Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([O:16][C:17]2[C:18]([F:39])=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:26](=[O:37])[NH:27][C:28]2[CH:32]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[O:30][N:29]=2)[C:21]([CH3:38])=[CH:20]3)[N:13]=[CH:12][N:11]=1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:33]([C:31]1[O:30][N:29]=[C:28]([NH:27][C:26]([N:22]2[C:23]3[C:19](=[C:18]([F:39])[C:17]([O:16][C:14]4[CH:15]=[C:10]([CH2:9][NH:7][CH3:6])[N:11]=[CH:12][N:13]=4)=[CH:25][CH:24]=3)[CH:20]=[C:21]2[CH3:38])=[O:37])[CH:32]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: Cc1cc2c(F)c(Oc3cc(CN(C)C(=O)OC(C)(C)C)ncn3)ccc2n1C(=O)Nc1cc(C(C)(C)C)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cc(Oc2ccc3c(cc(C)n3C(=O)Nc3cc(C(C)(C)C)on3)c2F)ncn1

Procedure:
To a solution of {6-[1-(5-tert-Butyl-isoxazol-3-ylcarbamoyl)-4-fluoro-2-methyl-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl}-methyl-carbamic acid tert-butyl ester (0.25 g, 0.452 mmol) in DCM (10 mL) is added TFA (1.5 mL). After 3 h the solvent is removed by rotary evaporation and the residue is diluted with DCM and water. Concentrated NH4OH is added to neutralize and the aqueous phase is extracted twice with DCM. The organic layers are washed with brine, dried over Na2SO4, and concentrated to give the title compound. MS (ESI) m/z 453.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (d, J=1.01 Hz, 1 H) 7.52 (d, J=8.59 Hz, 1 H) 7.19 (s, 1H) 7.15 (dd, J=8.72, 7.71 Hz, 1H) 6.65 (s, 1 H) 6.58 (s, 1 H) 3.76 (s, 2 H) 2.56 (s, 3 H) 2.33 (s, 3 H) 1.34 (s, 9 H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[Cl-].[CH:14](=[N+:21]([CH3:23])[CH3:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:22][N:21]([CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH3:23]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: C[N+](C)=Cc1ccccc1
Agent: [Cl-]
Product: CN(C)C(c1ccccc1)c1c[nH]c2cc(C(=O)O)ccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1H-indole-6-carboxylic acid and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[CH:7]1([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[CH:27]=[N:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[O:17])[C:13]([NH:28][C:29]3[CH:30]=[N:31][CH:32]=[N:33][CH:34]=3)=[CH:12][CH:11]=2)[CH2:9][CH2:8]1>>[OH:5][C:3]([CH3:6])([CH3:4])[CH2:2][NH:1][C:21]([C:20]1[CH:24]=[CH:25][N:26]=[CH:27][C:19]=1[NH:18][C:16]([C:14]1[C:13]([NH:28][C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)=[CH:12][CH:11]=[C:10]([CH:7]2[CH2:9][CH2:8]2)[N:15]=1)=[O:17])=[O:22]
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: CC(C)(O)CN
Product: CC(C)(O)CNC(=O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 28 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 1-amino-2-methyl-propan-2-ol with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (28%) as amorphous yellow solid.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([CH3:19])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].[C:20]([N:22]=[C:23](SC)[S:24][CH3:25])#[N:21]>CO>[C:20]([N:22]=[C:23]([S:24][CH3:25])[NH:9][CH:10]([CH3:19])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])#[N:21]
Reactant: CSC(=NC#N)SC
Reactant: CC(N)C(=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CSC(=NC#N)NC(C)C(=O)c1ccccc1
Yield: 80.2 %

Procedure:
Triethylamine (1 ml) was added to a solution of 2-aminopropiophenone hydrochloride (0.93 g) and dimethyl cyanodithioimidocarbonate (0.73 g) in methanol (3 ml), and the mixture was refluxed for 15 minutes and evaporated under reduced pressure. The residue was dissolved in chloroform and the solution was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in a small amount of ethyl acetate and diluted with diisopropyl ether. The resultant precipitates were collected by filtration, washed with diisopropyl ether and dried to give 2-(3-cyano-2-methyl-1-isothioureido)propiophenone (0.99 g).
Reaction SMILES: Br[C:2]1[C:16]([CH3:17])=[CH:15][C:5]([O:6][CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([Cl:18])[CH:3]=1.COC1C=CC(C)=C([B:27]([OH:38])[O:28]OCOCC[Si](C)(C)C)C=1>>[Cl:18][C:4]1[C:5]([O:6][CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:15][C:16]([CH3:17])=[C:2]([B:27]([OH:38])[OH:28])[CH:3]=1
Reactant: Cc1cc(OCOCC[Si](C)(C)C)c(Cl)cc1Br
Reactant: COc1ccc(C)c(B(O)OOCOCC[Si](C)(C)C)c1
Product: Cc1cc(OCOCC[Si](C)(C)C)c(Cl)cc1B(O)O
Yield: 54 %

Procedure:
5-Chloro-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronic acid was prepared in 54% yield from [2-(4-bromo-2-chloro-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane according to the procedure for 5-methoxy-2-methyl-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronic acid. 1H NMR (300 MHz, CDCl3) δ 8.11 (s. 1H), 7.09 (s, 1H), 5.37 (s, 2H), 3.84 (t, 2H, J=8.4 Hz), 2.76 (s, 3H), 0.98 (t, 2H, J=8.4 Hz), 0.01 (s, 9H). Anal. (C13H22BClO4Si—H2O)C, H. Calculated: C, 52.28; H, 6.75. Found: C, 51.98; H. 6.84.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](I)=[CH:4][N:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14].C(N(CC)CC)C>C(#N)C.[Cu]I.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])=[CH:4][N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1c(I)cnc(N)c1C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(C#C[Si](C)(C)C)cnc(N)c1C#N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 5.1 grams (0.020 mole) of 2-amino-3-cyano-5-iodo-4-methylpyridine (prepared as in Step E of Example 9) and 4.2 mL (0.030 mole) of trimethylsilylacetylene in 40 mL of acetonitrile is stirred, and 10.5 mL (0.078 mole) of triethylamine, 0.1 gram of copper(I) iodide, and 0.3 gram of bis(triphenyl-phosphine)palladium(II) chloride are added in order. Upon completion of addition, the reaction mixture is stirred at ambient temperature for about 20 hours and then is warmed to 70° C., where it stirred for about 7.5 hours. The reaction is monitored by thin layer chromatography. Upon completion of the reaction, the reaction mixture is concentrated under reduced pressure to a residue. The residue is dissolved in ethyl acetate, and the solution is washed with 50 mL of aqueous dilute hydrochloric acid. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 2-amino-3-cyano-4-methyl-5-(trimethyisilylethynyl)pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([N+:9]([O-])=O)=[C:6]([NH2:8])[CH:7]=1.[NH4+].[Cl-].CC(C)=O>[Zn].O>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[C:4]([F:12])[CH:3]=1
Reactant: Nc1cc(Br)cc(F)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CC(C)=O
Product: Nc1cc(Br)cc(F)c1N
Temperature: 23 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-3-fluoro-2-nitro-phenylamine (2 g, 8.5 mmol), NH4Cl (6.81 g, 127.6 mmol), acetone (100 mL) and water (20 mL), was added zinc powder portion-wise (three equal portions over 5 minutes) (8.34 g, 127.6 mmol) at 0° C. The mixture was stirred for 2 h then warmed to 23° C. The mixture was filtered through Celite® and the solvents were concentrated under reduced pressure. The mixture was re-dissolved in EtOAc/DCM and filtered a second time through Celite® and the solvents were evaporated. The crude mixture was diluted with EtOAc (200 mL), washed with brine (40 mL), dried, filtered, and concentrated under reduced pressure. The resultant residue was used in the next reaction without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH:9]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([CH3:11])[CH3:10].C(N(CC)CC)C>O1CCOCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:15]2[CH2:16][CH2:17][N:12]([CH:9]([CH3:11])[CH3:10])[CH2:13][CH2:14]2)[N:3]=1
Reactant: CC(C)N1CCNCC1
Reactant: Clc1cncc(Cl)n1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)N1CCN(c2cncc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 2,6-dichloropyrazine (250.0 mg, 1.678 mmol) in 1,4-dioxane (2 mL) was added 1-isopropylpiperazine (0.29 mL, 2.014 mmol) and triethylamine (0.70 mL, 5.034 mmol). The reaction mixture was stirred at room temperature for 1 day, filtered through Celite (1,4-dioxane eluent) then concentrated. Purification by flash column chromatography on silica gel using 100:5:1 EtOAc/MeOH/NH4OH (0 to 100%) in EtOAc provided the product. LCMS-ESI+ calc'd for C11H18ClN4 (M+H+): 241.1; Found: 241.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([C@@H:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]([NH:25][C:26]([C@@H:28]([NH:30]C(=O)OCC1C3C=CC=CC=3C3C1=CC=CC=3)[CH3:29])=[O:27])[C:5]=2[NH2:48].C(Cl)Cl.[OH-].[Na+]>CO>[NH2:30][C@@H:28]([CH3:29])[C:26]([NH:25][C:6]1[C:5]([NH2:48])=[C:4]2[C:9]([C@@H:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]([C:12]#[N:13])=[C:2]([NH2:1])[O:3]2)=[CH:8][CH:7]=1)=[O:27]
Reactant: COc1cc([C@H]2C(C#N)=C(N)Oc3c2ccc(NC(=O)[C@H](C)NC(=O)OCC2c4ccccc4-c4ccccc42)c3N)cc(Br)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1cc([C@H]2C(C#N)=C(N)Oc3c2ccc(NC(=O)[C@H](C)N)c3N)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.3 %

Procedure:
To an oven-dried one-neck round bottom reaction flask charged with a magnetic stir bar at room temperature under argon was added (9H-fluoren-9-yl)methyl(S)-1-((R)-2,8-diamino-3-cyano-4-(3-bromo-4,5-dimethoxyphenyl)-4H-chromen-7-ylcarbamoyl)-ethylcarbamate (0.045 g, 0.063 mmol), CH2Cl2:MeOH, 1:1 (2.11 mL) and 2N NaOH (0.063 mL, 0.13 mmol). The orange suspension was stirred at room temperature overnight. The suspension was concentrated leaving a brown residue. The residue was extracted with CHCl3 (3×40 mL), dried over MgSO4, filtered and concentrated to give the crude product. Purification by flash column chromatography (silica gel 4 g pre-packed column, elution with CH2Cl2:MeOH, 1:1) gave 0.005 g (16%) of the title compound as a yellow solid: 1H-NMR (DMSO-d6): δ 8.32 (s, 1H), 7.02 (d, J=8.2 Hz, 1H), 6.98 (d, J=1.9 Hz, 1H), 6.91 (br s, 2H), 6.86 (d, J=1.9 Hz, 1H), 6.33 (d, J=8.5 Hz, 1H), 4.78 (br s, 2H), 4.69 (s, 1H), 3.80 (s, 3H), 3.70 (s, 3H), 1.22 (d, J=6.9 Hz, 3H). ESI-MS (C21H22BrN5O4) 487.09 m/z (%): 488 [M+H]+ (100%), 490 [M+H]+ (90%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][O:31][CH2:30]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][O:31][CH2:30]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: BrCCC1CCCOC1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCC1CCCOC1

Procedure:
Prepared similarly to Intermediate 216 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(2-bromoethyl)tetrahydro-2H-pyran.
Reaction SMILES: Br[C:2]1[C:3]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:4][C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:10][C:8]1([CH3:11])[CH2:7][C:6]2[CH:12]=[C:2]([N:31]3[CH2:30][CH2:29][N:28]([C:25]4[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=4)[CH2:33][CH2:32]3)[C:3]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[CH:4][C:5]=2[O:9]1
Reactant: Cc1ccc(-c2cc3c(cc2Br)CC(C)(C)O3)cc1
Reactant: COc1ccc(N2CCNCC2)cc1
Product: COc1ccc(N2CCN(c3cc4c(cc3-c3ccc(C)cc3)OC(C)(C)C4)CC2)cc1
Yield: 16.3 %

Procedure:
By using 5-bromo-2,2-dimethyl-6-(4-methylphenyl)-2,3-dihydro-1-benzofuran (250 mg, 0.788 mmol) synthesized in Reference example 9 and 1-(4-methoxyphenyl)piperazine (455 mg, 2.36 mmol), the reaction was carried out in the same manner as Example 1 to synthesize the title compound 55 mg (yield 16%). Melting point was 187 to 190° C. (ethyl acetate-hexane).
Reaction SMILES: CN(C=O)C.[NH2:6][C:7]1[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[CH:10]=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13].I[CH2:22][CH2:23][CH2:24][CH2:25]I>CN(C)C1C=CN=CC=1.O>[N:6]1([C:7]2[CH:16]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[C:9]([CH:8]=2)[C:17]([O:19][CH3:20])=[O:18])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: ICCCCI
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C(=O)OC)cc(N2CCCC2)c1
Temperature: 90 °C

Procedure:
Anhydrous DMF (3 ml) was added to a flask charged with dimethyl 5-aminoisophthalate (0.250 g, 1.2 mmol, 1 eq) and 4-dimethylaminopyridine (0.308 g, 2.52 mmol, 2.1 eq) under Ar. 1,4-diiodobutane (0.16 ml, 0.37 g, 1.20 mmol, 1 eq) was added with stirring and the solution was heated to 90° C. After heating overnight the reaction was not complete. More diiodide (0.25 ml, 1.9 mmol, 1.6 eq) was added and the reaction was heated to 100° C. After heating overnight the reaction was cooled to room temperature and poured in water. The mixture was extracted with EtOAc (×2). The combined organic extracts were washed with water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo. The residue was stirred in CH2Cl2 and filtered through cotton to remove any insoluble material. The solvent was removed in vacuo. Purification via flash chromatography yielded the crude product. The crude was triturated with hexanes and the solid was collected via filtration. 0.167 g (0.63 mmol, 53% yield) of the product was collected.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[C:11](O)(=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: NCc1ccc(F)cc1F
Reactant: CCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCC(=O)NCc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of 2,4-difluorbenzylamine (0.43 g, 3.0 mmol) in methylene chloride (30 mL) were added heptanoic acid (0.39 g, 3.0 mmol) and DMAP (0.37 g, 3.0 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.58 g, 3.0 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with methylene chloride (100 mL), and the organic phase was washed with 5% HCl (3×75 mL), aqueous NaHCO3 (75 mL) and brine (75 mL), and dried over Na2SO4. Concentration in vacuo afforded 0.63 g (82%) of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](Cl)=[CH:6][C:3]=1[C:4]#[N:5].[F:14][C:15]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:16]=1[S-:17].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([S:17][C:16]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:15]=2[F:14])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(Cl)c([N+](=O)[O-])cc1Cl
Reactant: Fc1ccc([S-])c(F)c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1cc(Sc2ccc(F)cc2F)c([N+](=O)[O-])cc1Cl
Reaction time: 8 h
Yield: 45.2 %

Procedure:
A mixture of 2,5-dichloro-4-nitrobenzonitrile (2.5 g) and potassium 2,4-difluorothiophenoxide (2.54 g) in toluene was stirred overnight. Ethyl acetate was added and the resulting mixture was washed with water, dried and evaporated. The residue was filtered and washed with toluene to give pale brown crystals of 2-chloro-5-(2,4-difluorophenylthio)-4-nitrobenzonitrile (1.7 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:28]2[CH:32]=[CH:31][NH:30][N:29]=2)[C:5]2[N:6]([C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH2:21])[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[CH3:33][O-:34].[Na+].O>CO>[CH3:33][O:34][C:2]1[CH:3]=[C:4]([C:28]2[CH:32]=[CH:31][NH:30][N:29]=2)[C:5]2[N:6]([C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH2:21])[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1
Reactant: NC1(c2ccc(-c3nc4c(-c5cc[nH]n5)cc(Cl)nn4c3-c3ccccc3)cc2)CCC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(-c2cc[nH]n2)c2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2n1
Yield: 36 %

Procedure:
To a solution of 1-{4-[6-chloro-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine that was prepared in a manner analgous to that described for Example 19 (0.14 g, 0.32 mmol) and sodium methoxide (0.051 g, 0.95 mmol, 3.0 equiv) in MeOH (0.8 mL) was irradiated in a microwave apparatus at 120° C. for 90 min. The resulting mixture was added to water 10 mL. The aqueous mixture was extracted with DCM (3×15 mL), dried (Na2SO4 anh.) and concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; Snap 10 g cartridge, 100% hexane 2.0 min, gradient to 80% hexane/20% EtOAc 1.0 min, 80% hexane/20% EtOAc 3.0 min, gradient to 50% hexane/50% EtOAc 2.5 min, 50% hexane/50% EtOAc 3.5 min, gradient to 100% EtOAc 3.0 min, 100% EtOAc 4.8 min) to give an oil which was triturated with MeOH to give 1-{4-[6-methoxy-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine (0.052 g, 36%):
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12]P(OCC)(OCC)=O.C1OCCOCCOCCOCCOC1.[CH3:37][N:38]1[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]1>C1COCC1>[CH3:3][O:4][C:5](=[O:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=[C:41]1[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]1
Reactant: CCOP(=O)(Cc1ccccc1C(=O)OC)OCC
Reactant: CN1CCC(=O)CC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1C=C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 21.2 %

Procedure:
NaH (55-65%, 231 mg; 5.3 mmol; 1.2 eq.) was added to a cold (0° C.) solution of 2-(diethoxy-phosphorylmethyl)-benzoic acid methyl ester (from Intermediate B11 step 1) (1.52 g; 5.3 mmol; 1.2 eq.) and 15-crown-5 (26 μL; 0.13 mmol; 0.03 eq.) in THF (5 mL) and the reaction mixture was stirred at room temperature for 30 minutes whereupon a solution of 1-methyl-piperidin-4-one (500 mg; 4.42 mmol; 1 eq.) in THF (5 mL) was added dropwise over 10 minutes at 0° C. The resulting mixture was stirred at room temperature for 3.5 hours then concentrated in vacuo. The residue was taken up in water and extracted with EA (2×). The combined organics were washed with 1M NaOH then brine, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (DCM to 10% MeOH in DCM) afforded the title compound (230 mg, 21%) as a yellow oil. UPLC/MS: (MS+) 246.3 ([M+H]+).
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=3)[C:6]([C:14]#[N:15])=[C:5]2[C:16]2[CH:21]=[CH:20][C:19]([NH:22][CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:33]1[N:38]=[CH:37][CH:36]=[CH:35][N:34]=1.O>CN(C=O)C>[CH:1]1([N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:33]4[N:38]=[CH:37][CH:36]=[CH:35][N:34]=4)[CH:11]=3)[C:6]([C:14]#[N:15])=[C:5]2[C:16]2[CH:17]=[CH:18][C:19]([NH:22][CH:23]([CH3:25])[CH3:24])=[CH:20][CH:21]=2)[CH2:3][CH2:2]1
Reactant: CC(C)Nc1ccc(-c2c(C#N)c3ccc(O)cc3n2C2CC2)cc1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Nc1ccc(-c2c(C#N)c3ccc(Oc4ncccn4)cc3n2C2CC2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
A mixture of (1-cyclopropyl-6-hydroxy-2-(4-isopropylamino-phenyl)-1H-indole-3-carbonitrile (0.099 g, 0.3 mmol), Cs2CO3 (0.244 g, 0.75 mmol), 2-chloropyrimidine (0.069 g, 0.6 mmol) in DMF (2.0 mL) was stirred at 70° C. overnight. After cooling to room temperature the mixture was poured into water (15 mL) and the precipitate was collected via filtration and washed with water and purified on silica gel (CH2Cl2/EtOAc, 9:1) to provide 1-cyclopropyl-2-(4-isopropylamino-phenyl)-6-(pyrimidin-2-yloxy)-1H-indole-3-carbonitrile as a solid (0.104 g, 85%).
Reaction SMILES: Cl.NCC[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.C(OC1C=CC(Cl)=CC=1C(Cl)=O)C>[OH-].[Na+].CC(C)=O.O>[C:9]([OH:11])(=[O:10])[C:8]1[CH:12]=[CH:13][CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1ccc(C(=O)O)cc1
Agent: CCOc1ccc(Cl)cc1C(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccccc1
Reaction time: 2 h

Procedure:
10 g of 4-(2-aminoethyl)-benzoic acid hydrochloride were dissolved in 60 ml of 2 N-sodium hydroxide solution and, after addition of 75 ml of acetone, a solution of 11 g of 2-ethoxy-5-chloro-benzoylchloride in 20 ml of acetone was added dropwise, while stirring. Stirring was continued for 2 hours, the mixture was diluted with water, filtered and acidified with dilute hydrochloric acid. After filtration with suction, the product was recrystallized from ethanol. The 4-(2-<2-ethoxy-5-chloro-benzamido>-ethyl)-benzoic acid obtained was found to melt at 180° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[C:4]([NH:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:47]1([CH2:53][CH2:54][NH2:55])[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.C(N(CC)CC)C>O1CCCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[C:4]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:55][CH2:54][CH2:53][N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)=[O:20])=[CH:21][CH:22]=2)[N:3]=1
Reactant: NCCN1CCOCC1
Reactant: Nc1nc(Nc2ccc(C(=O)O)cc2)nn1-c1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1nc(Nc2ccc(C(=O)NCCN3CCOCC3)cc2)nn1-c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.3 %

Procedure:
To 4-(5-amino-1-pyridin-2-yl-1H-[1,2,4]triazol-3-ylamino)-benzoic acid (4.635 g, 15.643 mmole) in tetrahydrofuran (50 mL) was added (7.12 g, 1.2 equivalents) of HBTU, followed by 2-morpholin-4-yl-ethylamine (2.24 g, 1.1 equivalents) and triethylamine (5.45 mL, 2.5 equivalents). The reaction was stirred overnight at room temperature. The solid was filtered, washing with tetrahydrofuran, cold ethanol, water, ethanol, and finally ether. The compound was dried to provide 4-(5-amino-1-pyridin-2-yl-1H-[1,2,4]triazol-3-ylamino)-N-(2-morpholin-4-yl-ethyl)-benzamide (1.17 g, 18% yield) as a white solid. The organic phases contained product also but was not further isolated.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].Cl.O1CCOCC1>CO.[Pt]=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccnc2)c1
Agent: O=[Pt]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1

Procedure:
A solution of 4-Methyl-2-(5-pyridin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester, compound 33a (1.0 g, 2.27 mmol) in MeOH (75 ml), platinum oxide (51 mg, 0.97 mmol) and 4N HCl/dioxane (0.62 ml) was hydrogenated at 40 psi for 5.5 hours. The reaction mixture was filtered through celite, washed with MeOH and concentrated in vacuo. The residue was partitioned between dichloromethane and Na2CO3 to give the free base, (977 mg, 97% ). Calculated for C26H32F3NO2 (M+H) 447.53, Found 448.3