Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].Cl[CH2:4][CH2:5][O:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[N:13][C:14]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)=[C:19]([Cl:32])[CH:18]=2)[NH:9][N:8]=1>O.C(O)C>[Cl:32][C:19]1[CH:18]=[C:17]([NH:16][C:14]2[N:13]=[CH:12][N:11]=[C:10]3[NH:9][N:8]=[C:7]([O:6][CH2:5][CH2:4][NH:2][CH3:1])[C:15]=23)[CH:22]=[CH:21][C:20]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)c1
Reactant: CN
Solvent: CCO
Solvent: O
Product: CNCCOc1n[nH]c2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 120 °C
Yield: 14 %

Procedure:
Methylamine in water (40% solution, 2 ml) was added to a suspension of 3-(2-chloroethoxy)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 12/0.4 g, 0.89 mmol) in ethanol (4 ml) and the reaction mixture was heated at 120° C. for 5 minutes in a microwave reactor. The resulting solution was concentrated in vacuo and the residue purified by chromatography using DCM to DCM-10% methanol/7N ammonia as eluant to give the title compound as a white solid (57 mg, 14%); Mass Spectrum: 443.3 (MH+/retention time 1.5 minutes).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[F:14].[Cl:15]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[C:11]2[O:10][C:9]([CH3:12])([CH3:13])[CH:8]=[CH:7][C:6]=2[C:5]([Cl:15])=[CH:4][C:3]=1[F:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1(C)C=Cc2ccc(F)c(N)c2O1
Solvent: CN(C)C=O
Product: CC1(C)C=Cc2c(Cl)cc(F)c(N)c2O1
Yield: 329.4 %

Procedure:
By a method analogous to that of Example 11, Step J, 1.5 grams (0.0008 mole) of 8-amino-2,2-dimethyl-7-fluoro-2H-1-benzopyran was reacted with 1.1 grams (0.008 mole) of N-chlorosuccinimide in 50 mL of N,N-dimethylformamide. The crude reaction product was purified with column chromatography on silica gel, with hexane and 1:1 methylene chloride:hexane hexane as the eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.6 gram of 8-amino-5-chloro-2,2-dimethyl-7-fluoro-2H-1-benzopyran. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][C@H:29]([CH3:34])[C:30](OC)=[O:31])[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[CH2:35]([CH2:37][NH2:38])[OH:36]>>[OH:36][CH2:35][CH2:37][NH:38][C:30](=[O:31])[C@H:29]([O:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:18]([NH:17][C:13]1[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[N:9]=[CH:10]3)=[N:19][CH:20]=[N:21]2)[CH3:34]
Reactant: NCCO
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12)C(=O)NCCO
Yield: 61.7 %

Procedure:
Using the same procedure as in Example 5, methyl (2R)-2-[(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (250 mg, 0.55 mmol) was reacted with ethanolamine (0.332 ml, 5.5 mmol) to give the title compound as a white solid (164 mg, 62%); NMR Spectrum 1.64 (d, 3H), 3.21 (m, 2H), 3.43 (m, 2H), 4.75 (t, 1H), 5.22 (q, 1H), 5.77 (s, 2H), 6.95 (d, 1H), 7.01 (d, 1H), 7.29 (m, 1H), 7.36 (d, 1H), 7.72 (m, 4H), 8.16 (s, 1H), 8.48 (br t, 1H), 8.53 (m, 3H), 10.73 (br s, 1H); Mass spectrum MH+ 484.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH3:15])[C:6]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[N:7][CH:8]=1.[N-:16]=[N+:17]=[N-:18].[Na+].O>CC(N(C)C)=O>[N:16]([CH2:2][C:3]1[CH:4]=[C:5]([CH3:15])[C:6]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[N:7][CH:8]=1)=[N+:17]=[N-:18]
Reactant: Cc1cc(CCl)cnc1OCC(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(CN=[N+]=[N-])cnc1OCC(F)(F)F
Temperature: 90 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
A mixture of 5-(chloromethyl)-3-methyl-2-(2,2,2-trifluoroethoxy)pyridine (0.75 g, 3.15 mmol, Step-3) and sodium azide (0.41 g, 6.29 mmol) in DMA (8 mL) is stirred at 90° C. for 2 hours. The reaction mixture is poured into water (50 mL), and extracted with n-hexane/EtOAc (1:10, 50 mL). The organic layer is washed with water (50 mL) and dried over sodium sulfate. After filtration, the organic fraction is concentrated in vacuo to give 0.77 g (>99% yield) of the title compound as colorless oil. This material is used for the next reaction (Step-5) without further purification.
Reaction SMILES: ClC1C=CC(C(Cl)=O)=CC=1.Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][N:13]=1.Cl[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[C:28]1[C:33]([C:34]2[NH:35][CH:36]=[CH:37][N:38]=2)=[CH:32][N:31]=[C:30]([NH:39][CH2:40][CH2:41][NH:42]C2C=CC([N+]([O-])=O)=CN=2)[N:29]=1>>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([C:28]2[C:33]([C:34]3[NH:38][CH:37]=[CH:36][N:35]=3)=[CH:32][N:31]=[C:30]([NH:39][CH2:40][CH2:41][NH:42][C:12]3[N:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=3)[N:29]=2)=[CH:21][CH:26]=1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C(Cl)c1ccc(Cl)cc1
Product: N#Cc1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3)n2)nc1

Procedure:
6-[(2-{[4-(4-chlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]amino}ethyl)amino]-pyridine-3-carbonitrile was prepared from 4-chlorobenzoyl chloride and 2-chloro-5-(cyano)pyridine using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [C:1]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[CH3:19])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1C2C(=CC=CC=2)C=[N:22][N:21]=1>>[CH3:20][N:21]1[N:22]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:12]=[CH:11][C:10]=2[CH2:19]1
Reactant: c1ccc2cnncc2c1
Reactant: Cc1ccc2ccccc2c1C(=O)c1ccccc1
Product: CN1Cc2ccc3ccccc3c2C(c2ccccc2)=N1

Procedure:
By the procedure described in Example 189, 4.4 g (18 mmol) of the benzoylnaphthalene was converted to 1.73 g of the phthalazine product, which was reduced immediately as shown in Table G.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8].Br[CH2:11][CH:12]([OH:14])[CH3:13].[OH-].[Na+]>C1(C)C=CC=CC=1>[OH:14][CH:12]([CH3:13])[CH2:11][NH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cccc(C)c1N
Reactant: CC(O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1NCC(C)O

Procedure:
A solution consisting of 121 g (1.0 mole), of 2,6-xylidine, 70 g (0.5 mole) 1-bromo-2-propanol and 100 ml of absolute toluene is heated under reflux for 24 hours. After cooling 300 ml 2 N sodium hydroxide are added. The organic layer is separated, washed with water until neutral, dried over sodium sulfate and evaporated in vacuo. The crude product is fractionally distilled to yield 59.6 g of N-(2'-hydroxypropyl)-2,6-xylidine, b.p. 81°-83°/0.1 Torr.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](Cl)=[O:8].C(N(CC)CC)C.[NH2:17][C:18]1[CH:39]=[CH:38][C:21]([C:22]([N:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH2:28][N:27]3[CH:35]=[CH:36][CH:37]=[C:26]3[CH2:25]2)=[O:23])=[CH:20][CH:19]=1>C(Cl)Cl>[CH:37]1[CH:36]=[CH:35][N:27]2[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[N:24]([C:22]([C:21]3[CH:20]=[CH:19][C:18]([NH:17][C:7]([C:3]4[S:4][CH:5]=[CH:6][C:2]=4[CH3:1])=[O:8])=[CH:39][CH:38]=3)=[O:23])[CH2:25][C:26]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: Cc1ccsc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccsc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 0.05 h
Yield: 113.5 %

Procedure:
To a solution of 318 mg of 3-methyl-2-thiophenecarbonyl chloride in 5 ml of methylene chloride at 0° C. is added 346 μl of triethylamine. After stirring for 3 minutes, 500 mg of the 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added. The bath is removed and the reaction mixture stirred at room temperature for 18 hours. The volatiles are concentrated in vacuo to give a residue which crystallizes from ethyl acetate to afford 800 mg of solid. The solid is dissolved in methylene chloride washed with water, 2N citric acid, 1M NaHCO3 and brine. The organic layer is filtered through hydrous magnesium silicate, dried with Na2SO4 and concentrated in vacuo to give a residue which crystallizes from ethyl acetate to afford 400 mg of the desired product as a white solid, m.p. 232°-235° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]C#N)=[CH:12][C:11]=1[F:19].Cl.[C:21](=[O:24])(O)[O-:22].[Na+].C>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:21]([OH:22])=[O:24])=[CH:12][C:11]=1[F:19]
Reactant: N#CCc1ccc(-c2nc3ccccc3o2)c(F)c1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: O=C(O)Cc1ccc(-c2nc3ccccc3o2)c(F)c1

Procedure:
A mixture of 0.7 gm. of the above crude 4-(benzoxazol-2-yl)-3-fluorophenylacetonitrile and 30 cc. of concentrated hydrochloric acid is heated on the steam bath for 1 hour. The reaction mixture is then filtered through a sintered glass filter into ice water and the resulting precipitate collected to give 0.65 gm. of crude product. The crude acid is stirred with 50-60 cc. of saturated sodium bicarbonate solution, a small amount of charcoal is added, and the mixture is then filtered. The filtrate is acidified with concentrated hydrochloric acid and the resulting precipitate collected and dried to give 4-(benzoxazol-2-yl)-3-fluorophenylacetic acid, m.p. 207°-211°C. dec.
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=3)[C:18]([NH:20][C:21]([CH3:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[F:33].C1C([N+]([O-])=O)=CC=C([Cl-][C:44]([O-])=[O:45])C=1.[CH2:47]([NH2:52])[C:48]([CH3:51])([CH3:50])[CH3:49]>ClCCl>[F:33][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:2]=1[NH:1][C:44]([NH:52][CH2:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:45])[C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=2)[C:18]([NH:20][C:21]([CH3:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[O:19])[CH2:12][CH2:13]1)=[O:7]
Reactant: CC(C)(C)CN
Reactant: CC(C)(NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)c1)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CNC(=O)Nc1ccc(C(=O)N2CCN(Cc3cccc(C(=O)NC(C)(C)C(F)(F)F)c3)CC2)cc1F
Yield: 66.1 %

Procedure:
3-((4-(4-Amino-3-fluorobenzoyl)piperazin-1-y)methyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide (0.480 mmol, 224 mg) and 4-nitrophenylchloroformate (0.528 mmol, 108 mg) were stirred together in dichloromethane (2 mL) for 16 hours. Neopentylamine (2.4 mol, 300 μL) was added and the volatiles were removed under vacuum. The residue was purified by silica chromatography to yield the title compound (184 mg). MS (ESI) m/z 580.1 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(N(CC)CC)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>ClCCl>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-3-nitroaniline (5 g, 32.2 mmol, 1.0 eq.) and triethylamine (5.38 ml, 38.6 mmol, 1.2 eq.) in dichloromethane (100 ml) is added a solution of 3-trifluoromethylbenzoyl chloride 33.8 mmol, 1.05 eq.) within 30 min. The suspension formed is stirred for 1 h at room temperature. Then, the reaction mixture is diluted with dichloromethane (800 ml) and extracted with water (100 ml), 2M aqueous Na2CO3 (100 ml), 2M HCl (100 ml), water (100 ml). The organic layer is dried over Na2SO4, evaporated to a volume of about 100 ml and diluted with hexanes (100 ml). The precipitate is filtered off, washed with hexanes/dichloromethane 1:1 and hexanes. Vacuum drying over night at room temperatures gives light yellow fine needles: HPLC: tR=6.72 min (purity: >99%, gradient A), ESI-MS: 325.2 [MH]+
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=2[S:15]([CH3:18])(=[O:17])=[O:16])[C:9](O)=[O:10])=[N:2]1.C1C=CC=CC=1.S(Cl)([Cl:28])=O>C(N(CC)CC)C>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=2[S:15]([CH3:18])(=[O:17])=[O:16])[C:9]([Cl:28])=[O:10])=[N:2]1
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1-c1ccon1
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1c(C(=O)Cl)ccc(S(C)(=O)=O)c1-c1ccon1

Procedure:
To 0.55 g of 3-(isoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoic acid were added 10 ml of benzene, then 0.17 ml of thionyl chloride and a drop of triethylamine to heat at reflux for 2 hours. The reaction solution was cooled down. The solvent was distilled out under reduced pressure to give 3-(isoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoyl chloride.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][C:5](=[O:15])[CH:4]=1)[CH3:2].[Cl:16]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:16][C:4]1[C:5](=[O:15])[NH:6][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cc(=O)[nH]c(-c2ccccc2)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: CCc1nc(-c2ccccc2)[nH]c(=O)c1Cl
Temperature: 0 °C
Yield: 87.1 %

Procedure:
A stirred solution of 7.81 g (39.1 mmol) of 6-ethyl-2-phenyl-4(3H)-pyrimidinone and 5.80 g (43.4 mmol) of N-chlorosuccinimide in 100 mL of glacial acetic acid was heated at 90° C. for 4 h. The mixture was cooled, poured onto crushed ice and allowed to stand until the ice had melted. The mixture was filtered and the solid collected was washed with water and a little ether. The solid was dried in a vacuum oven at 50 C. to afford 7.99 g of 5-chloro-6-ethyl-2-phenyl-4(3H)-pyrimidinone (an intermediate for compound 172) as a white solid. 1H-NMR (d6-DMSO) 1.30(3H,t), 2.8(2H,q), 7.6(3H,m), 8.2(2H.m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.CC1ON=C(C2C=CC=CC=2)C=1COC1C=CC(C(O)=O)=CN=1.[NH2:48][C:49]([CH3:53])([CH3:52])[CH2:50][OH:51]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:48][C:49]([CH3:53])([CH3:52])[CH2:50][OH:51])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(N)CO
Reactant: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)O)cn1
Agent: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)NC(C)(C)CO)cn1
Yield: 30 %

Procedure:
As described for example 191, 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.29 mmol) was converted, instead of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid, using 2-amino-2-methyl-1-propanol instead of 2-aminoethyl isopropylether, to the title compound (37 mg, 30%) which was obtained as a white solid. MS: m/e=416.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14]4=[C:15]([CH2:17][CH2:18][N:13]4[C:12](=O)[CH2:11][CH2:10]3)[CH:16]=2)[CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1.Cl>C1(C)C=CC=CC=1.C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14]4=[C:15]([CH2:17][CH2:18][N:13]4[C:12](=[S:29])[CH2:11][CH2:10]3)[CH:16]=2)[CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CCc2cc(-c3cccnc3)cc3c2N1CC3
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: S=C1CCc2cc(-c3cccnc3)cc3c2N1CC3

Procedure:
A mixture of 8-pyridin-3-yl-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinoline-4-one (900 mg, 3.60 mmol) and Lawessons reagent (1.45 g, 3.60 mmol) was refluxed in a mixture of 50 ml toluene and 5 ml THF for 2 h. After evaporation of the solvent under reduced pressure, the residue was purified by flash chromatography on silica gel (hexanes/ethyl acetate, 1/1, Rf=0.25). 8-Pyridin-3-yl-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinoline-4-thione was obtained as a yellow solid (155 mg, 0.58 mmol, 26%), mp (HCl salt, THF) 283° C. 1H-NMR (500 MHz, CDCl3): δ=2.96 (t, 3J=7.9 Hz, 2H), 3.25 (t, 3J=7.6 Hz, 2H), 3.29 (t, 3J=8.0 Hz, 2H), 4.42 (t, 3J=8.2 Hz, 2H), 7.23 (s, 1H), 7.33 (s, 1H), 7.34 (ddd, 3J=7.9 Hz, 3J=4.7 Hz, 5J=0.6 Hz, 1H), 7.81 (ddd, 3J=7.9 Hz, 4J=2.5 Hz, 4J=1.9 Hz, 1H), 8.57 (dd, 3J=4.7 Hz, 4J=1.6 Hz, 1H), 8.59 (d, 4J=2.2 Hz, 1H). 13C-NMR (125 MHz, CDCl3): δ=23.5, 27.1, 40.3, 52.0, 122.7, 123.0, 123.6, 125.1, 131.7, 134.2, 135.2, 136.4, 139.6, 148.1, 148.5, 192.5. MS m/z 267.10 (MH+).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7]CC)=O.[CH2:14]([N:18]1[C:23]2[N:24]=[CH:25][CH:26]=[CH:27][C:22]=2C(=O)[O:20][C:19]1=O)[CH2:15][CH2:16][CH3:17]>CC(N(C)C)=O>[CH2:14]([N:18]1[C:23]2[C:22](=[CH:27][CH:26]=[CH:25][N:24]=2)[C:5]([OH:7])=[C:4]([C:3]([O:11][CH2:12][CH3:13])=[O:10])[C:19]1=[O:20])[CH2:15][CH2:16][CH3:17]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCCn1c(=O)oc(=O)c2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCCn1c(=O)c(C(=O)OCC)c(O)c2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To a slurry of NaH (95%, 0.44 g, 18.2 mmol) in 15 mL anhydrous DMA at 10° C. under N2 was added diethyl malonate (2.9 g, 18.2 mmol) dropwise over 10 minutes. The mixture was stirred at ambient temperature for 30 minutes, treated with the product of Example 1B (2.0 g, 9.1 mmol) and heated at 120° C. for 3 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and cold water adjusting the pH to with 1 M HCl. The organic layer was washed 2×100 mL with water, 2×100 mL with saturated brine, dried (Na2SO4), filtered and the filtrate was concentrated under vacuum. The residue was recrystallized from hexane/ethyl acetate to give the desired compound as a white solid (1.84 g, 70% yield). MS (APCI+) m/z 291 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:22])([C:6]([F:21])([F:20])[C:7]([F:19])([F:18])[C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])C(O)=O.FF.[I:25]I>>[F:1][C:2]([I:25])([F:22])[C:6]([F:21])([F:20])[C:7]([F:19])([F:18])[C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11]
Reactant: II
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: FF
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Yield: 13 %

Procedure:
Perfluoroheptanoic acid 9.5 g (0.026 mole), iodine 4.0 g (0.016 mole) and Freon 113 (500 ml) were mixed and treated with approximately 33% fluorine diluted with nitrogen until the color due to iodine disappeared. The mixture was washed with water containing a small amount of sodium thiosulfite and dried over magnesium sulfate. 1.5 g (13% yield) of perfluorohexyl iodide was obtained.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:18][C:19]2[N:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=2)[CH2:13]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH:1]1([C:7]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:18][C:19]3[N:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=3)[CH2:13]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)C1CCCCC1
Reactant: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCCNC2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCCN(C(=O)C3CCCCC3)C2)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A mixture of cyclohexanecarboxylic acid (133 mg, 1.03 mmol), ethyl (2E)-3-{6-[(3R)-3-piperidinylamino]-3-pyridinyl}acrylate dihydrochloride (300 mg, 0.86 mmol), HOBt (163 mg, 1.21 mmol) and EDCI (174 mg, 1.12 mmol) in DMF (6 mL) was stirred at 0° C. for 1 hr and the mixture was stirred at ambient temperature for 18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between saturated sodium bicarbonate solution and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (hexane-EtOAc=1-1) to give ethyl (2E)-3-(6-{[(3R)-1-(cyclohexylcarbonyl)-3-piperidinyl]amino}-3-pyridinyl)acrylate (313 mg, 94%) as an amorphous powder.
Reaction SMILES: CO[C:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6].O.[NH2:23][NH2:24]>C(O)C>[NH2:6][C:5]1[NH:24][N:23]=[C:3]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[C:4]=1[C:7]#[N:8]
Reactant: NN
Reactant: COC(=C(C#N)C#N)c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Solvent: O
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.8 %

Procedure:
To a solution of 2-(methoxy(4-phenoxyphenyl)methylene)malononitrile (80 g, 290 mmol) in ethanol (200 mL) was added hydrazine hydrate (20 mL). The mixture was stirred at RT for 16 hr then was concentrated to give the crude product and washed with MeOH (30 mL) to afford 55 g (68.8%) of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile as a off-white solid. 1H NMR (DMSO-d6) δ 12.11 (br s, 1H), 7.80 (d, J=8.8 Hz, 2H), 7.46-7.39 (m, 2H), 7.18 (t, J=7.6 Hz, 1H), 7.12-7.04 (m, 4H), 6.43 (br s, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:22][CH:23]([OH:25])[CH3:24])=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[NH:5][CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].N1C=CN=C1.[C:31]([Si:35]([CH3:38])([CH3:37])Cl)([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl>[F:1][C:2]1[C:3]([CH2:22][CH:23]([O:25][Si:35]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:38])[CH3:37])[CH3:24])=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[NH:5][CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)C(=CNc1ccc(F)c(F)c1CC(C)O)C(=O)OCC
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCOC(=O)C(=CNc1ccc(F)c(F)c1CC(C)O[Si](C)(C)C(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76 %

Procedure:
14.2 g (40 mmol) of the compound (151) and 3.27 g (48 mmol) of imidazole were added to 100 ml of methylene chloride, and 20 ml of methylene chloride containing 7.23 g (48 mmol) of t-butyldimethylchlorosilane was dropped to the solution through 30 minutes. After the solution was stirred for 2.5 hours at room temperature, it was heated at reflux for 2 hours. 3.27 g of imidazole and 7.23 g of t-butyldimethylchlorosilane were supplemented to the solution, and the solution was heated at reflux for 11 hours. The solution was washed 100 ml of water, 50 ml of aqueous citric acid solution and 50 ml of saturated aqueous sodium hydrogen carbonate solution in this order, and after drying over magnesium sulfate, the solvent was removed by distillation. The solid matter was separated by column chromatography (silica gel 600 g, eluent solvent; chloroform:n-hexane=1:1) to obtain 14.2 g of an oily subject compound (152) in a 76% yield.