Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:48][C:49]1[CH:54]=[CH:53][C:52]([NH:55][C:56]2[O:60][C:59]([C:61]3[C:66]([F:67])=[CH:65][CH:64]=[CH:63][C:62]=3[F:68])=[N:58][C:57]=2[C:69]#[N:70])=[CH:51][CH:50]=1>CN(C=O)C>[C:69]([C:57]1[N:58]=[C:59]([C:61]2[C:62]([F:68])=[CH:63][CH:64]=[CH:65][C:66]=2[F:67])[O:60][C:56]=1[NH:55][C:52]1[CH:51]=[CH:50][C:49]([NH:48][C:11](=[O:13])[CH2:10][CH2:9][N:8]([CH3:14])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:54][CH:53]=1)#[N:70]
Reactant: CN(CCC(=O)O)C(=O)OC(C)(C)C
Reactant: N#Cc1nc(-c2c(F)cccc2F)oc1Nc1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCC(=O)Nc1ccc(Nc2oc(-c3c(F)cccc3F)nc2C#N)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-3-methylaminopropanoic acid (0.022 g, 0.11 mmol) in DMF (1.25 ml) were added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.040 g, 0.11 mmol) and diisopropylethylamine (0.018 ml, 0.11 mmol) followed by 5-(4-aminophenylamino)-2-(2,6-difluorophenyl)oxazole-4-carbonitrile (0.030 g, 0.10 mmol) and the resultant mixture stirred at room temperature overnight. A further portion of N-(tert-butoxycarbonyl)-3-methylaminopropanoic acid (0.022 g, 0.11 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.040 g, 0.11 mmol) and diisopropylethylamine (0.018 ml, 0.11 mmol) was added and the reaction stirred for 2 hours at room temperature. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford tert-butyl 3-(4-(4-cyano-2-(2,6-difluorophenyl)oxazol-5-ylamino)phenylamino)-3-oxopropyl(methyl)carbamate (0.021 g, 0.04 mmol, 44%) as a white solid. LCMS (2) Rt: 3.03 min; m/z (ES+) 498.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([O:17]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:20][NH2:21]>CO.O>[O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([NH:20][NH2:21])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccccc1Oc1ccccc1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)Cc1ccccc1Oc1ccccc1
Reaction time: 2 h
Yield: 96 %

Procedure:
A solution of methyl (2-phenoxyphenyl)acetate (6.0 g) in methanol (100 ml) was added dropwise with stirring to hydrazine hydrate (12 ml). The resulting mixture was stirred for 2 hours, then diluted with water and extracted with ether. The extracts were washed with water, dried and concentrated to give almost pure (2-phenoxyphenyl)acetohydrazide (5.8 g, 96% yield) as a waxy solid with amp of about 65° C., 1H NMR (CDCl3): delta 3.60 (2H,s) ppm. Concentrated sulphuric acid (4 drops) was added to a mixture of this hydrazide and triethyl orthoformate (20 ml) and the resulting mixture was heated at 90° C. for one hour. After cooling, water was added to the mixture and it was extracted with ether. The extracts were washed, dried, concentrated and chromatographed using increasing proportions (up to 50%) of ethyl acetate in hexane as eluant to give 2-(2-phenoxyphenylmethyl)oxa-1,3,4-diazole (3.14 g, 52% yield) as a yellow oil, IH NMR (CDCl3): delta 4.31 (2H,s) and 8.28 (1H,s) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]2([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:37]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:45]3[CH2:46][CH2:47][C:42]([C:38]4[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=4)([C:48]([NH2:50])=[O:49])[CH2:43][CH2:44]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: NC(=O)C1(c2cccnc2)CCNCC1
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4cccnc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 4-(pyridin-3-yl)-piperidine-4-carboxylic acid amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10](=[CH:11][C:12]3[NH:13][CH:14]=[N:15][C:16]=3[CH3:17])[C:9](=[O:18])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C(O)C>[CH3:17][C:16]1[N:15]=[CH:14][NH:13][C:12]=1[CH:11]=[C:10]1[C:3]2[C:2]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:7][CH:6]=[N:5][C:4]=2[NH:8][C:9]1=[O:18]
Reactant: C1COCCN1
Reactant: Cc1nc[nH]c1C=C1C(=O)Nc2ncnc(Cl)c21
Solvent: CCO
Product: Cc1nc[nH]c1C=C1C(=O)Nc2ncnc(N3CCOCC3)c21
Temperature: 110 °C
Yield: 70.4 %

Procedure:
A mixture of 4-chloro-5-(5-methyl-3H-imidazol-4-ylmethylene)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (26 mg, 0.1 mmol) and morpholine (100 mg, 1.15 mmol) in ethanol (1.5 mL) was heated in a sealed tube at 110° C. for 3 hours. The reaction solution was evaporated to dryness and treated with cold ethanol. The yellow precipitate was filtered to give 22 mg (70.5%) of the title compound. MS-EI 312 [M+].
Reaction SMILES: C(O[C:4]([NH:6][C:7]([N:22]1[CH:26]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]=[N:23]1)=[N:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=1)=[O:5])C.CCO>ClC(Cl)C.Cl[Ti](Cl)(Cl)Cl>[O:5]=[C:4]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:13]=2)[N:8]=[C:7]([N:22]2[CH:26]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]=[N:23]2)[NH:6]1
Reactant: CCOC(=O)NC(=Nc1cccc(Oc2ccccc2)c1)n1cc(C(=O)OCC)cn1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCO
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cnn(-c2nc3cc(Oc4ccccc4)ccc3c(=O)[nH]2)c1
Reaction time: 3 h
Yield: 81.5 %

Procedure:
To a solution of ethyl 1-(N-(ethoxycarbonyl)-N′-(3-phenoxyphenyl)carbamimidoyl)-1H-pyrazole-4-carboxylate (1.51 g, ca 2.51 mmol) in dichloroethane (DCE) (18 mL), neat TiCl4 (1.18 mL, 10.7 mmol) was added over 2 min. The mixture was then heated to reflux for 2 h, and then cooled in an ice bath. EtOH (50 mL) was added, and the mixture was stirred for 3 h. The resulting precipitate was collected by filtration, washed with cold EtOH, and dried to provide the titled compound (0.77 g, 57%). MS (ESI/CI): mass calcd. for C20H16N4O4, 376.1; m/z found, 377.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 12.85 (s, 1H), 9.00 (d, J=0.5 Hz, 1H), 8.31 (s, 1H), 8.13 (d, J=8.8 Hz, 1H), 7.58-7.45 (m, 2H), 7.38-7.27 (m, 1H), 7.26-7.20 (m, 2H), 7.18 (dd, J=8.8, 2.4 Hz, 1H), 6.98 (s, 1H), 4.39-4.13 (m, 2H), 1.42-1.21 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[H-].[Na+].[CH3:20]I>CN(C)C=O>[CH3:20][O:1][C:2]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:5]
Reactant: CI
Reactant: Cc1cccc(C(=O)c2ccc(Cl)cc2)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C)cccc1C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
A solution of 195.9 g of 2-hydroxy-3-methyl-4'-chlorobenzophenone [Huston et al., JACS, Vol. 73, (1951), p. 2483] in 1 liter of dimethylformamide was added with stirring to a suspension of 40.8 g of sodium hydride in 200 ml of dimethylformamide and the mixture was stirred for 1 hour with cooling in an ice-water bath. Then, a solution of 170.4 g of methyl iodide in 800 ml of dimethylformamide was added thereto over 40 minutes and the mixture was then stirred for 16 hours in the ice-water bath. The mixture was filtered to remove insolubles and the filtrate was treated with activated carbon, filtered and was evaporated to dryness under reduced pressure. The residue was taken up in 1 liter of ether and 200 ml of water and the aqueous phase was reextracted with ether. The combined ether phases were washed with water, dried over magnesium sulfate, treated with activated carbon, filtered and evaporated to dryness. The residue was chromatographed over silica and was eluted with methylene chloride to obtain 171 g of 2-methoxy-3-methyl-4'-chlorobenzophenone in the form of colorless crystals melting at 43° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:10](=[O:23])[C:11]3[CH:16]=[N:15][N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[CH3:31][S-:32].[Na+]>CN(C)C=O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([N:9]2[C:10](=[O:23])[C:11]3[CH:16]=[N:15][N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:12]=3[N:13]=[C:8]2[C:5]2[CH:4]=[CH:3][C:2]([S:32][CH3:31])=[CH:7][CH:6]=2)=[CH:25][CH:26]=1
Reactant: O=c1c2cnn(-c3ccccc3)c2nc(-c2ccc(Br)cc2)n1-c1ccc(Cl)cc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6-(4-bromo-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (2.50 g, 5.23 mmol) in dry N,N-dimethyl-formamide (20 mL), sodium thiomethoxide (0.55 g, 7.84 mmol) is added and the resulting mixture is stirred at 80° C. After 1.5 h, the reaction mixture is concentrated and the crude product obtained is purified by column chromatography (silica gel, 60-120 mesh) to afford 5-(4-chloro-phenyl)-6-(4-methylsulfanyl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one.
Reaction SMILES: [Br-].[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:9][CH:10]1[CH2:15][CH2:14][O:13][C:11]1=[O:12]>>[C:3]1([NH:2][CH:10]2[CH2:15][CH2:14][O:13][C:11]2=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BrH:9].[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1OCCC1Br
Agent: [Br-]
Solvent: Nc1ccccc1
Product: Br
Product: O=C1OCCC1Nc1ccccc1

Procedure:
Frankel et al [Israel J. Chem. 1, 379-84 (1963)] found that carbonyl attack on, and resulting ring opening of, alpha-bromo-gamma-butyrolactone by aniline is favored over bromide displacement (alkylation) at high temperature (100° C. vs. 0° ). In Frankel, an excess of aniline was contacted with alpha-bromo-gamma-butyrolactone to give alpha-phenylamino-gamma-butyrolactone after aniline hydrobromide salt was removed. The alpha-phenylamino-gamma-butyrolactone was stirred with a 10% aqueous solution of sodium hydroxide resulting in hydrolysis or fission of the lactone ring to yield alpha-phenylamino-gamma-hydroxy butyranilide.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([OH:10])=[O:9])[CH3:2].C(N1CCC[C@@H]1C(OC(C)(C)C)=O)C>>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[C:8]([OH:10])=[O:9])[CH3:2]
Reactant: CCN1CCC[C@H]1C(=O)O
Agent: CCN1CCC[C@@H]1C(=O)OC(C)(C)C
Product: CCN1CCC[C@@H]1C(=O)O

Procedure:
Prepared by proceeding in a similar manner to Intermediate 106, starting from tert-butyl (R)-1-ethylpyrrolidine-2-carboxylate (Intermediate 148) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[C:22]([C:23](=[O:32])[NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:21]([Cl:33])[N:20]=[C:19](S(C)(=O)=O)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:38]#[N:39].[Na+]>C(Cl)Cl.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[C:22]([C:23](=[O:32])[NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:21]([Cl:33])[N:20]=[C:19]([C:38]#[N:39])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2nc(S(C)(=O)=O)nc(Cl)c2C(=O)NCc2ccccc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCOc2nc(C#N)nc(Cl)c2C(=O)NCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the above product, 4-[2-(5-benzylcarbamoyl-6-chloro-2-methanesulfonylpyrimidin-4-yloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester in CH2Cl2/H2O (20 mL/2 mL) is added NaCN (3.3 mmol) and tetra-n-butylammonium bromide (0.14 mmol) at 0° C. After warmed up to room temperature, the reaction mixture is vigorously stirred for 1.5 h at room temperature. The mixture is diluted with CH2Cl2, washed with aq. NaHCO3. The organic layer is dried over Na2SO4, filtered, and concentrated. The residue is purified by silica gel column chromatography to give 4-[2-(5-benzylcarbamoyl-6-chloro-2-cyano-pyrimidin-4-yloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester as a white solid. 1H-NMR (CDCl3), δ 1.09-1.19 (2H, m), 1.46 (9H, s), 1.63-1.74 (5H, m), 2.66 (2H, br t), 4.07 (2H, m), 4.51 (2H, t), 4.66 (2H, d), 6.11 (1H, t), 7.31-7.37 (5H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:12]=2)[CH:8]=[N:7]1.[ClH:52]>O1CCOCC1.CO>[ClH:52].[F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([CH:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:43]=[CH:44][C:45]([CH3:46])=[CH:47][CH:48]=3)(=[O:40])=[O:41])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Yield: 99 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (191 mg, 0.270 mmol) was deprotected in HCl in dioxane/MeOH (5/5 ml). This afforded 173 mg (99% yield) of the titled. MS: m/z=606.8 (M+1).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]1[CH:16]=[C:15]([F:17])[C:14]([N+:18]([O-:20])=[O:19])=[CH:13]C=1C(O)=O.C(Cl)Cl>CN(C)C=O>[F:7][C:8]1[CH:16]=[C:15]([F:17])[C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1F
Temperature: 25 °C
Yield: 101.8 %

Procedure:
Oxalyl chloride (94.0 g, 0.739 mol) is added dropwise to a mixture of 2,4-difluoro-5-nitrobenzoic acid (100.0 g, 0.492 mol), methylene chloride and N,N-dimethylformamide (0.600 ml). The resultant mixture is stirred 3.25 hours at reflux, cooled to room temperature, and concentrated in vacuo to afford the title compound as a brown oil (111 g, 95.2%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N:15]1([CH2:20][CH2:21][CH2:22]O)[CH2:19][CH2:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:22][CH2:21][CH2:20][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc2c(Cl)ccnc2cc1O
Reactant: OCCCN1CCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1cc2c(Cl)ccnc2cc1OCCCN1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To a suspension of 4-chloro-6-cyano-7-hydroxyquinoline (10.22 g, 50 mmol), (prepared as described for the starting material in Example 1), 3-(pyrrolidin-1-yl)propan-1-ol (8.1 ml, 60 mmol) and triphenylphosphine (26.2 g, 100 mmol) in methylene chloride (200 ml) was added diethyl azodicarboxylate (16.4 ml, 100 mmol) in portions. After stirring the reaction mixture for 2 hours at ambient temperature, the volatiles were removed under vacuum and the residue was purified by column chromatography eluting with ethyl acetate/methylene chloride (1/1) followed by methanol/ethyl acetate/methylene choride (1/4/5 followed by 1/0/9) followed by methanol saturated with ammonia/methylene chloride (1/9 followed by 2/8). The fractions containing the expected product were combined and the volatiles were removed under vacuum. The residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-chloro-6-cyano-7-(3-(pyrrolidin-1-yl)propoxy)quinoline (14.3 g, 90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:19])=[C:16]([F:18])[F:17])=[CH:11][C:10]=2[O:20]C)[N:3]=1.B(Br)(Br)Br>>[F:1][C:2]1[N:3]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:19])=[C:16]([F:17])[F:18])=[CH:11][C:10]=2[OH:20])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(F)=C(F)F)ccc1Oc1cccc(F)n1
Agent: BrB(Br)Br
Product: Oc1cc(C(F)=C(F)F)ccc1Oc1cccc(F)n1
Yield: 64 %

Procedure:
According to the procedure of example 5(b) except substituting 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine by 2-fluoro-6-[2-methoxy-4-(trifluorovinyl)phenoxy]pyridine (0.033 mmol; 10 mg) and adding 3.5 equivalents (0.117 mmol; 117 μl) of boron tribromide, the title compound was prepared in 64% yield (0.021 mmol; 6 mg) after purification by preparative TLC on silica gel (ethyl acetate/cyclohexane—30/70).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].C([Li])CCC.[C:17]1(=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1.[OH-].[Na+]>[OH:22][C:17]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[CH3:11])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C1CCCC1
Reactant: Cc1cc(C(=O)O)ccc1Br
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1C1(O)CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
4-Bromo-3-methyl-benzoic acid (4.00 g, 18.6 mmol) was dissolved in tetrahydrofuran (80 mL) and the solution was cooled to −78° C. n-Butyllithium (16.4 mL of 2.5 M in hexanes, 40.9 mmol) was added dropwise over 20 min while maintaining the internal temperature below −65° C. resulting in a thin, light yellow slurry. The reaction mixture was allowed to stir for 30 min at −78° C. Cyclopentanone (1.57 g, 1.65 mL, 18.6 mmol) was then added in a dropwise manner. The mixture was stirred at −78° C. for 30 min, warmed to room temperature and stirred for 2 h. The reaction mixture was then diluted with 1 M NaOH (100 mL) and washed with diethyl ether. The organic layer was discarded and the aqueous layer was acidified with 4 M HCl to <pH 3. The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined extracts were dried over Na2SO4 and concentrated in vacuo. The crude product was filtered through silica gel eluting with 0-10% methanol/dichloromethane, and all product containing fraction concentrated in vacuo. The resulting solid was slurried in dichloromethane and filtered to provide 4-(1-hydroxycyclopentyl)-3-methylbenzoic acid (1.10 g, 26%) as a white solid. ESI-MS m/z calc. 220.10994. Found 221.5 (M+1)+; Retention time: 1.16 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 7.70 (d, J=1.4 Hz, 1H), 7.67 (dd, J=8.1, 1.7 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 4.77 (s, 1H), 2.54 (s, 3H), 2.07-1.98 (m, 2H), 1.98-1.89 (m, 2H), 1.87-1.77 (m, 2H), 1.72-1.59 (m, 2H).
Reaction SMILES: C(O[CH:5]([C:22]1[N:23]=[CH:24][N:25]([C:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]=1[CH3:27])[CH:6]1[C:20](=[O:21])[N:10]2[C:11]3[C:16]([C:17]([CH2:18][CH3:19])=[C:9]2[CH2:8][CH2:7]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)(=O)C.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.O>[CH2:18]([C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]2[C:20](=[O:21])[C:6](=[CH:5][C:22]3[N:23]=[CH:24][N:25]([C:28]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:26]=3[CH3:27])[CH2:7][CH2:8][C:9]=12)[CH3:19]
Reactant: CCc1c2n(c3ccccc13)C(=O)C(C(OC(C)=O)c1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1c2n(c3ccccc13)C(=O)C(=Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Temperature: 75 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of 7-[(acetoxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-10-ethyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one (2.06 g) in toluene (30 ml) at room temperature was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.2 ml). After being stirred at 75° C. for 3 hours, the solution was diluted with chilled water. The organic layer separated was washed with aqueous oxalic acid solution, water, and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was triturated with methanol and filtered to give 10-ethyl-8,9-dihydro-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methylene]pyrido[1,2-a]indol-6(7H)-one (1.41 g).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([OH:16])=O)[CH:13]=[C:8]2[CH:7]=[CH:6]1.Cl.[CH3:23][NH:24][OH:25]>>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([N:24]([OH:25])[CH3:23])=[O:16])[CH:13]=[C:8]2[CH:7]=[CH:6]1
Reactant: O=C(O)c1cc2ccn(Cc3ccc(F)cc3F)c2cn1
Reactant: CNO
Agent: Cl
Product: CN(O)C(=O)c1cc2ccn(Cc3ccc(F)cc3F)c2cn1

Procedure:
The title compound was prepared by coupling of 1-(2,4-difluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid and N-methyl hydroxylamine hydrochloride in a manner similar to step (c) of example 1. 1H NMR (DMSO-d6) δ: 11.10 (br, 1H), 8.92 (s, 1H), 8.04 (s, 1H), 7.82 (s, 1H), 7.26-7.38 (m, 2H), 7.07-7.08 (m, 1H), 6.72 (s, 1H), 5.64 (s, 2H), 3.33 (s, 3H). LCMS (API-ES, M+H+): 318.0. HRMS calcd for C16H14F2N3O2(M+H) 318.1054, found 318.1037. HPLC: 100% purity.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:7]([C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[NH:8])=[CH:14][CH:13]=1
Reactant: CSc1ccc(C#N)cc1
Reactant: Nc1ccc(F)cc1
Product: CSc1ccc(C(=N)Nc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared from 4-methylthiobenzonitrile (0.50 g, 33.6 mmol) and 4-fluoroaniline (0.372 g, 33.6 mmol) by following the procedure described in preparation 1, (0.43 g, 49.3%, mp 145-147° C., purity 94.7% by HPLC). 1H-NMR (CDCl3):δ 2.52 (s, 3H), 6.93-6.94 (m, 3H), 7.17-7.32 (m, 5H). MS m/z:261.1(M+)