Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([O:9][C:10]([CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:22])[CH:18]=2)[CH2:13]1)=[O:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].FC(F)(F)[C@H:25]([OH:32])CCCCCC.[CH2:35]([C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[CH:55][C:54](C(O)=O)=[CH:53][CH:52]=2)=[CH:47][CH:46]=1)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:1][C@@H:2]([O:9][C:10]([CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][C:25]([C:56]3[C:51]([C:48]4[CH:49]=[CH:50][C:45]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:46][CH:47]=4)=[CH:52][CH:53]=[CH:54][CH:55]=3)=[O:32])[CH:18]=2)[CH2:13]1)=[O:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCCCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: CCCCCC[C@@H](O)C(F)(F)F
Reactant: CCCCCC[C@@H](C)OC(=O)C1CCc2cc(O)ccc2C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCc1ccc(-c2ccccc2C(=O)Oc2ccc3c(c2)CCC(C(=O)O[C@H](C)CCCCCC)C3)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 0.37 g (1.1 mmol) of 1,2,3,4-tetrahydro-6-hydroxynaphthalene-2-carboxylic acid (R)-1-methylheptyl ester obtained as in the fourth stage of Example 23 where (R)-1-methyl heputanol was used in stead of (R)-1-trifluoromethylheptanol, 0.33 g (1.1 mmol) of 4'-decylbiphenyl-4-carboxylic acid (FK-1124-10 from Teikoku Kagaku Sangyo K.K.), 0.013 g (0.11 mmol) of 4-N,N-dimethylaminopyridine and 10 ml of methylene chloride was added dropwise 5 ml of a methylene chloride solution containing 0.27 g (1.3 mmol) of N,N'-dicyclohexylcarbodiimide with stirring at room temperature over a period of 2.5 hours.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>>[F:1][C:2]1[C:10]([N+:18]([O-:20])=[O:19])=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(F)c(F)c([N+](=O)[O-])c1F
Temperature: 70 °C

Procedure:
3.5 g 0.02 mol of 2,4,5-trifluorobenzoic acid are introduced into a mixture of 6.8 ml of concentrated sulphuric acid and 8 ml of 98% strength nitric acid at 5°-10° C., and the mixture is then stirred without cooling. The temperature increases to 70° C. The mixture is heated for 5 hours at 80°-90° C., a further 8 ml of 98% strength nitric acid are added, and the mixture is heated at 80° C. for 2 hours. The mixture is then introduced into 100 ml of ice water, extracted thoroughly with dichloromethane, dried using sodium sulphate and concentrated. The oil remaining crystallizes. It is stirred with light petroleum, and the solid product is filtered off under suction and dried.
Reaction SMILES: C1(C)C=C[C:4]([S:7]([OH:10])(=[O:9])=[O:8])=CC=1.[C:12]([C:15]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(O)=O.B.CO.Cl>C1COCC1.CCOCC>[CH3:4][S:7]([OH:10])(=[O:9])=[O:8].[C:21]1([C:15]23[CH2:12][N:18]([CH2:19][CH2:20]2)[CH2:17][CH2:16]3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: B
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)O
Product: c1ccc(C23CCN(CC2)C3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 151.8 %

Procedure:
A mixture of 10.25 g of 4-carboxy-4-phenyl piperidine p-toluenesulfonate and 150 ml of a 1M solution of borane in THF is refluxed for 1 hour. 30 ml of MeOH are added under the action of heat and over 20 minutes, then after cooling to RT, a saturated solution of gaseous HCl in ether is added until the pH is 1 and the reaction mixture is left under stirring overnight at RT. The solvents are concentrated under vacum, the residue is taken up with acetone and then with ether to give 11,1 g of the expected product, M.p.=263° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH3:35][N:36]([CH3:45])[C:37]1[CH:42]=[CH:41][C:40]([CH2:43][NH2:44])=[CH:39][CH:38]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:27]([NH:44][CH2:43][C:40]2[CH:41]=[CH:42][C:37]([N:36]([CH3:45])[CH3:35])=[CH:38][CH:39]=2)=[O:33])=[CH:20][CH:21]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN(C)c1ccc(CN)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)NCc4ccc(N(C)C)cc4)cc3)c2cc1OC
Yield: 14.8 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (51 mg) was dissolved in toluene (5 ml) with heat, after the addition of triethylamine (1 ml), triphosgene (55 mg) was added, and the admixture was refluxed with heat for 2 minutes. (4-Dimethylaminophenyl)methylamine (104 mg) was added to the reaction mixture, and the admixture was refluxed with heat for 12 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 12 mg of the title compound (yield: 15%).
Reaction SMILES: [CH2:1]([C:3]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:24]([O:34]CC2C=CC=CC=2)=[CH:23][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])[CH3:2].[OH-].[Na+]>C(O)C.Cl>[CH2:1]([C:3]1[CH:26]=[C:25]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[C:24]([OH:34])=[CH:23][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH3:2]
Reactant: CCOC(=O)CCc1ccccc1OCCCOc1cc(OCc2ccccc2)c(-c2ccc(F)cc2)cc1CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(-c2ccc(F)cc2)c(O)cc1OCCCOc1ccccc1CCC(=O)O
Reaction time: 16 h
Yield: 93 %

Procedure:
A solution of 375 mg of ethyl 3-(2-(3-(2-ethyl-4-(4-fluorophenyl)-5-benzyloxyphenoxy)propoxy)phenyl)propionate in 25 ml of ethanol was mixed with 5 ml of 5.0N sodium hydroxide and stirred 16 hours. The mixture was diluted with 1.0N hydrochloric acid and extracted with 3:1 dichloromethane/isopropanol. The organic phase was washed with saturated sodium chloride, dried over sodium sulfate, and evaporated in vacuo providing the desired 3-(2-(3-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy)propoxy)phenyl)propionic acid in 93% yield. NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.ClC(OCC)=O.[CH2:24]([N:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[CH2:31][NH2:32])[CH3:25]>CC(C)=O>[CH2:24]([N:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[CH2:31][NH:32][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])[C:10]([NH2:12])=[CH:11][C:3]=1[O:2][CH3:1])[CH3:25]
Reactant: CCS(=O)(=O)c1cc(C(=O)O)c(OC)cc1N
Reactant: CCN1CCC[C@H]1CN
Agent: CCOC(=O)Cl
Solvent: CC(C)=O
Product: CCN1CCC[C@H]1CNC(=O)c1cc(S(=O)(=O)CC)c(N)cc1OC
Yield: 84.9 %

Procedure:
95 g of 2-methoxy-4-amino-5-ethylsulphonylbenzoic acid dissolved in 370 ml of acetone, in the presence of 37 g of trielthylamine, is treated with 40 g of ethyl chloroformate with 57 g of (S)-(−)-1-ethyl-2-aminomethylpyrrolidine. 115 g of (S)-(−)-N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-amino-5-ethylsulphonylbenzamide is obtained (yield=84%).
Reaction SMILES: [H-].[Na+].[N:3]1[C:11]([NH2:12])=[C:10]2[C:6]([N:7]=[CH:8][NH:9]2)=[N:5][CH:4]=1.Cl[CH2:14][O:15][CH2:16][O:17][CH2:18][P:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22].C([O:28]P([O-])(OCC)=O)C.ClCOCOCCl>CN(C=O)C>[CH2:21]([O:20][P:19]([CH2:18][O:17][CH2:16][O:15][CH2:14][N:7]1[CH:8]=[N:9][C:10]2[C:6]1=[N:5][CH:4]=[N:3][C:11]=2[NH2:12])([O:23][CH2:24][CH3:25])=[O:28])[CH3:22]
Reactant: CCOP(=O)([O-])OCC
Reactant: CCOP(COCOCCl)OCC
Reactant: Nc1ncnc2nc[nH]c12
Agent: ClCOCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOP(=O)(COCOCn1cnc2c(N)ncnc21)OCC
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a suspension of 60% sodium hydride in mineral oil (1.4 g, 34.5 mmol) in DMF (100 mL) was added adenine (4.7 g, 34.5 mmol) and the mixture was stirred at 80° C. for 1 hr. To the resulting yellow solution was added dropwise a solution of chloromethoxy(diethoxyphosphinomethoxy)methane [(prepared from diethylphosphate (4.4 mL, 34.5 mmol) and bis(chloromethoxy)methane (25 g, 172 mmol)] in DMF (20 mL) under nitrogen. After stirring at 25° C. for 15 hr, volatiles were removed in vacuo, and the resulting oily residue was purified by silica gel column chromatography using CH2Cl2 /10% MeOH as eluent to obtain the title compound as a colorless oil: yield 6.0 g (50%).
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].[H-].[Na+].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24]Cl>O>[F:6][C:7]1[CH:14]=[C:13]([O:15][CH2:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=2)[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: O=Cc1ccc(O)cc1F
Reactant: ClCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
To an N,N-dimethylformamide (10.0 mL) solution of 2-fluoro-4-hydroxy-benzaldehyde (1.60 g, 11.4 mmol) was added sodium hydride (547 mg, 13.7 mmol, 60% in oil) under nitrogen atmosphere at 0° C., which was stirred for 30 minutes at room temperature. 2-Picolyl chloride (2.80 g, 17.1 mmol) was then added at room temperature and stirred for 1 hour at 70° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:3) to obtain the title compound (1.07 g, 40.6%).
Reaction SMILES: [O:1]=[C:2]([Cl:8])[O:3][C:4](Cl)(Cl)Cl.[Cl:9][CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])CO.CCN(CC)CC>C1COCC1>[Cl:9][CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])[CH2:4][O:3][C:2]([Cl:8])=[O:1]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1ccccc1C(Cl)CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cl)OCC(Cl)c1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
A solution of diphosgene (1.7 ml, 14 mmol) in THF (10 ml, dist. over CaH2) was cooled by means of an ice bath to about 0° C. A solution of 2-chloro-2-(2-nitrophenyl)ethanol (705 mg, 3.5 mmol) and Et3N (354 mg, 0.485 ml, 3.5 mmol) in THF (10 ml, dist. over CaH2) was dropped thereto for about 30 min. After the solution had been stirred for a further hour, the ice bath was removed. The mixture was stirred for another 3 h at room temperature. The mixture was filtered over Celite. The precipitate was rewashed with THF (10 ml, dist. over CaH2). The combined filtrates were concentrated under reduced pressure and then dried in a high vacuum at room temperature. 2-chloro-2-(2-nitrophenyl)ethoxycarbonyl chloride (896 mg, 97%) was obtained as a light brown oil.
Reaction SMILES: C([O:8][C:9]1[CH:29]=[CH:28][C:12]([CH2:13][N:14]([N:23]2[CH:27]=[N:26][N:25]=[CH:24]2)[C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[C:30]([F:33])([F:32])[F:31])C1C=CC=CC=1>[Pd].CCO.C1COCC1.CC#N>[OH:8][C:9]1[CH:29]=[CH:28][C:12]([CH2:13][N:14]([N:23]2[CH:27]=[N:26][N:25]=[CH:24]2)[C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[C:30]([F:33])([F:32])[F:31]
Reactant: N#Cc1ccc(N(Cc2ccc(OCc3ccccc3)c(C(F)(F)F)c2)n2cnnc2)cc1
Agent: [Pd]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1ccc(N(Cc2ccc(O)c(C(F)(F)F)c2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Palladium on charcoal (100 mg, 10% Pd) was added to a solution of 4-[(4-benzyloxy-3-trifluoromethyl-benzyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile (CAB03054, 1.75 g, 3.89 mmol) in EtOH/THF/MeCN (50 mL/50 mL/30 mL). The mixture was stirred under hydrogen atmosphere (balloon) for 18 h at room temperature. The reaction mixture was filtered through celite and the clear colourless filtrate was concentrated under reduced pressure. The residue was suspended in 2-propanol (20 mL) and heated to reflux for 5 minutes. The white solid was filtered off after cooling to room temperature and dried under high vacuum. Yield: 1.31 g (94%). 1H-NMR (400 MHz, d6-DMSO) δ=4.98 (s, 2H), 6.78 (d, J=9.0 Hz, 2H), 6.91 (d, J=8.6 Hz, 1H), 7.31 (dd, J=8.6, 2.0 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H), 7.76 (d, J=9.0 Hz, 2H), 8.74 (s, 2H), 10.66 (s, 1H, —OH).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)[CH3:2].Cl.[N:14](OC)=[O:15]>O>[CH2:11]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([NH2:14])=[C:6]([CH3:10])[CH:5]=1)[CH3:12].[CH2:11]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([N:14]=[O:15])=[C:6]([CH3:10])[CH:5]=1)[CH3:12]
Reactant: CCN(CC)c1cccc(C)c1
Reactant: CON=O
Agent: Cl
Solvent: O
Product: CCN(CC)c1ccc(N)c(C)c1
Product: CCN(CC)c1ccc(N=O)c(C)c1

Procedure:
81.5 g of N,N-diethyl-m-toluidine is initially introduced into a stirred flask with 46 ml of hydrochloric acid in 400 ml of water, the reaction mixture is cooled to 0° and gaseous methyl nitrite is passed in, while stirring and cooling. When the introduction of methyl nitrite has ended, the reaction mixture is brought to room temperature, the excess of nitrite is removed in the customary manner by adding urea and the residual gases are removed by applying reduced pressure. The entire reaction mixture is then passed to the catalytic hydrogenation to give 4N,4N-diethyl-2-methyl-p-phenylenediamine without the N,N-diethyl-3-methyl-4-nitroso-aniline formed being isolated. When the hydrogenation has ended, 4N,4N-diethyl-2-methyl-p-phenylenediamine hydrochloride is isolated by precipitation with ethanol. M.p. 268°-272°.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:41])[CH2:21][NH:22][C:23]2([CH2:26][CH2:27][N:28]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[C:31]([CH3:39])([CH3:38])[O:30][C:29]3=[O:40])[CH2:25][CH2:24]2)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:41][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[CH2:21][NH:22][C:23]1([CH2:26][CH2:27][N:28]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[C:31]([CH3:39])([CH3:38])[O:30][CH:29]2[OH:40])[CH2:25][CH2:24]1
Reactant: CC1(C)OC(=O)N(CCC2(NCC(O)c3cc(OCc4ccccc4)cc4c3OCC(=O)N4)CC2)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)OC(O)N(CCC2(NCC(O)c3cc(O)cc4c3OCC(=O)N4)CC2)c2ccccc21

Procedure:
590 mg (1.06 mmol) of 1-(2-{1-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]cyclopropyl}ethyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one is dissolved in 30 mL of methanol and hydrogenated in the presence of palladium on charcoal (10%) at ambient temperature and 3 bar hydrogen pressure. Yield: 180 mg (36%); mass spectroscopy: [M+H]+=468.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[OH:12])=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31]CC)=[CH2:30])CCC.Cl.O>C(Cl)Cl.[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>[F:23][C:22]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][CH:18]=[N:19]2)=[CH:14][C:13]=1[CH:11]([OH:12])[C:8]1[N:6]2[N:7]=[C:2]([C:29](=[O:31])[CH3:30])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: OC(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1ccc2ncc(C(O)c3cc4cccnc4cc3F)n2n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A flask was charged with tetrakis-(triphenylphosphine)-palladium (176 mg, 0.15 mmol) under nitrogen. A solution of (6-chloroimidazo[1,2-b]pyridazin-3-yl)(7-fluoroquinolin-6-yl)methanol (500 mg, 1.52 mmol) in CH2Cl2 (20 mL) was added. The system was purged with nitrogen gas three times and tributyl-(1-ethoxy-vinyl)-stannane (0.54 ml, 1.59 mmol) was added. The temperature was increased to 100° C. and stirred overnight. The reaction mixture was cooled to room temperature, 3N HCl was added and the mixture was stirred for additional 4 hrs. Water was added and the mixture was then extracted with EtOAc, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (3% to 10% MeOH in CH2Cl2) to afford 500 mg (yield: 88%) title compound. LCMS (method B): [MH]+=337, tR=1.88 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[S:15][C:14]=1[NH2:22].[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30]>>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:22][C:14]1[S:15][C:16]2[C:21]([N:13]=1)=[CH:20][CH:19]=[CH:18][N:17]=2
Reactant: Nc1nc2cccnc2s1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: Oc1ccccc1F
Product: Fc1ccccc1Oc1ccc2ncnc(Nc3nc4cccnc4s3)c2c1

Procedure:
The compound of Example 8 was manufactured by the same method as in Example 1, by a similar method thereto or by a combination of such a method with a conventional method using 4-chloro-6-iodo-quinazoline, thiazolo[5,4-b]pyridin-2-yl-amine and 2-fluorophenol.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[CH3:29][N:30]([CH3:45])[C:31]([CH3:44])([CH3:43])[CH2:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][C:35]=1[F:42]>>[CH3:29][N:30]([CH3:45])[C:31]([CH3:44])([CH3:43])[CH2:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[C@@H:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:36][C:35]=1[F:42]
Reactant: CN(C)C(C)(C)COc1ccc(C=O)cc1F
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCC(C)(C)N(C)C)c(F)c2)c1
Yield: 24.2 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 4-(2-dimethylamino-2-methylpropoxy)-3-fluorobenzaldehyde (55 mg) according to an analogous synthetic method to Example 264 described below and purified by LC-MS, the title compound (6.6 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:29][Si:30]([CH3:37])([CH3:36])[CH2:31][CH2:32][O:33][CH2:34]Cl>CN(C=O)C.C1COCC1.CC(=O)OCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:34][O:33][CH2:32][CH2:31][Si:30]([CH3:37])([CH3:36])[CH3:29])[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(Br)cc3)[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(Br)cc3)n2COCC[Si](C)(C)C)cc1
Reaction time: 2 h
Yield: 0 %

Procedure:
To a solution of 2-(4-bromophenyl)-5-(4-(heptyloxy)phenyl)-1H-imidazole (370 g, 900 mmol) in DMF (4 ml) was added NaH (40 mg, 980 mmol). After 2 h, 2-(trimethylsilyl)ethoxymethyl chloride (160 g, 990 mmol) in THF (2 ml) was added dropwise and reaction mixture was stirred overnight. The reaction mixture was diluted with EA and washed with aq. NaHCO3. The organics were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The crude product was purified by chromatography (EA/hexane) to afford 32 mg (65%) of 2-(4-bromophenyl)-5-(4-(heptyloxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole as a tan solid. LCMS-ESI (m/z) calculated for C28H39BrN2O2Si: 542.2. found 543.3 [M+H]+, tR=3.35 min (Method 8).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:19])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:4]1=[O:18].Cl[C:21]1[S:22][C:23]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:24]=2[N:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:2][C:3]1([CH3:19])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]([CH:12]2[CH2:17][CH2:16][N:15]([C:21]3[S:22][C:23]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:24]=4[N:25]=3)[CH2:14][CH2:13]2)[C:4]1=[O:18]
Reactant: CC1(C)C(=O)N(C2CCNCC2)c2nccnc21
Reactant: FC(F)(F)c1ccc2nc(Cl)sc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)C(=O)N(C2CCN(c3nc4ccc(C(F)(F)F)cc4s3)CC2)c2nccnc21
Temperature: 110 °C
Yield: 67.2 %

Procedure:
A mixture of 7,7-dimethyl-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one hydrochloride (Intermediate 78) (0.088 g, 0.311 mmol), 2-chloro-6-(trifluoromethyl)benzo[d]thiazole (0.089 g, 0.373 mmol), and potassium carbonate (0.172 g, 1.245 mmol) in DMSO (3 mL) was heated at 110° C. overnight. The reaction mixture was cooled, H2O was added, and the solid was collected, dried and purified by ISCO (35% EtOAc/Hexanes) to give the title compound (93.5 mg, 67%). MS (M+1): 448. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.27 (1 H, s), 8.03-8.18 (2 H, m), 7.52-7.68 (2 H, m), 4.51-4.68 (1 H, m), 4.23 (2 H, d, J=12.5 Hz), 3.36-3.49 (2 H, m), 2.52-2.61 (2 H, m), 1.86 (2 H, d, J=10.4 Hz), 1.33 (6 H, s).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH2:7]([O:14][C:15]([N:17]1C[CH2:23][CH2:22][C@@H:18]1C(O)=O)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1.CN(C=O)C>[Cl:4][C:2]([C@H:1]1[CH2:23][CH2:22][CH2:18][N:17]1[C:15]([O:14][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:16])=[O:3]
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)[C@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 22.5 °C
Reaction time: 0.5 h

Procedure:
A mixture composed of 40 mL of toluene and 40 mL of oxalyl chloride was added—in 30 minutes at room temperature—to a solution of 100 g of 1-[(benzyloxy)carbonyl]-D-proline in 200 mL of toluene and 0.5 mL of DMF. After stirring for 2 hours at 20-25° C. the HPLC showed complete conversion and the reaction mixture was concentrated with oil at about 40° C. under vacuum, redissolved to toluene and reconcentrated obtaining 122.1 g of residue. At 20-25° C. the residue was dissolved in 100.00 mL of THF and this solution was used in example 2.