 mmol, example 69c) was dissolved in DMF (2 mL). 4-Aminomethyltetrahydropyran (51.9 mg, 0.45 mmol) was added and the reaction mixture was stirred at 85° C. overnight. The reaction was allowed to reach room temperature and the solvent was evaporated under reduced pressure. The crude was purified by flash column chromatography using dichloromethane and methanol as eluent yielding tert-butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-((tetrahydro-2H-pyran-4-yl)methylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (62.0 mg, 26.5%). MS (ES+) m/z 520.4 (M+H)+
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:13])[CH2:11][CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:13])[CH2:11][CH3:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CCC(=O)c1ccc2c(c1)CCO2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CCC(=O)c1ccc2occc2c1
Yield: 26 %

Procedure:
A solution of 1-(2,3-dihydrobenzofuran-5-yl)propan-1-one (40 g, 1.0 eq) and 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (62 g, 1.2 eq) in 400 mL anhydrous 1,4-dioxane was refluxed overnight, cooled, quenched with sat NaHCO3 (aq), and extracted with EtOAc. The extract was washed with brine, dried, concentrated, and purified by column chromatography to give the desired product (10.3 g, 26%). 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J=2.0 Hz, 1H), 7.98 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 6.86 (d, J=2.0 Hz, 1H), 3.07 (q, J=7.2 Hz, 2H), 1.26 (t, J=7.2 Hz, 3H).