Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1.N1C=CC=CC=1.[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>ClCCl>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH:22][S:37]([C:34]3[CH:35]=[CH:36][C:31]([CH3:30])=[CH:32][CH:33]=3)(=[O:39])=[O:38])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C(F)(F)F)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Nc2cccc(C3CC(C)(C)c4cc(C(F)(F)F)ccc4N3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a stirred solution of 3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (100 mg, 0.31 mmol) in pyridine (49 mg, 0.62 mmol) and dichloromethane (1.5 mL) at 0° C. was added dropwise a solution of 4-Methyl-benzenesulfonyl chloride (71 mg, 0.37 mmol) in dichloromethane (0.5 mL). The mixture was stirred at room temperature overnight. The mixture was quenched with water (5 mL) and extracted with dichloromethane (5 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel to afford N-[3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-4-methyl-benzenesulfonamide (122 mg, 77.2%) as a white solid. MS (ESI+APCI) M+1=475.2.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=O)[CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24](=[O:26])[CH3:25])[CH:19]=2)=O)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[C:28]([NH:31][NH2:32])([NH2:30])=[NH:29].[ClH:33]>CO.Cl.Cl.NNC(N)=N>[ClH:33].[ClH:33].[C:28]([NH:31][N:32]=[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24](=[O:26])[CH3:25])[CH:19]=1)[CH2:14][CH2:13][CH2:12][C:11](=[N:32][NH:31][C:28](=[NH:29])[NH2:30])[NH:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1)(=[NH:30])[NH2:29]
Reactant: N=C(N)NN
Reactant: CC(=O)c1cccc(NC(=O)CCCC(=O)Nc2cccc(C(C)=O)c2)c1
Agent: Cl
Solvent: CO
Product: CC(=O)c1cccc(NC(CCCC(=NNC(=N)N)Nc2cccc(C(C)=O)c2)=NNC(=N)N)c1
Yield: 98.2 %

Procedure:
N,N'-bis(3-acetylphenyl)pentanediamide (3.66 g), aminoguanidine hydrochloride (2.75 g), and aminoguanidine dihydrochloride (0.05 g) were heated in methanol (35 mL) for 18 hr. Cooling and filtration gave 5.412 g of N,N'-bis(3-acetylphenyl)pentanediamide bis(amidinohydrazone) dihydrochloride, mp 187°-191° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][CH:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C([Sn](=O)CCCC)CCC.[N:45]([Si](C)(C)C)=[N+:46]=[N-:47].C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH2:23]([C:6]1[N:5]2[N:26]=[CH:27][CH:28]=[C:4]2[N:3]([CH:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[C:2](=[O:1])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[NH:47][N:46]=[N:45][N:22]=2)=[CH:11][CH:10]=1)[CH2:24][CH3:25]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2ccnn12
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n(C2CCOCC2)c2ccnn12
Temperature: 110 °C
Reaction time: 48 h
Yield: 41.5 %

Procedure:
A mixture of 4′-{[5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.33 g), dibutyltin oxide (0.083 g), azidotrimethylsilane (2.3 g) and toluene (20 mL) was stirred at 110° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.15 g, 46%).
Reaction SMILES: [CH3:1][Si:2]([CH3:25])([CH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17]1)[CH:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.[CH2:26]([Li])CCC.CI.[Cl-].[NH4+]>CCOCC.CCCCCC>[CH3:1][Si:2]([CH3:25])([CH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH3:26])=[CH:17]1)[CH:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: C[Si](C)(C1C=Cc2ccccc21)C1c2ccccc2-c2ccccc21
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CI
Solvent: CCCCCC
Product: CC1=CC([Si](C)(C)C2c3ccccc3-c3ccccc32)c2ccccc21
Yield: 89 %

Procedure:
A 200 ml four-necked flask equipped with a reflux tube, a thermometer and a dropping tunnel was thoroughly purged with nitrogen and dried. To the flask, dimethyl(1-indenyl)(9-fluorenyl)silane (2.00 g, 5.91 mmol) synthesized above and dehydrated ether (50 ml) were introduced. To the flask was dropwise added a hexane solution of n-butyllithium (6.21 mmol) at −40° C. with stirring. The temperature of the reaction liquid was allowed to spontaneously and slowly rise to room temperature. After stirring over night, the reaction liquid became a yellow solution. To the solution, methyl iodide (3.78 g, 26.6 mmol) was added and the temperature of the system was allowed to spontaneously and slowly rise to room temperature, followed by stirring for one day. The reaction liquid became an orange solution. To the resulting solution, 100 ml of ether and 100 ml of a saturated aqueous solution of ammonium chloride were added and the mixture was introduced into a separatory funnel to separate an organic phase. The organic phase was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After the solvent was distilled off, it was purified by column chromatography (developer: hexane) to obtain two kinds of isomers (one was a colourless transparent liquid, the other was a yellow liquid) totalling to 1.85 g (yield: 89%).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS([O-])=O.[Na+].[NH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[NH2:30])[C:25]#[N:26].C(O)C>O>[O:1]([C:8]1[CH:15]=[CH:14][C:11]([C:12]2[NH:30][C:29]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=3[N:21]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: N#Cc1ccc(N)c(N)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc2[nH]c(-c3ccc(Oc4ccccc4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
To 4-phenoxybenzaldehyde (4.0 g, 0.020 mol) was added 20 mL of 40% NaHSO3 (aq). The mixture was stirred for 2 h at 25° C. 3,4-Diaminobenzonitrile (3.36 g, 0.0252 mol) and ethanol (50 mL) were added. The mixture was refluxed for 4 h. The reaction was then poured into water. The precipitate was filtered and recrystallized from ethyl acetate to afford 3.6 g (57%) of 2-(4-phenoxyphenyl)-1H-benzimidazole-5-nitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[O:13])=[O:10])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:25]3[C:26]([NH2:30])=[N:27][CH:28]=[CH:29][C:24]=3[NH:23][CH:22]=2)=[CH:17][CH:16]=1.[ClH:31].O1CCOCC1>C(Cl)Cl.CC#N>[ClH:31].[NH2:30][C:26]1[C:25]2[C:21]([C:18]3[CH:19]=[CH:20][C:15]([NH:14][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[O:13])=[CH:16][CH:17]=3)=[CH:22][NH:23][C:24]=2[CH:29]=[CH:28][N:27]=1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: Nc1ccc(-c2c[nH]c3ccnc(N)c23)cc1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1nccc2[nH]cc(-c3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3)c12
Temperature: 25 °C
Reaction time: 6 h
Yield: 50 %

Procedure:
2-(4-Fluorophenyl)acetyl isocyanate (Compound C of Example 3, 0.29 M, 0.062 mL, 0.018 mmol, 2.0 eq) was added to a solution of 3-(4-aminophenyl)-1H-pyrrolo[3,2-c]pyridin-4-amine (0.002 g, 0.009 mmol, 1.0 eq) in 1/1 DCM/CH3CN (1 mL) and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (SiO2, eluting 0-5% MeOH in CHCl3). The appropriate fractions were isolated and concentrated in vacuo. The residue was dissolved in THF (1 mL), cooled to 0° C. and treated with anhydrous 4 N HCl in dioxane (1 mL, 4.0 mmol, 168 eq). The reaction mixture was stirred at 0° C. for 1 h and the resulting heterogeneous solution was concentrated in vacuo. The residue was triturated with Et2O, discarding the filtrate and the solid dried in vacuo to afford the title compound (0.002 g, 50%) as a pale yellow solid. MS(ESI+) m/z 404 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C@H:3]1[C@H:16]([CH2:17][CH3:18])[C@@H:15]2[C@:6]3([CH2:21][CH2:20][N:19]([CH3:22])[C@@H:14]2[CH2:13][C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]3=2)[CH2:5][C:4]1=[O:23].[C:24](=[O:27])([O-])[O-].[K+].[K+].[N:30]#CBr>C(Cl)(Cl)Cl>[C:22]([N:19]1[CH2:20][CH2:21][C@@:6]23[C:7]4[CH:8]=[C:9]([O:27][CH3:24])[CH:10]=[CH:11][C:12]=4[CH2:13][C@@H:14]1[C@@H:15]2[C@@H:16]([CH2:17][CH3:18])[C@H:3]([CH3:2])[C:4](=[O:23])[CH2:5]3)#[N:30]
Reactant: O=C([O-])[O-]
Reactant: CC[C@@H]1[C@H]2[C@H]3Cc4ccccc4[C@@]2(CCN3C)CC(=O)[C@H]1C
Reactant: N#CBr
Agent: Cl
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC[C@@H]1[C@H]2[C@H]3Cc4ccc(OC)cc4[C@@]2(CCN3C#N)CC(=O)[C@H]1C
Yield: 90.8 %

Procedure:
To a mixture of 9 (11.30 g, 34.5 mmol) and potassium carbonate (7.15 g, 51.8 mmol) in chloroform (75 ml) was added dropwise cyanogen bromide (4.45 g, 42.0 mmol) in chloroform. The reaction mixture was refluxed for 2 hours and processed as above to give 10.6 g (86%) of 12 as a foam after azeotroping with EtOH. The foam was used without further characterization in the hydrolysis reaction.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]4=[CH:18][S:19][C:20]([C:21]([OH:23])=[O:22])=[C:16]4[N:15]=[C:14]3[C:24](=[O:35])NC3CCN(C4CC4)CC3)[CH:8]=2)=[CH:4][CH:3]=1.NCC[OH:39]>>[Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]4=[CH:18][S:19][C:20]([C:21]([OH:23])=[O:22])=[C:16]4[N:15]=[C:14]3[C:24]([OH:35])=[O:39])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: O=C(O)c1scc2c1nc(C(=O)NC1CCN(C3CC3)CC1)n2Cc1cc(-c2ccc(Cl)s2)on1
Product: O=C(O)c1scc2c1nc(C(=O)O)n2Cc1cc(-c2ccc(Cl)s2)on1

Procedure:
6-[(2-hydroxy-ethyl)-amide]2-[(1-isopropyl-piperidin-4-yl)-amide] was prepared by a procedure according to example 22 starting from 96 mg (0.18 mmol) 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid and 11.0 μl (0.18 mmol) 2-amino-ethanol. The title compound was obtained as its formiate in form of a white amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][N:15]=3)[S:13][C:6]=12.[CH3:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][NH2:36].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][C:17]([CH2:18][NH:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH3:29])=[CH:20][CH:21]=3)[S:13][C:6]=12
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Reactant: COCCOCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COCCOCCNCc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
A suspension of carbaldehyde 325 (0.50 g, 1.3 mmol), amine 326 (0.30 g, 2.5 mmol) and acetic acid (0.14 ml, 2.5 mmol) in dichloromethane (20 ml) was stirred for 1 h at room temperature. Then sodium triacetoxyborohydride (0.80 g, 3.8 mmol) was added and stirred at r.t. for 16 h. A further amount of sodium triacetoxyborohydride (1.0 g) was then added, and stirring continued for 2 h. The reaction mixture was partitioned between dichloromethane and 1N NaOH. The yellow suspension was removed by filtration and rinsed with dichloromethane and 1N NaOH. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified via Biotage (linear gradient 0-20%, methanol/dichloromethane; Snap 100 g column) to yield 327 (280 mg, 0.562 mmol, 44%) as a yellow solid. LRMS (M+H): 499.4
Reaction SMILES: [CH:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH2:17][C:18]#[CH:19])[CH:13]=[CH:12][C:11]=2[NH:20][CH2:21][C:22]#[N:23])=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Sn]([N:39]=[N+:40]=[N-:41])(CCCC)(CCCC)CCCC.[OH-].[K+].CO>C1(C)C=CC=C(C)C=1>[CH:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH2:17][C:18]#[CH:19])[CH:13]=[CH:12][C:11]=2[NH:20][CH2:21][C:22]2[NH:41][N:40]=[N:39][N:23]=2)=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: C#CCOc1ccc(NCC#N)c(C(=O)c2ccc(C(C)C)cc2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1cccc(C)c1
Product: C#CCOc1ccc(NCc2nnn[nH]2)c(C(=O)c2ccc(C(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
A solution of 0.82 g (2.47 mmol) [2-(4-isopropyl-benzoyl)-4-prop-2-ynyloxy-phenyl-amino]-acetonitrile and 0.8 ml (3.31 mmol) Bu3SnN3 in 20 ml m-xylene is stirred at reflux temperature for 5 h. Then the reaction mixture is cooled to room temperature and 15 ml 2N KOH and 2 ml MeOH are added. This mixture is stirred vigorously for 15 min. After that the phases are separated and to the water layer 4 N HCl is added until a pH ˜1 is reached. The aqueous layer is extracted with dichloromethane/isopropanol=3:1. The combined organic layers are washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting solid is suspended in diethyl ether, stirred for 0.5 h, filtered and dried to afford 0.89 g of the title compound as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[CH2:29]OC[CH2:26][C:11]=3[N:12]([C:14]([NH:16][C@@H:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:18]([NH:20][CH3:21])=[O:19])=[O:15])[N:13]=2)[CH:5]=[CH:6][C:7]=1[F:8].FC1C=C(C2C3C[CH2:45][O:44]CC=3NN=2)C=CC=1F.N[C@@H](C(C)(C)C)[C:49](NCCO)=[O:50]>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[CH2:29][CH2:45][O:44][CH2:26][C:11]=3[N:12]([C:14]([NH:16][C@@H:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:18]([NH:20][CH2:21][CH2:49][OH:50])=[O:19])=[O:15])[N:13]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(C)(C)C
Reactant: CC(C)(C)[C@H](N)C(=O)NCCO
Reactant: Fc1ccc(-c2n[nH]c3c2CCOC3)cc1F
Product: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1COCC2)C(=O)NCCO

Procedure:
Compound 95 was prepared according to the procedure for the synthesis of compound 28 by replacing intermediate 16 with intermediate 16B, and replacing tert-leucine methylamide with intermediate 23. LCMS (+ESI) m/z=437.4 [M+H]+. 1H NMR (CDCl3) δ 7.84 (d, J=9.2 Hz, 1H), 7.59-7.64 (m, 1H), 7.50 (br, 1H), 7.22 (q, J=9.0 Hz, 1H), 4.99 (d, J=8.1 Hz, 2H), 4.20 (d, J=9.3 Hz, 1H), 3.85-3.94 (m, 2H), 3.72 (s, 2H), 3.43 (m, 2H), 2.80 (br, 2H), 1.06 (s, 9H). Purity: 96%.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:8]([C:9](O)=[O:10])=[C:7]([CH3:12])[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:5]=1.[N:23]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:1][O:2][CH2:3][C:4]1[C:8]([C:9]([N:31]2[CH2:32][CH2:33][CH:28]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:29][CH2:30]2)=[O:10])=[C:7]([CH3:12])[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:20])[F:22])[CH:14]=2)[N:5]=1
Reactant: COCc1nn(-c2cccc(C(F)(F)F)c2)c(C)c1C(=O)O
Reactant: C1CCN(C2CCNCC2)C1
Product: COCc1nn(-c2cccc(C(F)(F)F)c2)c(C)c1C(=O)N1CCC(N2CCCC2)CC1
Yield: 94 %

Procedure:
In analogy to the procedure described in Example 18], 3-methoxymethyl-5-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid and 4-pyrrolidine-1-yl-piperidine gave the title compound in 94% yield as light yellow viscous oil. MS: 451.2 (MH+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[S-:12][C:13]#[N:14].[Na+].[C:16]([O:20][C:21](=[O:26])[NH:22][CH2:23][CH2:24][NH2:25])([CH3:19])([CH3:18])[CH3:17]>C(O)C>[C:16]([O:20][C:21](=[O:26])[NH:22][CH2:23][CH2:24][NH:25][C:13]1[S:12][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[N:14]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: N#C[S-]
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCNc1nc(-c2ccc(F)cc2)cs1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
2.5 g (11.52 mmol) of 2-bromo-1-(4-fluorophenyl)ethanone and 0.93 g (11.52 mmol) of sodium thiocyanate were stirred in ethanol at 50° C. for 2 h. 1.845 g (11.52 mmol) of (2-aminoethyl)carbamic acid tert-butyl ester were added, and the reaction mixture was stirred at 50° C. for 2 h. After concentrating, water was added, and the mixture was extracted with ethyl acetate. The organic phase was separated and concentrated. Yield: 3.04 g (78%).
Reaction SMILES: [OH:1][CH:2]=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.S(Cl)(Cl)=O.[Cl:15][C:16]1[CH:35]=[CH:34][C:19]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27](O)=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)=[C:18]([F:36])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CN(C=O)C>[Cl:15][C:16]1[CH:35]=[CH:34][C:19]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:1][CH2:2][CH:3]=[CH:4][C:5]4[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=4)=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)=[C:18]([F:36])[CH:17]=1
Reactant: OC=CCc1ccncc1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCC=Cc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 2.6 %

Procedure:
A mixture of 4-(3-hydroxyprop-2-en-1-yl)pyridine (180 mg, 1.3 mmol) and thionyl chloride (0.3 ml) in toluene (10 ml) was stirred at room temperature for 2 hours. The volatiles were removed by evaporation to give crude 4-(3-chloroprop-2-en-1-yl)pyridine hydrochloride (180 mg, 0.94 mmol)) This product was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (500 mg, 1.6 mmol) and potassium carbonate (500 mg, 4.9 mmol) in DMF (20 ml) and the mixture stirred at 100° C. for 1 hour. The reaction mixture was allowed to cool and partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (100/0 increasing to 95/5) and then by reverse phase (C18) HPLC eluting with methanol/water (30/7 increasing to 50/50) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(pyrid-4-yl)prop-2-en-1-yloxy)quinazoline (15 mg, 4%).
Reaction SMILES: [CH2:1](I)[CH3:2].CN(C=O)C.[OH:9][C:10]1[C:18]2[O:17][C:16]([CH3:20])([CH3:19])[C:15](=[O:21])[C:14]=2[C:13]([CH3:22])=[C:12]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)[C:11]=1[CH3:37].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH2:1]([O:9][C:10]1[C:18]2[O:17][C:16]([CH3:19])([CH3:20])[C:15](=[O:21])[C:14]=2[C:13]([CH3:22])=[C:12]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)[C:11]=1[CH3:37])[CH3:2]
Reactant: CCI
Reactant: COc1ccc(N2CCN(c3c(C)c(O)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1c(C)c(N2CCN(c3ccc(OC)cc3)CC2)c(C)c2c1OC(C)(C)C2=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.6 %

Procedure:
Ethyl iodide (88 mg, 0.567 mmol) was added to a suspension of DMF (4 mL) containing 7-hydroxy-5-[4-(4-methoxyphenyl)piperazin-1-yl]-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one (150 mg, 0.378 mmol) synthesized in Reference Example 73 and potassium carbonate (104 mg, 0.756 mmol) at 0° C. The reaction solution was warmed to room temperature and stirred for 15 hours. The resulting mixture was poured into water and extraction was performed using ethyl acetate. The extract was washed with saturated saline, and dried using anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 95:5 to 80/20), and recrystallized from ethyl acetate and hexane to give 70 mg of the title compound (yield: 44%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([F:24])=[C:20]([CH:23]=1)[CH:21]=O>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([F:24])=[C:20]([CH2:21][C:12]2[S:11][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)=[CH:14][CH:13]=2)[CH:23]=1
Reactant: CCOc1cccc(-c2cccs2)c1
Reactant: O=Cc1cc(Br)ccc1F
Product: CCOc1cccc(-c2ccc(Cc3cc(Br)ccc3F)s2)c1

Procedure:
2-(3-Ethoxyphenyl)thiophene obtained in Reference Example 69-(1) and 5-bromo-2-fluorobenzaldehyde were treated in a manner similar to Reference Example 9 to give the target compound. APCI-Mass m/Z 391/393 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[CH3:26][O:27][C:28](=[O:56])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C@H:35]1[C@H:39]([CH:40]=[CH:41][Sn](CCCC)(CCCC)CCCC)[CH2:38][CH2:37][C:36]1=[O:55]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:26][O:27][C:28](=[O:56])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C@H:35]1[C@H:39]([CH:40]=[CH:41][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:38][CH2:37][C:36]1=[O:55]
Reactant: CCCC[Sn](C=C[C@@H]1CCC(=O)[C@H]1CCCCCCC(=O)OC)(CCCC)CCCC
Reactant: O=C(Cl)c1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1CCOC1
Product: COC(=O)CCCCCC[C@@H]1C(=O)CC[C@H]1C=CC(=O)c1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of benzoyl chloride (0.224 mL, 1.94 mmol) in tetrahydrofuran (20 mL) was added tris(dibenzylideneacetone)dipalladium(0) (Pd2(DBA)3) (8.8 mg, 0.01 mmol) and tri-2-furylphosphine (9.2 mg, 0.04 mmol). The mixture was stirred for 10 minutes and trans-7-[2-oxo-5-(2-tributylstannanyl-vinyl)-cyclopentyl]-heptanoic acid methyl ester (the compound of Preparation 1, Step D, 1.0 g, 1.85 mmol) was added. The reaction was stirred for 24 h and was concentrated in vacuo. Radial chromatography (hexanes to 20% hexanes in ethyl acetate) provided the title compound of Step A as a clear and colorless oil (569 mg). 1H NMR (CDCl3, 250 MHz) d 7.94 (m, 2H), 7.62-7.42 (m, 3H), 7.00 (m, 2H), 3.64 (s, 3H), 2.75 (m, 1H), 2.44 (m, 1H), 2.23 (m, 5H), 2.03 (m, 1H), 1.86-1.16 (m, 8H), 0.90 (t, 2H).