Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][C:10]=2[Cl:12])[N:5]=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([SH:22])[N:16]=1.O>CN1CCN(C)C1=O>[Cl:12][C:10]1[CH:9]=[C:8]([Cl:13])[CH:7]=[C:6]2[C:11]=1[C:2]([S:22][C:17]1[N:18]=[C:19]([CH3:21])[CH:20]=[C:15]([CH3:14])[N:16]=1)=[CH:3][CH:4]=[N:5]2
Reactant: Clc1cc(Cl)c2c(Cl)ccnc2c1
Reactant: Cc1cc(C)nc(S)n1
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: Cc1cc(C)nc(Sc2ccnc3cc(Cl)cc(Cl)c23)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
A solution was prepared by dissolving 15.7 g of 4,5,7-trichloroquinoline in 60 ml of dry dimethylimidazolidinone. To the solution, 10.4 g of 4,6-dimethyl-2-mercaptopyrimidine was added with stirring at the room temperature. The reaction was progressed with heat evolution and the temperature of the reaction mixture was increased to 50° C. Crystals were precipitated in the course of the reaction. After finishing the addition, stirring was continued for about 2 hours to complete the reaction. The reaction mixture was mixed with 300 ml of water. Precipitated crystals were filtered and recrystallized from acetone to obtain 20.8 g (91.9% yield) of 5,7-dichloro-4-(4,6-dimethyl-2-pyrimidinylthio)quinoline. Melting point was 182.0°-183.2° C.
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([F:18])=[CH:16][N:15]([CH2:19][CH2:20][C@@:21]([CH3:31])([S:27]([CH3:30])(=[O:29])=[O:28])[C:22]([O:24]CC)=[O:23])[C:14](=[O:32])[CH:13]=2)=[CH:8][CH:7]=1)[CH3:4].Cl>O1CCCC1.O>[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([F:18])=[CH:16][N:15]([CH2:19][CH2:20][C@@:21]([CH3:31])([S:27]([CH3:30])(=[O:28])=[O:29])[C:22]([OH:24])=[O:23])[C:14](=[O:32])[CH:13]=2)=[CH:8][CH:7]=1)[CH3:4]
Reactant: CCOC(=O)[C@@](C)(CCn1cc(F)c(-c2ccc(OCC)cc2)cc1=O)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(-c2cc(=O)n(CC[C@](C)(C(=O)O)S(C)(=O)=O)cc2F)cc1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
Lithium hydroxide (108 mg, 4.37 mmol) was added to a solution of ethyl (2R)-4-[4-(4-ethoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoate (320 mg, 0.728 mmol) in tetrahydrofuran:water (1:1, 20 mL) and the reaction was allowed to stir at rt until complete. The reaction mixture was acidified with 4 M aq HCl and extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated to afford the title compound as a solid (220 mg, 73%). MS (LCMS) m/z 412.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26-1.40 (m, 3H) 1.54 (s, 3H) 2.07-2.26 (m, 1H) 2.43 (d, J=6.24 Hz, 1H) 3.14 (s, 3H) 3.83-4.15 (m, 4H) 6.42 (d, J=7.81 Hz, 1H) 6.93-7.07 (m, 2H) 7.50 (dd, J=8.68, 1.85 Hz, 2H) 7.97 (d, J=6.83 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:18]=[N:17][C:16]([N:19]3[CH2:23][CH2:22][NH:21][C:20]3=[O:24])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=[O:6].[H-].[Na+].I[CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37].O>CN(C=O)C>[CH3:37][CH:36]([CH3:38])[CH2:35][CH2:34][N:21]1[CH2:22][CH2:23][N:19]([C:16]2[N:17]=[N:18][C:13]([N:10]3[CH2:9][CH2:8][N:7]([C:5](=[O:6])[C:4]4[CH:25]=[CH:26][CH:27]=[CH:28][C:3]=4[C:2]([F:1])([F:29])[F:30])[CH2:12][CH2:11]3)=[CH:14][CH:15]=2)[C:20]1=[O:24]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(N3CCNC3=O)nn2)CC1
Reactant: CC(C)CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCN1CCN(c2ccc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)nn2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
A mixture of 1-{6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazin-3-yl}imidazolidin-2-one (0.080 g, 0.180 mmol), sodium hydride in 60% mineral oil (0.0035 g, 0.150 mmol) in DMF (10 mL) was stirred at room temperature for 30 minutes. 1-Iodo-3-methylbutane (0.0376 g, 0.190 mmol) was added and the mixture was stirred at 60° C. for 24 hours, followed by the dilution with 50 mL of water, and then extracted with ethyl acetate (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The title compound was obtained as a pale yellow solid in 32% yield (0.028 mg) after column chromatography purification. 1H NMR (300 MHz, CDCl3) δ 8.45 (d, J=9.9 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.48-7.65 (m, 2H), 7.32 (d, J=7.5 Hz, 1H), 6.98 (d, J=9.9 Hz, 1H), 3.82-4.12 (m, 4H), 3.42-3.64 (m, 6H), 3.24-3.34 (m, 4H), 1.38-1.66 (m, 3H), 0.92 (d, J=6.5 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 167.8, 157.3, 150.5, 134.8, 132.6, 129.7, 127.5, 127.1, 125.8, 122.1, 120.4, 116.6, 46.8, 46.3, 45.9, 42.5, 42.1, 41.5, 36.5, 26.1, 22.8. MS (ES+) m/z 491 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)=O)[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[O:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[C:19]1[N:12]2[C:13]([CH:14]=[N:15][C:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[N:11]2)=[C:16]([CH3:17])[N:18]=1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccco3)nn2)cc1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Nc2ncc3c(C)nc(-c4ccco4)n3n2)cc1
Yield: 24.9 %

Procedure:
Applying the Cyclization Procedure 1, using N[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-2-furancarboxamide (Intermediate 59) (85 mg, 0.25 mmol), 1,2-dichloroethane (5 mL) and phosphorus oxychloride (0.19 mL, 2.04 mmol), to afford 7-(2-furanyl)-5-methyl-N-[4-(methyloxy)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (20 mg) as a yellow solid. MS m/z 322 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].Cl[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:29])[CH:7]([NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([CH2:27][O:28][C:33]3[N:32]=[CH:31][C:40]4[C:35]([CH:34]=3)=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(CO)cc2)cc1)C(=O)OC(C)(C)C
Reactant: Clc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(COc3cc4ccccc4cn3)cc2)cc1)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
Step 3C 2-(4′-Hydroxymethyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester (700 mg, 1.68 mmol, 1 equiv), 2-chloroquinoline (1.1 g, 6.7 mmol, 4 equiv) were dissolved in DMF (20 mL) and added with and NaH (202 mg,60% in oil, 5.04 mmol, 3 equiv). The mixture was heat to 100° C. for 2 hrs. After cooling to room temperature, the reaction mixture was quenched with sat. NH4Cl (aq). After stirring for 0.5 h, solid precipitated from the mixture. Solid was collected by filtration and washed with water and dried overnight to produce 793 mg of 2-[4′-(Isoquinolin-3-yloxymethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester in 87% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:9])[CH3:8])=[CH:3][CH:2]=1.[H-].[Na+].[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.O>C1COCC1>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:9][CH:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH3:8])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O)c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OC(C)c2ccncc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
To a solution of 1-(pyridine-4-yl)ethanol (400 mg, 3.25 mmol) in THF (10 mL) was added sodium hydride (301 mg, 12.54 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min. 4-methylbenzene-1-sulfonyl chloride (744 mg, 3.90 mmol) was added and the mixture was stirred at room temperature for 4 hr. Water (10 mL) was added and THF was removed under reduced pressure. The residue was extracted with ethyl acetate (20 mL×3). The organic layer was washed with brine and dried over sodium sulfate. The solvent was removed under vacuum and the residue was purified by column chromatography on silica gel (eluted: petroleum ether/ethyl acetate=2/1) to give 1-(pyridine-4-yl)ethyl 4-methylbenzenesulfonate (0.56 g, 62.2%). LCMS 278 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:15](OS(C(F)(F)F)(=O)=O)=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[CH2:31]([O:33][CH:34]=[CH:35][Sn](CCCC)(CCCC)CCCC)[CH3:32].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:34]([O:33]/[CH:31]=[CH:32]/[C:15]1[C:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:13][CH:12]=[C:11]2[N:7]([CH2:6][C:5]3[CH:29]=[CH:30][C:2]([F:1])=[CH:3][CH:4]=3)[CH:8]=[CH:9][C:10]=12)[CH3:35]
Reactant: CCOC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1OS(=O)(=O)C(F)(F)F
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCO/C=C/c1c(C(=O)OCC)ncc2c1ccn2Cc1ccc(F)cc1
Temperature: 140 °C

Procedure:
To a stirred solution of ethyl 1-(4-fluorobenzyl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (10.0 g, 22.4 mmol) and ethoxyvinyl tributyltin [prepared according to A. Leusik, H. A. Budding, J. W. Marsman, J. Organomet. Chem., 1967, 9, 285-294] (9.7 g, 26.9 mmol, mixture of E-1,2: Z-1,2: 1:1, ratio=1:0.3:0.1) in DMF (30 mL) under a nitrogen atmosphere were added triethylamine (3.2 mL, 22.4 mmol) and dichlorobis(triphenylphosphine)palladium(II) (1.0 g, 1.4 mmol). The resulting mixture was heated to 140° C. for 10 minutes. It was quenched with aq NaHCO3 solution, and extracted with ethyl acetate. The organic layer was washed with brine (2×), dried over sodium sulfate, concentrated in vacuo and purified by Biotage flash chromatography. Elution with hexane:ethyl acetate (3:2) provided the title compound as a brown glue (1.0 g pure E-isomer) and 7.7 g of a mixture of E, Z and alpha with ratio=1:0.3:0.4). 1H NMR (DMSO-d6) δ; 8.69 (s, 1H), 7.85 (d, J=3.3 Hz, 1H), 7.33 (t, J=6.8 Hz, 2H), 7.13-7.20 (m, 3H), 6.86 (d, J=3.3 Hz, 1H), 6.43 (d, J=13 Hz, 1H), 5.55 (s, 2H), 4.27 (q, J=7.2 Hz, 2H), 3.98 (q, J=7.0 Hz, 2H), 1.29 (t, J=7.1 Hz, 6H). LCMS (APCI, M+H+): 369.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=O)[CH3:15])[CH:9]=1.[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10](/[C:14](=[C:21]2/[C:20](=[O:22])[NH:19][C:18](=[O:23])[S:17]/2)/[CH3:15])[CH:9]=1
Reactant: O=C1CSC(=O)N1
Reactant: CC(=O)c1cccc(-c2ccccc2Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CC(=O)OC(C)=O
Product: C/C(=C1/SC(=O)NC1=O)c1cccc(-c2ccccc2Cl)c1
Temperature: 25 °C

Procedure:
To a solution of 1-(2′-chloro-1,1′-biphenyl-3-yl)ethanone (145 mg, 0.63 mmol) and 2,4-thiazolidinedione (67 mg, 0.57 mmol) in xylene (1.9 mL), sodium acetate (38 mg, 0.28 mmol) and acetic anhydride (53 μL, 0.57 mmol) were added and the solution was heated in a sealed tube for 16 h. It was then cooled to rt, partitioned between ethyl acetate and water, washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. Finally filtered, concentrated and purified by chromatography. (hexanes:ethyl acetate; 4:1) to give the product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([NH:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][N:39]([C:42](=[O:48])[CH2:43][O:44]C(=O)C)[CH2:38][CH2:37]2)=[O:32])[C:25]=1[CH3:49])(=[O:12])=[O:11].C(=O)([O-])[O-].[K+].[K+]>O.CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([NH:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][N:39]([C:42](=[O:48])[CH2:43][OH:44])[CH2:38][CH2:37]2)=[O:32])[C:25]=1[CH3:49])(=[O:12])=[O:11]
Reactant: CC(=O)OCC(=O)N1CCN(CCNC(=O)Cc2c(C)[nH]c(/C=C3\C(=O)Nc4ccc(S(=O)(=O)Cc5c(Cl)cccc5Cl)cc43)c2C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)NCCN1CCN(C(=O)CO)CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A mixture of acetic acid 2-{4-[2-(2-{5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetylamino)-ethyl]-piperazin-1-yl}-2-oxo-ethyl ester (100 mg), 10% potassium carbonate in water and methanol (5 mL) was stirred at 40° C. for overnight. The reaction was concentrated, extracted with DCM. The combined DCM was dried, concentrated and purified on a silica gel column to give the titled compound as an orange-red solid. MS m/z 686 [M−1].
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][N:8]([C:16]2[CH:21]=[C:20]([O:22][CH2:23][C@H:24]3[CH2:26][C@@H:25]3[C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=3)[N:19]=[C:18]([CH3:34])[N:17]=2)C(=O)OC(C)(C)C)=[N:4][N:3]=1.C([O-])([O-])=O.[K+].[K+]>CO.CCOC(C)=O>[CH3:34][C:18]1[N:17]=[C:16]([NH:8][CH2:7][C:5]2[S:6][C:2]([CH3:1])=[N:3][N:4]=2)[CH:21]=[C:20]([O:22][CH2:23][C@H:24]2[CH2:26][C@@H:25]2[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=2)[N:19]=1
Reactant: Cc1ccc([C@H]2C[C@@H]2COc2cc(N(Cc3nnc(C)s3)C(=O)OC(C)(C)C)nc(C)n2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc([C@H]2C[C@@H]2COc2cc(NCc3nnc(C)s3)nc(C)n2)nc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
To a solution of 2-2 (51.0 mg, 0.11 mmol) in MeOH (0.53 mL) was added K2CO3 (17.5 mg, 0.13 mmol). The resulted suspension was stirred at 70° C. for 2 hour. The mixture was diluted with EtOAc, and then extracted with 1N HCl. The aqueous layer was basified with 5N NaOH and extracted with DCM three times. The combined DCM layers were dried over Na2SO4 and concentrated to give 2-3″ as an off white solid (29 mg, 72%). MS (M+H)+: observed=383.1654, calculated=383.1649. 1H NMR (400 MHz, DMSO-d6): δ 8.22 (s, 1H), 7.82 (br t, J=5.0 Hz, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.17 (d, J=7.7 Hz, 1H), 5.64 (s, 1H), 4.76 (d, J=5.0 Hz, 2H), 4.23 (m, 1H), 4.14 (m, 1H), 2.65 (s, 3H), 2.31 (s, 3H), 2.22 (s, 3H), 2.09 (m, 1H), 1.71 (m, 1H), 1.12 (m, 1H), 0.98 (m, 1H)
Reaction SMILES: [F:1][C@H:2]1[CH2:4][C@H:3]1[C:5](=O)[CH2:6][C:7]#[N:8].[NH2:10][NH2:11]>CCO>[F:1][C@H:2]1[CH2:4][C@H:3]1[C:5]1[NH:11][N:10]=[C:7]([NH2:8])[CH:6]=1
Reactant: NN
Reactant: N#CCC(=O)[C@@H]1C[C@@H]1F
Solvent: CCO
Product: Nc1cc([C@@H]2C[C@@H]2F)[nH]n1
Yield: 60.9 %

Procedure:
To a solution of MeCN (7.28 mL, 139 mmol) in anhydrous THF (130 mL) at −78° C. under N2 was added n-butyllithium (2.4 mol/L) in hexanes (58 mL, 139 mmol) dropwise. The mixture was stirred at −78° C. for 30 min then cis-ethyl-2-fluorocyclo-propanecarboxylate (1.5 g; 87.0 mmol) was added dropwise with stirring while maintaining the temperature at −78° C. The resulting solution was stirred at 25° C. for 2 h, quenched by the addition of 50% satd. aq. NH4Cl solution and extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum to afford 7.7 g of crude cis-3-(2-fluorocyclopropyl)-3-oxopropanenitrile as a red oil. Crude cis-3-(2-fluoro-cyclopropyl)-3-oxopropanenitrile was dissolved in EtOH (130 mL) and hydrazine (8.45 mL, 261 mmol) was added. The reaction mixture was heated at reflux for 16 h then concentrated in vacuo. The resultant orange solid was triturated with DCM (ca. 50 mL). The precipitate was filtered, rinsed with DCM, and dried in vacuo to obtain 7.48 g (60.9%) of cis-5-(2-fluorocyclopropyl)-1H-pyrazol-3-amine as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 11.18 (br s, 1H), 5.16 (s, 1H), 4.81 (ddd, J=66.3, 9.5, 5.2 Hz, 1H), 4.46 (br s, 2H), 1.99-1.81 (m, 1H), 1.23-1.02 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([F:9])=[C:7]([O:10][CH3:11])[CH:6]=[CH:5][C:4]=1I.[C:13]([C:15]1[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=1)#[CH:14].C(#N)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:8]([F:9])=[C:7]([O:10][CH3:11])[CH:6]=[CH:5][C:4]=1[C:14]#[C:13][C:15]1[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=1
Reactant: COc1ccc(I)c(OC)c1F
Reactant: C#Cc1cnn(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2cnn(C)c2)c(OC)c1F
Reaction time: 1 h
Yield: 86 %

Procedure:
To a mixture of (0.95 mmol) of 2,4-dimethoxy-3-fluoro-iodo benzene, 0.122 g (1.15 mmol) of 4-ethynyl-1-methyl-1H-pyrazole, 0.028 g (0.04 mmol) of dichlorobis(triphenylphosphine)palladium (II) and 8 mg (0.042 mmol) of copper (I) iodide 4 mL of anhydrous acetonitrile and 2 mL of triethylamine were added under nitrogen atmosphere at room temperature. The resulting mixture was stirred for 1 hour, when TLC indicated a consumption of the iodobenzene. The solvent was evaporated under reduced pressure and the residue purified by flash column chromatography (silica gel; dichloromethane:ethyl acetate 9:1) to give the title compound in an 86% yield as creamy crystals. H1 NMR (CDCl3) 3.88 (s, 3H, Me); 3.89 (s, 3H, MeO); 4.05 (d, 3H, MeO, J=1.34 Hz); 6.62 (tr, 1H, CH, J=8.2 Hz); 7.12 (dd, 1H, CH, J=8.2 Hz, J=2.55 Hz); 7.53 (s, 1H, CH pyr); 7.62 s, 1H, CH pyr).
Reaction SMILES: C[O-].[Na+].CO.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[SH:13].Cl[C:15]1[S:19][C:18]([C:20](=[O:22])[CH3:21])=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24]>>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][C:15]1[S:19][C:18]([C:20](=[O:22])[CH3:21])=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: Sc1ccccc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2ccccc2Cl)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.6 %

Procedure:
To a 0.1 M stock solution of sodium methoxide in anhydrous methanol (11 mL, 1.1 mmol) was added the 2-chlorobenzenethiol (0.144 g, 1 mmol) and the resulting mixture stirred at ambient temperature for 15 minutes. 1-(5-Chloro-4-nitro-2-thienyl)ethanone (206 mg, 1 mmol) was added and the mixture was stirred at ambient temperature for 2 hours. After this time the reaction was quenched by the addition of water (15 mL) and the resulting precipitate was collected by filtration, washed with water (10 mL) and dried in vacuo at 40° C. overnight. The solid was then crystallized from acetonitrile to afford the title compound as a dark orange solid (165 mg, 52.6% yield). 1H NMR (300 MHz, CDCl3) δ: 8.09 (1H, s), 7.77 (1H, ddd, J=7.58, 1.58, 0.36 Hz), 7.40-7.67 (3H, m), 2.49 (3H, s).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O>C(COC)OC>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[CH:24]=[C:23]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[O:27][CH3:26])[N:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1
Reactant: COc1ccccc1B(O)O
Reactant: Clc1cc(Nc2ccc(CNc3nc4ccccc4[nH]3)cc2)ncn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccccc1-c1cc(Nc2ccc(CNc3nc4ccccc4[nH]3)cc2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
235 mg (1H-Benzoimidazol-2-yl)-[4-(6-chloro-pyrimidin-4-ylamino)-benzyl]-amine (prepared in Example 86) (0.70 mmol) was suspended in 30 cm3 dimethoxyethane and the flask was filled with argon properly. 58 mg Tetrakis(thriphenylphosphine) palladium[0] (0.05 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Then 152 mg 2-methoxyphenyl-boronic acid (1 mmol), 318 mg anhydrous Na2CO3 (3 mmol) and 6 ml water were added. The mixture was refluxed overnight while slow argon flow was being applied. The reaction mixture was poured to 80 cm3 1M NaH2PO4 solution and it was extracted three times with 50-50 cm3 of ethyl-acetate. The combined organic layer was washed with brine, dried over MgSO4, decolorized with activated carbon and evaporated to dryness. The residual solid was recrystallized from minimal amount of acetonitrile and air-dried to give the desired product (125 mg, 44% yield). For analitical results and compound identification see Table 1.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:34])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:32])([O:30][CH3:31])[C:26]([F:29])([F:28])[F:27])[CH:23]=3)[N:18]([CH3:33])[N:17]=2)[CH2:9]1.[OH:35][C:36]1([C:43]2[CH:44]=[N:45][C:46]([CH3:49])=[CH:47][CH:48]=2)[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1>>[OH:35][C:36]1([C:43]2[CH:44]=[N:45][C:46]([CH3:49])=[CH:47][CH:48]=2)[CH2:37][CH2:38][CH:39]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:34])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:32])([O:30][CH3:31])[C:26]([F:29])([F:27])[F:28])[CH:23]=4)[N:18]([CH3:33])[N:17]=3)[CH2:11]2)[CH2:40][CH2:41]1
Reactant: Cc1ccc(C2(O)CCC(=O)CC2)cn1
Reactant: COC(F)(c1ccc2c(c1)c(NCC(=O)NC1CNC1)nn2C)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COC(F)(c1ccc2c(c1)c(NCC(=O)NC1CN(C3CCC(O)(c4ccc(C)nc4)CC3)C1)nn2C)C(F)(F)F

Procedure:
The title compound was prepared as a white solid from reaction of a N-azetidin-3-yl-2-[1-methyl-5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1H-indazol-3-ylamino]-acetamide TFA salt and 4-hydroxy-4-(6-methyl-pyridin-3-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:10].[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl>O.C1(C)C=CC=CC=1>[C:4]1([CH3:10])[CH:5]=[CH:6][CH:7]=[C:8]([O:9][CH2:11][CH:13]2[O:15][CH2:14]2)[CH:3]=1
Reactant: ClCC1CO1
Reactant: Cc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc(OCC2CO2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
To a solution of 50 g (1.25 mol) of NaOH in 1200 ml H2O was added 108 g (1 mol) of m-cresol freshly distilled and at 15° C. in one lot 117ml (1.5 mol) of epichlorohydrin. The emulsion was stirred at room temperature for 16 hours in a creased flask. The product was taken up in 1000 ml of toluene and washed with 500 ml water. Distillation yielded 135.7 g=82% of product, bp 61° C. (0.05 mm).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Br[C:28]1[CH:33]=[N:32][C:31]([CH3:34])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][N:23]([C:28]5[CH:33]=[N:32][C:31]([CH3:34])=[CH:30][N:29]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: Cc1cnc(Br)cn1
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cnc(N2CCC([C@]3(C)Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O3)CC2)cn1

Procedure:
The title compound is prepared from (S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 41; the configuration of the stereocenter is arbitrarily assigned) and 2-bromo-5-methyl-pyrazine in dimethylsulfoxide at 125° C. in the presence of potassium carbonate. LC (method 4): tR=0.84 min; Mass spectrum (ESI+): m/z=470 [M+H]+.