Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[C:5]2=[N:13][NH:14][C:15](=[O:16])[N:4]2[CH:3]=1.[C:17]([O:21][C:22](=[O:36])[NH:23][CH2:24]/[CH:25]=[CH:26]/B1OC(C)(C)C(C)(C)O1)([CH3:20])([CH3:19])[CH3:18]>O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>[C:17]([O:21][C:22](=[O:36])[NH:23][CH2:24]/[CH:25]=[CH:26]/[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[C:5]2=[N:13][NH:14][C:15](=[O:16])[N:4]2[CH:3]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=c1[nH]nc2c3cc(Cl)ccc3c(Br)cn12
Reactant: CC(C)(C)OC(=O)NC/C=C/B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC/C=C/c1cn2c(=O)[nH]nc2c2cc(Cl)ccc12
Temperature: 100 °C
Reaction time: 18 h

Procedure:
6-bromo-9-chloro[1,2,4]triazolo[3,4-a]isoquinolin-3(2H)-one (3-9) (60 mg, 0.201 mmol, 1.0 equiv.) and tert-butyl[(2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-yl]carbamate (3-3) (228 mg, 0.804 mmol, 4.0 equiv.) were dissolved in anhydrous 1,4-dioxane (0.6 ml) and 2 M K2CO3 aqueous solution (0.2 mL). The reaction mixture was heated to 100° C. LCMS at 18 hours showed complete conversion. Purification with reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA) afforded the title product 3-10. LRMS m/z (M+H) 375.1 found, 375.1 required.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][NH2:11].CN([CH:15]=[C:16]([C:22]([CH3:24])=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:22]([CH3:24])=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=[N:11]1
Reactant: CCOC(=O)C(=CN(C)C)C(C)=O
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2c(Cl)cc(Cl)cc2Cl)c1C

Procedure:
By the method of Example 3, Step C, 25.9 g (0.122 mole) of 2,4,6-trichlorophenylhydrazine and 22.7 g (0.123 mole) of ethyl 2-dimethylaminomethyleneacetoacetate were reacted in ethanol, yielding 1-(2,4,6-trichlorophenyl)-4-ethoxycarbonyl-5-methyl-1H-pyrazole as tan solid; mp 112.5°-113° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:25][S:26]([C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[C:15]([CH2:33][C:32]3[CH:31]=[CH:30][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:36][CH:35]=3)=[C:14]([OH:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3ccc(S(C)(=O)=O)cc3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared by coupling 6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione from Step 1 of Example B(13), to 4-Methanesulfonyl-benzaldehyde using the Me2NHBH3 method described in the synthesis of Example B(31). 1H NMR (CDCl3): δ 1.45–1.86 (brm, 8H), 1.96 (m, 2H), 2.29 (t, J=7.6 Hz, 1H) 2.44–3.02 (m, 7H), 3.91 (s, 3H), 3.94 (s, 3H), 6.88–7.85 (m, 7H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:36]=[CH:37][CH:38]=1)[CH2:8][N:9]1[C@@H:17]2[C@H:12]([C@H:13]([CH2:20][C:21]3[CH:26]=[C:25]([F:27])[C:24]([NH:28][C:29](=[O:32])[CH2:30]Cl)=[C:23]([CH2:33][CH3:34])[CH:22]=3)[CH2:14][S:15](=[O:19])(=[O:18])[CH2:16]2)[O:11][C:10]1=[O:35])([CH3:4])([CH3:3])[CH3:2].[CH2:39]([NH2:41])[CH3:40].CCOC(C)=O.CO>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:36]=[CH:37][CH:38]=1)[CH2:8][N:9]1[C@@H:17]2[C@H:12]([C@H:13]([CH2:20][C:21]3[CH:26]=[C:25]([F:27])[C:24]([NH:28][C:29](=[O:32])[CH2:30][NH:41][CH2:39][CH3:40])=[C:23]([CH2:33][CH3:34])[CH:22]=3)[CH2:14][S:15](=[O:19])(=[O:18])[CH2:16]2)[O:11][C:10]1=[O:35])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN
Reactant: CCc1cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc(F)c1NC(=O)CCl
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNCC(=O)Nc1c(F)cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc1CC
Reaction time: 48 h

Procedure:
To a solution of N-{4-[(3aR,7S,7aS)-3-(3-tert-butyl-benzyl)-2,5,5-trioxo-octahydro-1-oxa-5lambda*6*-thia-3-aza-inden-7-ylmethyl]-2-ethyl-6-fluoro-phenyl}-2-chloro-acetamide 0.087 g, 0.15 mmol) in DMF (2 mL) was added a 4M solution of ethylamine in DMF (0.1 mL, 0.4 mmol) and the reaction mixture was kept for 2 days at 25° C. After evaporation, the product was dissolved in water and extracted with EtOAc. Combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated to provide a yellow foam: TLC (EtOAc-MeOH 9:1) Rf=0.25; UPLC RtD=1.443 min; ESIMS [M+NH4]+=574.
Reaction SMILES: [CH2:1]([CH:4]([NH2:8])[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.CO>C(OCC)C>[Br-:9].[Br-:9].[CH2:1]([CH:4]([NH2+:8][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2+:8][CH:4]([CH2:5][CH:6]=[CH2:7])[CH2:1][CH:2]=[CH2:3])[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3]
Reactant: C=CCC(N)CC=C
Reactant: BrCCCCCCBr
Solvent: CO
Solvent: CCOCC
Product: C=CCC(CC=C)[NH2+]CCCCCC[NH2+]C(CC=C)CC=C
Product: [Br-]
Temperature: 65 °C
Reaction time: 1 h
Yield: 184.8 %

Procedure:
To a 1 L Morton flask was added diallylmethylamine (74.6 g), 1,6-dibromohexane (77 g), and methanol (10 mL). The mixture was heated to 65° C. for 17 h, and then allowed to cool to room temperature. Diethylether (300 mL) was added and the mixture was stirred for 1 hr. The solid was collected by filtration and resuspended in diethylether (200 mL). The mixture was stirred for 1 hr, and the solid again collected by filtration. The solid was then dried in a vacuum oven at 50° C. for 3 days to yield 136 g of product.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH:9]([CH3:15])C(OCC)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:23]1CCC[CH2:24]1>>[CH3:16][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9][CH2:15][CH2:24][OH:23]
Reactant: C1CCOC1
Reactant: CCOC(=O)C(C)c1cnccc1N(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN(C)c1ccncc1CCCO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of the product of step iv) (2.6 g) in tetrahydrofuran (100 ml) was added lithium aluminium hydride (1.2 g) and the resulting suspension stirred for 4 hours at ambient temperature. Excess reducing agent was destroyed by the sequential addition of ethyl acetate, water, and conc. HCl. The mixture was then basified and extracted sequentially with ethyl acetate and dichloromethane. The organic extracts were combined, dried (PS paper and MgSO4) and evaporated to yield 4-dimethylamino-3-(3-hydroxypropyl)pyridine as a pale yellow oil (2.2 g), essentially pure by Tlc; NMR (d6DMSO) δ 1.6-1.8(2H,m): 2.65(2H,t); 2.8(6H,s); 3.5(2H,t); 4.5(1H,brs); 6.7(2H,d); 8.2(2H,d); m/e 181 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[C:8]([O:9]C)=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH2:13][C:12]=3[C:25](=[O:27])[O:26][C:5]=2[CH:4]=1>Br>[OH:2][C:3]1[C:8]([OH:9])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)[CH2:13][C:12]=3[C:25](=[O:27])[O:26][C:5]=2[CH:4]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OC)CCN(CCN1CCOCC1)C3
Agent: Br
Product: O=c1oc2cc(O)c(O)cc2c2c1CN(CCN1CCOCC1)CC2

Procedure:
A solution of 8.7 g 0f 1,2,3,4-tetrahydro-8,9-dimethoxy-3-(2-morpholinoethyl)-5H[1]benzopyrano[3,4-c]pyridin-5-one in 60 cc of 48% HBr was refluxed for 17 hr then cooled. Crystallization of precipitate from water afforded 5.5 g of product; mp 299°-302° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]([Cl:13])=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.[C:14]([O-])(=[O:16])[CH3:15].[Na+].C(OC(=O)C)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)(=O)C>[C:14]([N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:12]([Cl:13])[C:3]([Cl:2])=[CH:4][CH:5]=2)[CH2:10]1)(=[O:16])[CH3:15]
Reactant: CC(=O)[O-]
Reactant: Clc1ccc2c(c1Cl)CNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)N1CCc2ccc(Cl)c(Cl)c2C1
Reaction time: 4 h

Procedure:
A mixture containing (100 g., 0.425 m.) 7,8-dichlorotetrahydroisoquinoline hydrochloride and (41 g., 0.5 m.) sodium acetate in 760 ml. of acetic acid and 430 ml. of acetic anhydride was heated at 100° C. with stirring for four hours. The cooled reaction mixture was diluted with 800 ml. of water and brought to pH 8 by addition of 5% aqueous sodium carbonate (1400 ml.). The tan precipitate was collected by filtration, dried and recrystallized from isopropanol to give N-acetyl-7,8-dichloro-1,2,3,4-tetrahydroisoquinoline having a melting point of 98°-100° C.
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[CH2:20][CH2:19]1)[CH2:3][O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=O)[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH2:34]([NH:36][CH2:37][CH3:38])[CH3:35].P(C#N)(OCC)(OCC)=O>>[OH:1][C@@H:2]([CH2:17][N:18]1[CH2:19][CH2:20][CH:21]([C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[CH2:22][CH2:23]1)[CH2:3][O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([N:36]([CH2:37][CH3:38])[CH2:34][CH3:35])=[O:16])[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: O=C(O)c1cc2c(OC[C@@H](O)CN3CCC(c4ccc5ccccc5c4)CC3)cccc2o1
Reactant: CCNCC
Agent: CCOP(=O)(C#N)OCC
Product: CCN(CC)C(=O)c1cc2c(OC[C@@H](O)CN3CCC(c4ccc5ccccc5c4)CC3)cccc2o1

Procedure:
By the reactions in the same manner as in as in Example 3 using (S)-4-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)propyloxy)benzo(b)furan-2-carboxylic acid Starting Material Synthesis Example 22, diethylamine (0.24 ml) and diethyl cyanophosphate (0.5 ml), the title compound (0.61 g) was obtained as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][C:27]3([F:33])[F:32])=[CH:22][CH:21]=2)=[N:10]1.C(N(CC)CC)C.[C:41](OC(=O)C)(=[O:43])[CH3:42]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:21]=[CH:22][C:23]([CH:26]3[CH2:31][CH2:30][N:29]([C:41](=[O:43])[CH3:42])[CH2:28][C:27]3([F:32])[F:33])=[CH:24][CH:25]=2)=[N:10]1
Reactant: COc1nccc2c1c(-c1ccc(C3CCNCC3(F)F)cc1)nn2-c1c(F)cccc1F
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1nccc2c1c(-c1ccc(C3CCN(C(C)=O)CC3(F)F)cc1)nn2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
To a mixture of 1-(2,6-difluorophenyl)-3-(4-(3,3-difluoropiperidin-4-yl)phenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridine (186 mg) and triethylamine (91.0 mg) in dichloromethane (4 mL) was added acetic anhydride (67.0 mg) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hr, and diluted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (200 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.C(N([CH2:21][CH3:22])CC)C.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>C(Cl)(Cl)Cl>[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:21][CH:22]=1)[C:28]([O:15][CH:10]([CH2:9][N:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:35])([F:34])[F:23])[CH:26]=1)[C:11]([F:12])([F:14])[F:13])=[O:29]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: OC(CNc1cccc(F)c1)C(F)(F)F
Reactant: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(OC(CN(C(=O)c1cccc(C(F)(F)F)c1)c1cccc(F)c1)C(F)(F)F)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 14 h
Yield: 73.3 %

Procedure:
The 3-[(3-fluorophenyl)amino]-1,1,1-trifluoro-2-propanol (446 mg, 2.0 mmol) from EX-662A and triethylamine (544 mg) were dissolved in anhydrous CHCl3 (30 mL) and cooled to 0° C. Then a solution of 3-trifluoromethylbenzoyl chloride (1.04 g, 5.0 mmol) in anhydrous CHCl3 (6 mL) was added over a period of 15 min. The solution was stirred at room temperature. After 14 h, the solution was washed with 5% NaHCO3 (2×20 mL) and brine (2×10 mL), and then dried over anhydrous MgSO4. Removal of the solvent in vacuo gave 832 mg (73%) of the desired 2,2,2-trifluoro-1-[[(3-fluoro-phenyl)[3-(trifluoromethyl)benzoyl]amino]methyl]ethyl 3-trifluoromethyl-benzoate product as an amber oil, which was greater than 95% pure by reverse phase HPLC analysis. 1H NMR (CDCl3) δ 7.25-8.39 (m, 9H), 7.02 (q, 1H), 6.71 (m, 2H), 6.11 (m, 1H), 4.58 (dd, 1H), 4.35 (dd, 1H). 19F NMR (CDCl3) δ −64.4 (m, 6F), −77.4 (s, 3F), −111.3 (m, 1F). HRMS calcd. for C25H15F10NO3: 568.0970 [M+H]+, found: 568.0968.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[N:10]3[CH:12]=[CH:13][N:14]=[C:9]3[CH:8]=[N:7][C:6]=2[N:5](COCC[Si](C)(C)C)[C:4]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][CH:24]=1)[CH3:2].C(O)(C(F)(F)F)=O.[NH4+].[OH-]>C(Cl)Cl.O>[CH2:1]([C:3]1[C:11]2[N:10]3[CH:12]=[CH:13][N:14]=[C:9]3[CH:8]=[N:7][C:6]=2[NH:5][C:4]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][CH:24]=1)[CH3:2]
Reactant: CCc1c(-c2ccc(C(C)=O)cc2)n(COCC[Si](C)(C)C)c2ncc3nccn3c12
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1c(-c2ccc(C(C)=O)cc2)[nH]c2ncc3nccn3c12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 72.8 %

Procedure:
1-(4-(1-Ethyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-2-yl)phenyl)ethanone (0.12 g, 0.28 mmol) in DCM (2 mL) was treated with TFA (1.50 mL, 19.5 mmol) then stirred at rt for about 45 min. The solvents were evaporated under reduced pressure then the material was dissolved in 1,4-dioxane (2 mL) and treated with ˜28 wt % aqueous NH4OH (1.2 mL, 31 mmol). The mixture was stirred for about 15 min then diluted with water (10 mL). The volatiles were removed by evaporation under reduced pressure (bath temp 40° C., 85 mm Hg) then the mixture was further diluted with water (20 mL). The solids were collected by filtration then the material was dried to constant weight under vacuum at about 60° C. to give 1-(4-(1-ethyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-2-yl)phenyl)ethanone (0.062 g, 74%): LC/MS (Table 2, Method a) Rt=1.92 min; MS m/z 305 (M+H)+.
Reaction SMILES: [OH2:1].[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.[O:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>O>[OH:13][CH:17]([C:5]1[CH:6]=[CH:7][C:2]([CH:12]=[O:1])=[CH:3][CH:4]=1)[CH2:16][CH2:15][CH3:14]
Reactant: O
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCC(O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 51 %

Procedure:
A solution of 4-(diethoxymethyl)benzaldehyde (10.4 g, 50.0 mmol) in tetrahydrofuran (200 mL) was stirred at room temperature under a nitrogen atmosphere, 2 M n-propylmagnesium bromide tetrahydrofuran solution (27.5 mL, 55.0 mmol) was added dropwise. After 30 min, aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-20:80) to give 1-[4-(diethoxymethyl)phenyl]butane-1-ol (6.39 g, 25.3 mmol) as a colorless oil. The oil was dissolved in a mixture of tetrahydrofuran (75 mL) and water (25 mL) and p-toluenesulfonic acid monohydrate (0.500 g, 2.63 mmol) was added. The mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-40:60) to give the title compound (4.51 g, yield 51%, 2 step) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][NH:17][C:18](=O)[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[O:15])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C>O1CCCC1>[F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[O:15][C:18]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)=[N:17][N:16]=3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NNC(=O)[C@H]1CCCN(C(=O)c2ccc(F)cc2)C1)c1ccc(F)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)N1CCCC(c2nnc(-c3ccc(F)cc3)o2)C1
Yield: 85 %

Procedure:
A mixture of 4-fluoro-benzoic acid N′-[(S)-1-(4-fluoro-benzoyl)-piperidine-3-carbonyl]-hydrazide (100 mg, 0.26 mmol), 4-toluenesulfonyl chloride (60 mg, 0.31 mmol), solid supported 2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diaza-phosphorine (PS-BEMP, ex Fluka, 586 mg, 1.3 mmol, loading 2.2 mmol/g) in dry tetrahydrofuran (6 mL) was irradiated by microwaves under the following conditions: MW cycle: t=1 min, P=100 W, cooling time=2 min. After 5 MW cycles, the resin was filtered off and washed repeatedly with dichloromethane. The solvent was evaporated under reduced pressure to give a crude solid that was purified by flash chromatography (silica gel, eluent: hexane/ethyl acetate 1:1). The title compound was obtained as a white solid (82 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].Br[C:9]1[CH:14]=[C:13]([F:15])[C:12]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:11]([F:32])[CH:10]=1>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C:12]3[C:13]([F:15])=[CH:14][C:9]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][C:2]4=[O:7])=[CH:10][C:11]=3[F:32])=[O:17])[CH2:19][CH2:20]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: O=C1CCCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3c(F)cc(N4CCCCC4=O)cc3F)CC2)c(C)c1
Yield: 48.4 %

Procedure:
Using piperidin-2-one (51 mg) and (4-bromo-2,6-difluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (200 mg) described in Preparation Example 111 and by the reaction and treatment in the same manner as in Example 1, the title compound (101 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[N:14]([CH3:26])[C:13]2=[O:27])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O:28]1[CH2:32][CH2:31][CH:30](O)[CH2:29]1>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:24])([F:25])[C:20]([F:23])([F:21])[F:22])[N:14]([CH3:26])[C:13]2=[O:27])=[CH:7][C:3]=1[C:4]([O:6][CH:30]1[CH2:31][CH2:32][O:28][CH2:29]1)=[O:5]
Reactant: Cn1c(C(F)(F)C(F)(F)F)cc(=O)n(-c2cc(C(=O)O)c(Cl)cc2F)c1=O
Reactant: OC1CCOC1
Product: Cn1c(C(F)(F)C(F)(F)F)cc(=O)n(-c2cc(C(=O)OC3CCOC3)c(Cl)cc2F)c1=O

Procedure:
In an analogous manner, starting from 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-pentafluoroethyl-1(2H)-pyrimidinyl]-4-fluorobenzoic acid via its acid chloride and tetrahydrofuran-3-ol there is obtained 3-tetrahydrofuryl 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-pentafluoroethyl-1(2H)-pyrimidinyl]-4-fluorobenzoate, 1H-NMR (D6 -DMSO, 400 MHz): 2.00-2.09 (m, 1H), 2.20-2.32 (m,1H), 3.43 (s,3H), 3.74-3.92 (m,4H), 5.48-5.56 (m,1H), 6.50 (s,1H), 7.89 (d,1H), 8.08 (d,1H);
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5](B(O)O)[C:4]=2[CH:3]=[CH:2]1.Br[C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1/[C:16](=[CH:24]/[C:25]1[NH:26][CH:27]=[CH:28][C:29]=1[O:30][CH3:31])/[C:17](=[O:23])[NH:18]2.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH:1]1[C:9]2[C:4](=[C:5]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3/[C:16](=[CH:24]/[C:25]3[NH:26][CH:27]=[CH:28][C:29]=3[O:30][CH3:31])/[C:17](=[O:23])[NH:18]4)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(-c3cccc4[nH]ccc34)c21
Temperature: 90 °C
Yield: 38.1 %

Procedure:
A solution of 4-indoleboronic acid (64 mg, 0.40 mmol) (from Step A above), (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.31 mmol) (Starting Material 7), and sodium carbonate (35 mg, 0.33 mmol) in 3 mL DME and 1 mL water was degassed for 15 min. by bubbling argon through the solution. Dichlorobis(triphenylphosphine)palladium (II) (13 mg) (Aldrich) was then added and the reaction was heated at 90° C. for 2 days. The reaction was then poured into 100 mL water and the product was extracted with ethyl acetate (4×50 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The product was purified via flash column chromatography (1% CH3OH in CHCl3) to yield 42 mg (38%) orange powder.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C[Al](C)C.[O:28]1[C:30]([CH3:32])([CH3:31])[CH2:29]1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClC1C=CC=CC=1.C1COCC1>[OH:28][C:30]([CH3:32])([CH3:31])[CH2:29][N:5]1[C:4]([CH3:13])=[C:3]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C:2](=[O:1])[N:6]1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC1(C)CO1
Reactant: Cc1nn(-c2ccccc2)c(O)c1C(=O)OCc1ccccc1
Agent: C[Al](C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: Clc1ccccc1
Product: Cc1c(C(=O)OCc2ccccc2)c(=O)n(-c2ccccc2)n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.5 %

Procedure:
To a stirring suspension of benzyl 5-hydroxy-3-methyl-1-phenyl-1H-pyrazole-4-carboxylate (3380 mg, 11 mmol) in chlorobenzene (30 mL) at 10° C. under nitrogen was added trimethylaluminum (16 mL, 33 mmol, 2M in toluene). Internal temperature reached 27° C. At 25° C., 1,2-epoxy-2-methylpropane (1000 mg, 16 mmol) was added. The reaction mixture was stirred for 3 h at 25° C., and then diluted with THF (500 mL). The resultant was chilled to 10° C., and sodium sulfate decahydrate (2 g) was added. After 1 hr, another 2 g of sodium sulfate decahydrate added. After 2 h, the gel was filtered through a bed of celite and washed with EtOAc (3×100 mL). The filtrate was then washed with aq. 1 M HCl (50 mL) and brine. The organic layer was dried over MgSO4. and concentrated. The residue was purified on 120 g silica chromatography (30>90% EtOAc/hex). To give the title compound (1.11 g, 27% yield) as an amorphous solid. MS (ESI pos. ion) m/z: 381 (MH+). Calc'd exact mass for C22H24N2O4 380.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([CH3:19])=[C:13]([CH3:18])[CH:14]=3)[C:9]2=[O:20])[CH2:2]1.[Cl:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1>>[ClH:21].[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([O:25][CH2:24][CH2:23][CH2:22][N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]3[CH2:17][CH2:16][C:15]4[C:10](=[CH:11][C:12]([CH3:19])=[C:13]([CH3:18])[CH:14]=4)[C:9]3=[O:20])[CH2:2]2)=[CH:27][CH:28]=1
Reactant: COc1ccc(OCCCCl)cc1
Reactant: Cc1cc2c(cc1C)C(=O)N(CC1CCCNC1)CC2
Product: COc1ccc(OCCCN2CCCC(CN3CCc4cc(C)c(C)cc4C3=O)C2)cc1
Product: Cl

Procedure:
Prepared from 2-[(piperidin-3-yl)-methyl]-6,7-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline and 1-chloro-3-(4-methoxy-phenoxy)-propane analogously to Example 1.