Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=2)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][N:3]=1.Cl.[F:22][C:23]1[CH:24]=[N:25][C:26]([C@@H:29]([NH2:31])[CH3:30])=[N:27][CH:28]=1.C(N(C(C)C)CC)(C)C>CCCCO.C(OCC)(=O)C>[F:22][C:23]1[CH:24]=[N:25][C:26]([C@@H:29]([NH:31][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=3)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][N:3]=2)[CH3:30])=[N:27][CH:28]=1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: CC(C)Oc1cc(Nc2nc(Cl)ncc2[N+](=O)[O-])n[nH]1
Agent: Cl
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ncc2[N+](=O)[O-])n[nH]1
Temperature: 70 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
A mixture of 2-chloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-5-nitropyrimidin-4-amine (Intermediate 30, 0.2 g) and [(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amine hydrochloride (Intermediate 15, 0.15 g) in n-BuOH (5 mL) with diisopropylethylamine (1 mL) was stirred at 70° C. for 4 hours. The resulting mixture was diluted with ethyl acetate (20 mL), and washed with brine (10 mL×3). The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to yield 0.2 g of title compound. MS (electrospray): 404 (M+1) for C16H18FN9O3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:8]=[CH:7]2.C([Li])(CC)C.C(O[B:30]1[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]1)(C)C>C1COCC1>[F:1][C:2]1[C:3]([B:30]2[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[CH:8]=[CH:7]2
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cccc(F)c21
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c21
Temperature: -75 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
7-Fluoro-1-(triisopropylsilyl)-1H-indole (4.0 g, 14 mmol) (Prepared according to M. Schlosser, et al, Eur. J. Org. Chem. 2006, 2956-2969) was dissolved in 30 mL dry THF, cooled to −75° C., treated in portions with sec-butyl lithium (10 mL, 1.4 M, 14 mmol) and stirred for 2 h at −75° C. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.0 mL, 2.7 g, 14 mmol) was added in portions and the mixture was stirred for 1 h at −75° C. The cooling was removed and the temperature was allowed to rise to 5° C. over 30 min. The reaction was quenched by addition of 5 mL sat. NH4Cl and partitioned between ethyl acetate and water. The organic phase was washed with sat. NaCl, dried (Na2SO4), evaporated onto silica gel, and purified by flash chromatography (SiO2; eluting with hexanes) to give 4.2 g of the title compound as a thick oil (4.2 g, 73%): 1H NMR (400 MHz, CDCl3) δ 7.43 (dd, J=7.9, 4.6 Hz, 1H), 7.38 (m, 2H), 1.75 (m, 3H), 1.38 (s, 12H), 1.13 (d, J=7.6 Hz, 18H). 19F NMR (376 MHz, CDCl3) δ −113.07. EIMS m/z 417.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[N:13][CH:14]=1)=[O:6].[CH3:26][C:27]1[CH:28]=[CH:29][C:30](B2OC(C)(C)C(C)(C)O2)=[C:31]([CH:34]=1)[C:32]#[N:33].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[C:32]([C:31]1[CH:34]=[C:27]([CH3:26])[CH:28]=[CH:29][C:30]=1[C:2]1[CH:18]=[C:17]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[CH:16]=[C:4]([C:5]([NH:7][CH2:8][C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[N:13][CH:14]=2)=[O:6])[CH:3]=1)#[N:33]
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C#N)c1
Reactant: Cc1ncc(CNC(=O)c2cc(Br)cc(C(=O)N3CCCC3)c2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)nc3)cc(C(=O)N3CCCC3)c2)c(C#N)c1
Temperature: 90 °C

Procedure:
Into a Parr pressure reactor were charged 3-bromo-N-((2-methylpyrimidin-5-yl)methyl)-5-(pyrrolidine-1-carbonyl)benzamide (240 mg, 0.48 mmol), 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (160 mg, 0.58 mmol) (WO 2008/130481), toluene (5 mL), ethanol (1 mL), cesium carbonate (170 mg, 0.52 mmol), and water (0.5 mL). The mixture was degassed and purged with nitrogen several times and then tetrakis(triphenylphosphine)palladium(0) (28 mg, 0.024 mmol) was added. The tube was sealed and the mixture was heated at 90° C. overnight. After cooling, the mixture was filtered through Celite and the filtrate was concentrated. The residue was purified via flash chromatography and then preparative HPLC to afford the desired product as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42](C=O)[CH:41]=5)[CH:36]=[C:37]([CH3:39])[CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.[CH3:57]C(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:41]=[CH:42][CH:43]=[C:44]([CH2:50][N:51]6[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]6)[CH:45]=5)[CH:36]=[C:37]([CH3:39])[CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(=O)O
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(C)cc(-c3cccc(C=O)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(C)cc(-c3cccc(CN4CCN(C)CC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
To a solution of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-5-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (100 mg, 0.15 mmol) in DCM (2 mL) was added 1-methyl piperazine (22.8 mg, 0.23 mmol), and AcOH (0.01 mL, 0.18 mmol) followed by NaBH(OAc)3 (64.3 mg, 0.30 mmol). The reaction mixture was stirred at RT overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give a crude residue. It was purified using a Gilson HPLC (with 0.1% TFA condition) eluting with 10 to 90% CH3CN in water at a flowrate of 20 mL/min. Fractions containing product were combined and then converted to the free base with saturated NaHCO3. The organic layer was dried over sodium sulfate, filtered and then concentrated to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-({5-methyl-3′-[(4-methyl-1-piperazinyl)methyl]-3-biphenylyl}methyl)-1,3-benzenedicarboxamide as a white solid (42 mg, 37%). LC-MS m/z 743 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19](I)=[CH:18][C:17]=2[O:23][CH3:24])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:26][C:27]([Sn](C)(C)C)=[CH2:28].[OH2:33]>C1COCC1>[C:17]([OH:23])(=[O:26])[C:16]([OH:15])=[O:33].[C:27]([C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH:10]2[O:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9]2)=[C:17]([O:23][CH3:24])[CH:18]=1)(=[O:26])[CH3:28]
Reactant: C=C(OC)[Sn](C)(C)C
Reactant: O
Reactant: COc1cc(I)ccc1OCC1CN(Cc2ccccc2)CCO1
Solvent: C1CCOC1
Product: COc1cc(C(C)=O)ccc1OCC1CN(Cc2ccccc2)CCO1
Product: O=C(O)C(=O)O
Reaction time: 1 h

Procedure:
(±)-4-Benzyl-2-[(4-iodo-2-methoxyphenoxy)methyl]morpholine (360 mg, 0.82 mmol), 1-methoxyvin-1-yl trimethyltin (528 mg, 2.4 mmol), and palladium bis(triphenylphosphine)palladium(II)chloride (36 mg, 0.052 mmol) were refluxed in THF (15 ml) for 24 h. Water was added and was followed by extraction twice with ethyl acetate. The solvent was evaporated and the residue was stirred in aqueous hydrochloric acid (25 ml, 1 M) and methanol (10 ml) at 50° C. for 1 h. The product was extracted with ethyl acetate. Drying and evaporation of the solvent was followed by chromatography. The product was dissolved in ether and precipitated as the oxalate. Yield 40 mg. mp 122-127° C.
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].[CH2:8]([O:10][C:11](=[O:24])[CH2:12][CH2:13][C:14]1[C:22]2[C:21](=[O:23])[CH2:20][CH2:19][CH2:18][C:17]=2[NH:16][CH:15]=1)[CH3:9].COC(OC)OC.[OH-].[Na+]>O.C(OCC)(=O)C>[CH2:8]([O:10][C:11](=[O:24])[CH2:12][CH2:13][C:14]1[C:22]2[C:21](=[O:23])[CH2:20][CH2:19][CH2:18][C:17]=2[NH:16][C:15]=1[CH:3]=[O:4])[CH3:9]
Reactant: CCOC(=O)CCc1c[nH]c2c1C(=O)CCC2
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COC(OC)OC
Product: CCOC(=O)CCc1c(C=O)[nH]c2c1C(=O)CCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
To a trifluoroacetic acid solution (47 mL) containing 3-(3-ethoxy-3-oxopropyl)-4-oxo-4,5,6,7-tetrahydro-1H-indole (4, 10.0 g, 42.5 mmol) was added with trimethylorthoformate (13.6 g, 128 mmol) at 0° C. The reaction was stirred at 0° C. for 30 min, warmed up to room temperature and stirred for 2.0 h. The solution was added with ethyl acetate (250 mL), water (200 mL) and NaOH (18 g). The organic layer was collected and washed with saturated aqueous NaHCO3 (200 mL), dried over MgSO4 (s), and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (50% EtOAc in hexanes) to give 3-(3-ethoxy-3-oxopropyl)-2-formyl-4-oxo-4,5,6,7-tetrahydro-1H-indole (5, 2.1 g, 8.0 mmol) as yellow solids in 19% yield.
Reaction SMILES: [CH2:1]([CH:3]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:4][N:5]1[C:17]2[CH:16]=[CH:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[CH3:30][C:31]1[CH:39]=[C:38]([CH3:40])[CH:37]=[C:36]([CH3:41])[C:32]=1[C:33](Cl)=[O:34].[C:42]1([CH3:51])[C:43]([C:48](Cl)=[O:49])=[CH:44][CH:45]=[CH:46][CH:47]=1>C(Cl)Cl>[CH2:1]([CH:3]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:4][N:5]1[C:17]2[CH:16]=[CH:15][C:14]3[CH:18]=[C:19]([C:33](=[O:34])[C:32]4[C:31]([CH3:30])=[CH:39][C:38]([CH3:40])=[CH:37][C:36]=4[CH3:41])[CH:20]=[CH:21][C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([C:48]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[CH3:51])=[O:49])[CH:8]=[CH:7][C:6]1=2)[CH3:2]
Reactant: CCCCC(CC)Cn1c2ccccc2c2c3ccccc3ccc21
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCC(CC)Cn1c2ccc(C(=O)c3ccccc3C)cc2c2c3ccc(C(=O)c4c(C)cc(C)cc4C)cc3ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 21.1 %

Procedure:
To 7-(2-ethylhexyl)-7H-benzo[c]carbazole (0.66 g, 2.00 mmol) in CH2Cl2 are added AlCl3 (0.27 g, 2.06 mmol) and 2,4,6-trimethylbenzoyl chloride (0.37 g, 2.00 mmol) at 0° C., and then the mixture is stirred for 2 hours. To the reaction mixture are added AlCl3 (0.29 g, 2.20 mmol) and o-toluoyl chloride (0.32 g, 2.06 mmol) at 0° C., and then the mixture is stirred overnight. The reaction mixture is poured into ice-water, and the crude product is extracted with CH2Cl2, and washed with water and brine. After drying over MgSO4 and concentration, the crude product is purified by column chromatography on silica gel eluting with a mixed solvent of CH2Cl2 and n-hexane (4:1) to obtain a white solid (0.25 g, 21%). The structure is confirmed by 1H-NMR spectrum (CDCl3) δ [ppm]: 0.84 (t), 0.93 (t), 1.22-1.45 (m), 2.04-2.09 (m), 2.18 (s), 2.38 (s), 2.39 (s), 4.32-4.34 (m), 6.97 (s), 7.30-7.37 (m), 7.42-7.47 (m), 7.51 (d), 7.68 (d), 7.88 (br), 7.96 (d), 8.21 (dd), 8.37 (d), 8.78 (br), 9.19 (br).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21][C:22]([F:33])([F:32])C1C=CC(B(O)O)=CC=1>>[F:21][C:22]([F:33])([F:32])[C:4]1[CH:3]=[CH:2][C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)=[CH:6][CH:5]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: O=C1NCCc2c(-c3ccc(C(F)(F)F)cc3)[nH]c3cccc1c23

Procedure:
In a manner analogous to the method described above for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 4-trifluoromethylphenylboronic acid (322 mg, 1.70 mmol) were coupled to yield 2-(4-trifluoromethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 261 mg (70%), as an off-white solid. mp 208-209° C.; 1H NMR (300 MHz, d6-DMSO) δ3.09 (m, 2H), 3.40 (m, 2H), 7.27 (app t, 1H, J=7.8 Hz), 7.60 (dd, 1H, J=8.1, 0.9 Hz), 7.71 (dd, 1H, J=7.5, 0.6 Hz), 7.88 (m, 4H), 8.13 (br t, 1H), 11.77 (br s, 1H); MS (FAB, MH+) 331; Anal. (C18H13F3N2O. 1.0 H2O) C, H, N.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][C:16]=1[F:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([C:2]2[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=2[NH2:4])[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: Cc1ccc(N)c(Br)c1
Product: Cc1ccc(N)c(-c2ccc(F)c(Cl)c2)c1

Procedure:
2-bromo-4-methylaniline and 3-chloro-4-fluorobenzene boronic acid were combined to form 2-(3-chloro-4-fluorophenyl)-4-methylaniline,
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:13][CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16]>COCCO>[CH2:15]([CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH3:16]
Reactant: CCCCC(CC)CBr
Reactant: N#Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: CCCCC(CC)COc1ccc(C#N)cc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 84.3 %

Procedure:
A 1 l sulfonating flask equipped with stirrer, cooler, dropping funnel and internal thermometer is charged with 61.4 g (0.5 mol) of 4-hydroxybenzonitrile in 500 ml of methylcellosolve. After heating the batch to 80° C., 73.3 g of 30% NaOH (0.55 mol) are slowly run in with vigorous stirring. Stirring is continued for 15 minutes before adding 116.8 g (0.575 mol) of 3-bromomethylheptane dropwise over a period of 30 minutes. The reaction is continued at 100° C. for about 12 hours. The thin-layer chromatogram shows almost quantitative conversion. The solvent and excess bromide are removed in vacuo, and the residue (oil) is taken up in 500 ml of toluene. The resulting mixture is extracted three times with water, the organic phase is dried over sodium sulfate and evaporated to dryness. High-vacuum distillation through a 10-cm Vigreux column (127°-132° C., 0.15 mmHg) gives 97.5 g (84% of theory) of 4-(2-ethylhexyloxy)benzonitrile as a coloured oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.N1C=CC=CC=1.[F-:20]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([F:20])=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: [F-]
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(F)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 1 h

Procedure:
A solution of 5-chloro-1H-indole-2-carboxylic acid (10.0 g, 51.1 mmol) and pyridine (33.1 mmol) in acetonitrile was added to a solution of byanuric fluoride (2.76 g, 20.4 mmol) in acetonitrile (total 340 mL) at 25° C. The reaction was followed by TLC on aliquots quenched with butylamine and appeared nearly complete at 1 hour. The mixture was poured onto ice, extracted with ether, dried (Na2SO4), and concentrated giving a solid which was used without purification (10.0 g, 99%). TLC of a butylamine-quenched aliquot showed some 5-chloroindole-2-carboxylic acid and the less polar N-butylamide. A sample was purified by chromatography on silica gel eluting with ethyl acetate-hexanes (50-100%) for characterization (16368-130-1).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCC)[NH:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][NH:36][CH3:37]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:36]([CH2:35][CH2:34][N:33]([CH3:38])[CH3:32])[CH3:37])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: CCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CNCCN(C)C
Product: CN(C)CCN(C)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(2-dimethylamino-ethyl)-methyl-amino]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazolidin-4-one and N,N,N′-Trimethyl-ethane-1,2-diamine following General Procedure C.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[NH:12][CH3:13])=[CH:4][C:3]=1[F:18].[NH:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1>N1C=CC=CC=1>[F:18][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1)[N:9]([NH:12][CH3:13])[CH:8]=[C:7]([C:14]([OH:16])=[O:15])[C:6]2=[O:17]
Reactant: C1CSCCN1
Reactant: CNn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: c1ccncc1
Product: CNn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCSCC3)cc21

Procedure:
6-Fluoro-1,4-dihydro-1-methylamino-4-oxo-7-(4-thiomorpholinyl)-3-quinolinecarboxylic acid [I; R=CH3NH, R"=H, Z=N=4-thiomorpholinyl] was prepared from 3.5 g of 7-chloro-6-fluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid (Preparation 4A) and 6.5 ml of thiomorpholine in 80 ml of pyridine according to the procedure of Example 1. There was obtained 2 g of product, pale yellow solid, m.p. 260°-261° C. when recrystallized from dimethylformamide.
Reaction SMILES: C(C1C=NC(C2C=CC(O[CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([O:30][C:31]([F:48])([F:47])[C:32]([F:46])([F:45])[O:33][C:34]([F:44])([F:43])[C:35]([F:42])([F:41])[O:36][C:37]([F:40])([F:39])[F:38])([F:29])[F:28])=CC=2)=NC=1)CCCCCCC.[CH2:49]([O:57][C:58]1[CH:59]=[N:60][C:61]([C:64]2[CH:69]=[CH:68][C:67]([OH:70])=[CH:66][CH:65]=2)=[N:62][CH:63]=1)[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]>CN(C)C=O>[CH2:49]([O:57][C:58]1[CH:63]=[N:62][C:61]([C:64]2[CH:65]=[CH:66][C:67]([O:70][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([O:30][C:31]([F:47])([F:48])[C:32]([F:45])([F:46])[O:33][C:34]([F:43])([F:44])[C:35]([F:41])([F:42])[O:36][C:37]([F:40])([F:39])[F:38])([F:29])[F:28])=[CH:68][CH:69]=2)=[N:60][CH:59]=1)[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]
Reactant: CCCCCCCCc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Reactant: CCCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Solvent: CN(C)C=O
Product: CCCCCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
The title compound was prepared essentially as in Example 1 by combining 3-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-chloropropane (5.2 g, 10.9 mmol, Example 24) with 5-octyloxy-2-(4-hydroxyphenyl)pyrimidine (3 g, 10.0 mmol) in dimethylformamide and stirring at 120° C. overnight. The resulting product was further purified by Kugelrohr distillation (b.p. 195-210° C. at 0.3 torr), followed by recrystallization from ethanol and additional distillation (yield of 3.5 g).
Reaction SMILES: N([O-])=O.[Na+].FC(F)(F)C([O-])=O.[CH2:12]([O:14][C:15]([C:17]1[CH:18]=[N:19][N:20]2[CH:25]=[CH:24][C:23]([NH3+])=[C:22]([F:27])[C:21]=12)=[O:16])[CH3:13].[BrH:28]>O>[Br:28][C:23]1[CH:24]=[CH:25][N:20]2[N:19]=[CH:18][C:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])=[C:21]2[C:22]=1[F:27]
Reactant: CCOC(=O)c1cnn2ccc([NH3+])c(F)c12
Reactant: Br
Agent: O=C([O-])C(F)(F)F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cnn2ccc(Br)c(F)c12
Reaction time: 0.5 h

Procedure:
NaNO2 (2.26 g, 32.89 mmol) in water (7 mL) was added dropwise at 0° C. to a solution of 3-(ethoxycarbonyl)-4-fluoropyrazolo[1,5-a]pyridin-5-aminium 2,2,2-trifluoroacetate (7 g, 97.5 mmol) in aq. 47% HBr (56 mL) and continued stirring at same temperature for 30 min. CuBr (6.29 g, 44 mmol) in aq. 47% HBr (56 mL) was added dropwise to above solution at 0° C. and stirring was continued at 28° C. for 1 hr. Reaction mixture was quenched with ice water, extracted into EtOAc, washed it with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude. The crude obtained was purified by column purification (using 60-120 silicagel and 5% EtOAc in Hexane as eluant) to afford ethyl 5-bromo-4-fluoropyrazolo[1,5-a]pyridine-3-carboxylate. NMR (300 MHz, DMSO-d6) δ 9.45-9.43 (d, 1H), 8.51 (s, 1H), 8.33-8.30 (d, 1H), 4.35-4.28 (m, 2H), 1.36-1.31 (t, 3H).
Reaction SMILES: [N:1]1([C:7](=[O:9])[CH3:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:10](#[N:13])[CH:11]=[CH2:12]>CO>[C:7]([N:1]1[CH2:6][CH2:5][N:4]([CH2:12][CH2:11][C:10]#[N:13])[CH2:3][CH2:2]1)(=[O:9])[CH3:8]
Reactant: CC(=O)N1CCNCC1
Reactant: C=CC#N
Solvent: CO
Product: CC(=O)N1CCN(CCC#N)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.5 %

Procedure:
To 1-(piperazin-1-yl)ethanone (5 g, 39 mmol) in MeOH (50 mL) at 0° C. is added acrylonitrile (2.57 mL, 39 mmol) in one portion. The resulting reaction is stirred for 12 hours while allowing the reaction to warm to room temperature. The reaction mixture is concentrated in vacuo and the resulting residue diluted with 5 mL of water and extracted with EtOAc (3×25 mL). The combined organic layers are dried (MgSO4) and concentrated in vacuo. The residue is purified over silica (2% MeOH in CH2Cl2) to afford 6.4 g (91% yield) of the desired compound. 1H NMR (CDCl3, 300 MHz) δ2.08 (s, 3H), 2.46 (t, J=5.1 Hz, 2H), 2.51-2.53 (m, 4H), 2.71 (t, J=6.9 Hz, 2H), 3.48 (t, J=5.1 Hz, 2H), 3.26 (t, J=5.1 Hz, 2H). MS (ESI, pos. ion) m/z: 182 (M+1).
Reaction SMILES: [N:1](OCCC(C)C)=O.[CH2:9]([O:11][C:12](=[O:35])[C@@H:13]([CH2:20][C:21]1[CH:26]=[C:25]([Br:27])[C:24]([NH2:28])=[C:23]([CH3:29])[C:22]=1[CH2:30][O:31][C:32](=[O:34])[CH3:33])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10].C([O-])(=O)C.[K+]>C(O)(=O)C.C1(C)C=CC=CC=1>[CH2:9]([O:11][C:12](=[O:35])[C@@H:13]([CH2:20][C:21]1[C:22]([CH2:30][O:31][C:32](=[O:34])[CH3:33])=[C:23]2[C:24](=[C:25]([Br:27])[CH:26]=1)[NH:28][N:1]=[CH:29]2)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10]
Reactant: CCOC(=O)C[C@H](Cc1cc(Br)c(N)c(C)c1COC(C)=O)C(=O)OCC
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@H](Cc1cc(Br)c2[nH]ncc2c1COC(C)=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 77 %

Procedure:
Isoamyl nitrite (2.3 mL, 17 mmol), was added drop-wise to an ice cold solution of 2-(S)-(2-Acetoxymethyl-4-amino-5-bromo-3-methyl-benzyl)-succinic acid diethyl ester (7.14 g, 16 mmol) in 5% acetic acid in toluene (280 mL). Mixture stirred at 0° C. for 40 minutes. Potassium acetate (4.00 g, 41 mmol) was added to the mixture. Mixture was slowly warmed to room temperature. Reaction was stirred at room temperature for 14 hours. Mixture was washed twice with water and once with brine. Organic was dried (magnesium sulfate) filtered and concentrated. Silica gel chromatography (ethyl acetate-hexanes) afforded the desired product in 77% yield as an amber oil. MS m/e (M+H)+=455.0, 457.0.