Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].CS(C)=O.[Br:15][C:16]([F:22])([F:21])[C:17]([F:20])([F:19])Br>C1(C)C(C)=CC=CC=1>[Br:15][C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[O:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: Oc1cccc(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: Cc1ccccc1C
Product: FC(F)(Br)C(F)(F)Oc1cccc(Br)c1
Temperature: 100 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
3-bromophenol (0.582 mol), potassium hydroxide (0.582 mol), methyl sulfoxide (3.2 L) and xylene (0.08 L) were put in a 2-bulb flask equipped with a Dean-Stark azeotropic distillation unit, which has been purged with nitrogen. The reactor was heated to 100° C. and reaction was performed for 48 hours to remove water. The reactor was cooled to 30° C. and 1,2-dibromotetrafluoroethane (0.640 mol) was slowly dropped for 4 hours maintaining the reactor temperature below 30° C. The reaction solution was mixed at 22° C. for 12 hours, and then reaction was performed at 35° C. for 10 hours. After the reaction was completed, the reaction solution was extracted with methylene chloride diluted in water. The obtained product was washed with water for three times and dehydrated with magnesium sulfate. Methylene chloride was removed from the filtrate using a vacuum evaporator. From vacuum distillation, 3-(2-bromotetrafluoroethoxy)bromobenzene was obtained as clear liquid (boiling point: 107 to 110° C.). The yield was 72%.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][CH:12]=[N:11][C:10]=3[O:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC#N.C1C(=O)N([I:27])C(=O)C1.C([O-])([O-])=O.[K+].[K+]>ClC(Cl)C.CCOC(C)=O.O>[I:27][C:8]1[O:9][C:10]2[N:11]=[CH:12][NH:13][C:14](=[O:16])[C:15]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=c1[nH]cnc2occ(-c3ccccc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(Cl)Cl
Solvent: O
Product: O=c1[nH]cnc2oc(I)c(-c3ccccc3)c12
Temperature: 25 °C
Yield: 83 %

Procedure:
Compound 162 (1.0 g, 4.7 mmol) was dissolved in dichloroethane (50 mL) and CH3CN (50 mL) and NIS (1.7 g, 7.1 mmol) was added. The flask was equipped with a reflux condenser and the mixture was heated at reflux for 24 h. After cooling to rt and concentration, the crude reaction mixture was taken up in EtOAc and water. K2CO3 was added to raise the pH of the aqueous phase. After removal of the organic phase, the aqueous phase was extracted several times with EtOAc. The organics were then dried over Na2SO4 and concentrated to a brown oil. Flash chromatography (SiO2, gradient eluent: 25% EtOAc/Hexanes to 100% EtOAc) afforded 163 as a pale yellow solid (83% total yield).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[CH2:12]([NH2:15])[C:13]#[CH:14]>O.O.[Na+].Cl[Au-](Cl)(Cl)Cl.C(O)C>[N:15]1[C:1]2[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][C:2]=2[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C1CCCCC1
Reactant: C#CCN
Agent: Cl[Au-](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1CCc2ncccc2C1
Reaction time: 8 h

Procedure:
At 60° C., ethanol (250 mL) solution of 500 g of ethyl 4-cyclohexanecarboxylate is added to ethanol (2.5 L) solution of 376 mL of propargylamine and 29.2 g of sodium tetrachloroaurate(III) dihydrate, and stirred overnight with reflux. The insoluble solid substance was removed through filtration through Celite, and the solvent was evaporated off under reduced pressure. The residue was separated and purified through silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain 555 g of ethyl 5,6,7,8-tetrahydroquinoline-6-carboxylate as a brown oily substance. The compound contained impurities.
Reaction SMILES: [CH3:1]/[C:2](/[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[N:3]\[NH:4][C:5]([C:7]1[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=1)=[O:6].[C:19](OC(=O)C)(=[O:21])[CH3:20].C1OC=NN1>>[CH3:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]([C:19](=[O:21])[CH3:20])[N:4]=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[O:6]1
Reactant: CC(=O)OC(C)=O
Reactant: C/C(=N\NC(=O)c1ccncc1)c1ccccc1
Agent: C1=NNCO1
Product: CC(=O)N1N=C(c2ccncc2)OC1(C)c1ccccc1
Yield: 75 %

Procedure:
The title compound was prepared from the isonicotinoylhydrazone of acetophenone and acetic anhydride, using the General Structural Outline for Oxadiazoline Synthesis in 75% yield, mp 79-81° C.; IR ν □1667, 1628, 1597, 1551, 1329, 1311, 1258, 1216, 1199, 1157, 1084, 1062, 1028, 989, 956, 892, 830, 767, 722□cm−1; 1H NMR (300 Mhz) δ □8.7 (2H, d, J=6 cps), 7.7 (2H, d, J=6 cps), 7.5-7.3 (5H, m), 2.3 (3H, s), 2.2 (3H, s); 13C NMR δ 166, 153, 151, 138, 132, 129, 127, 125, 121, 102, 22.5, 22.7.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[C:14]3[NH:21][CH:20]=[C:19]([C:22]([OH:24])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:22]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:7]4[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:14]=3[NH:21][CH:20]=2)=[O:24])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1c[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc12
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A77) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[CH:16]=[N:15][C:14]([C:18]([O:20]CC)=[O:19])=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4].O.[OH-].[Na+].O(C1C=C2C(C3C=CN=C(C)C=3N2CC)=CC=1)C>C(O)C>[CH2:1]([N:5]1[C:17]2[CH:16]=[N:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c2ccccc2c2cc(C(=O)OCC)ncc21
Agent: CCn1c2cc(OC)ccc2c2ccnc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCn1c2ccccc2c2cc(C(=O)O)ncc21
Yield: 100.6 %

Procedure:
Compound 32 (3.0 g, 10 mmol), 100 ml of water, 50 ml of ethanol, and NaOH (2.0 g, 50 mmol) were added into a 100 ml round-bottom flask. The mixture was refluxed for 2 h. The subsequent operational steps were conducted according to those for synthesizing compound 3 to obtain light yellow solids (2.7 g, 99%), and mp 182-184° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[C:7]([C:10]#[N:11])[C:8]#[N:9].[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]>C(O)C.N1CCCC1>[NH2:9][C:8]1[O:15][C:14]([CH3:16])=[C:13]([C:12]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:7]=1[C:10]#[N:11]
Reactant: N#CC(C#N)=Cc1ccco1
Reactant: CCOC(=O)CC(C)=O
Solvent: C1CCNC1
Solvent: CCO
Product: CCOC(=O)C1=C(C)OC(N)=C(C#N)C1c1ccco1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
To a solution of (2-furanylmethylene)malononitrile (0.72 g, 5.0 mmole) in hot ethanol (5.0 ml) was added ethyl acetoacetate (0.647 ml, 5.0 mmole) followed by 1 drop of pyrrolidine. The mixture was refluxed for 15 h. Upon cooling the mixture to room temperature a precipitate formed. The mixture was filtered to provide the desired product (0.753 g, 55%) as pinkish powder. Rf=0.4 in 50% ethyl actetate:hexanes. 1H NMR (400 MHz; CDCl3) d 7.295 (m, 1H); 6.27 (dd, 1H, J=3.1, 1.95 Hz); 6.10 (d, 1H, J=3.1 Hz); 4.63 (s, 1H); 4.50 (bs, 2H); 4.22-4.07 (m, 2H); 2.36 (s, 3H); 1.20 (t, 3H, J=7.0 Hz). LC MS shows MH+ at 275.
Reaction SMILES: C(=O)([O-])O.[K+].Cl.[NH2:7][C@H:8]([C:14]([OH:16])=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][NH2:13].[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19].Cl.[Cl-].[Na+]>O.CC(C)=O>[C:17]([NH2:7])(=[O:21])[C:18]([CH3:20])=[CH2:19].[NH2:7][C@H:8]([C:14]([OH:16])=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][NH2:13]
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Agent: NCCCC[C@H](N)C(=O)O
Agent: O=C([O-])O
Solvent: CC(C)=O
Solvent: O
Product: C=C(C)C(N)=O

Procedure:
Potassium hydrogencarbonate(5.51 g) was dissolved in 100 ml of distilled water, 9.13 g of lysine hydrochloride was dissolved in the solution, and 80 ml of acetone was further added to the solution. The reaction mixture was added dropwise with 5.23 g of methacryloyl chloride over about 10 minutes with vigorous stirring under ice cooling, and further vigorously stirred for about 2 hours. The reaction mixture was adjusted to pH 1-2 with concentrated hydrochloric acid, and saturated with sodium chloride. The aqueous layer was washed twice with 100 ml of ethyl acetate, and extracted 3 times with 100 ml of ethyl acetate/isopropanol=1/2. The ethyl acetate/isopropanol layers were combined, concentrated to about 50 ml under reduced pressure, added with 500 ml of isopropanol, and again concentrated to about 200 ml. The deposited sodium chloride was removed by filtration, and the filtrate was concentrated (colorless syrup, 5.53 g)
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[C:3]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([NH2:25])[N:16]3[CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:12][N:11]=2)[CH:2]=1.CCN(C(C)C)C(C)C.Br[CH2:36][CH2:37][CH2:38][C:39](Cl)=[O:40]>CN(C=O)C>[N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[C:3]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([N:25]4[CH2:36][CH2:37][CH2:38][C:39]4=[O:40])[N:16]3[CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[CH:12][N:11]=2)[CH:2]=1
Reactant: O=C(Cl)CCCBr
Reactant: Nc1nc2cnc(-c3cnn4ccccc34)nc2n1C1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CCCN1c1nc2cnc(-c3cnn4ccccc34)nc2n1C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.6 %

Procedure:
To a suspension of example 33 (25 mg, 0.075 mmol) in DMF (1.5 mL), DIPEA (0.04 mL, 0.22 mmol) and 4-bromobutyryl chloride (0.01 mL, 0.082 mmol) ware added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated to dryness and 1.7 mg of the title compound were obtained (yield 6%) after HPLC preparative purification.
Reaction SMILES: O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[NH2:24][C:25]([NH:27][C:28]1[NH:29][C:30]2[C:35]([C:36]=1[C:37]([NH2:39])=[O:38])=[CH:34][CH:33]=[C:32]([C:40]#[C:41][Si](C(C)C)(C(C)C)C(C)C)[CH:31]=2)=[O:26].O>O1CCCC1>[NH2:24][C:25]([NH:27][C:28]1[NH:29][C:30]2[C:35]([C:36]=1[C:37]([NH2:39])=[O:38])=[CH:34][CH:33]=[C:32]([C:40]#[CH:41])[CH:31]=2)=[O:26]
Reactant: CC(C)[Si](C#Cc1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Temperature: 75 °C
Reaction time: 2.5 h
Yield: 90.8 %

Procedure:
1.0 M Tetrabutylammonium fluoride tetrahydrofuran solution (15 mL, 15 mmol) was added to a solution of 2-aminocarbonylamino-6-triisopropylsilylethynylindole-3-carboxamide (Compound 9-15, 4.0 g, 10 mmol) in anhydrous tetrahydrofuran (180 mL), and the mixture was stirred at 75° C. for 2.5 hours. Water (180 mL) was added to the reaction mixture, and the whole was extracted with ethyl acetate (180 mL). The organic layer was washed with brine (180 mL), and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resultant solid was washed with a solution mixture of ethanol and chloroform (ethanol/chloroform=1/3, 55 mL) and dried under reduced pressure to give the title compound (2.2 g) as a slightly brown solid (yield 90%).
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([NH2:40])[CH:35]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][C:2]3[N:20]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[CH:35]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)c2)CC1

Procedure:
180 a) 4-(3-Nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester was prepared from 1-bromo-3-nitro-benzene (3.0 g, 15 mmol) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5.0 g, 16 mmol) in a manner analogous to Example 2c. Product isolated as a yellow oil (3.95 g, 88%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.23 (s, 1H), 8.11 (d, J=8.1 Hz, 1H), 7.69 (d, J=7.7 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 6.20 (br s, 1H), 4.12 (s, 2H), 3.70-3.65 (m, 2H), 2.56 (s, 2H), 1.50 (s, 9H). 180 b) 4-(3-Amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester was prepared from 4-(3-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.0 g, 3.3 mmol) in a manner analogous to Example 111a. Product isolated as a light purple solid (0.84 g, 92%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.09 (t, J=7.6 Hz, 1H), 6.61 (d, J=7.5 Hz, 1H), 6.56-6.52 (m, 2H), 4.22 (br s, 2H), 3.62 (br s, 2H), 2.82-2.72 (m, 2H), 2.59-2.49 (m, 1H), 1.80 (d, J=13.0 Hz, 2H), 1.68-1.53 (m, 2H), 1.48 (s, 9H). 180 c) 4-{3-[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 1.625 mmol) and 4-(3-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (500.0 mg, 1.809 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (90.0 mg, 0.165 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.59 g, 66%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.52 (d, J=6.6 Hz, 1H), 8.23 (d, J=8.4 Hz, 2H), 8.09 (d, J=8.4 Hz, 2H), 7.66 (d, J=7.4 Hz, 1H), 7.47-7.41 (m, 2H), 7.30 (t, J=7.6 Hz, 1H), 7.03 (t, J=7.0 Hz, 1H), 6.92-6.85 (m, 2H), 4.27 (br m, 2H), 3.10 (s, 3H), 2.83 (t, J=11.9 Hz, 2H), 2.73-2.63 (m, 1H), 1.84 (d, J=13.1 Hz, 2H), 1.73-1.60 (m, 2H), 1.49 (s, 9H). MS=538 (MH)+.
Reaction SMILES: [Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[C@H:16]3[CH2:19][C@H:20]([F:22])[CH2:21][N:15]3[C:14]2=[O:23])[C:10]([F:24])=[CH:9][C:8]=1[Cl:25])(=[O:5])=[O:4].[CH2:26](OS(OCC)(=O)=O)[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][CH2:2][S:3]([N:6]([C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[C@H:16]3[CH2:19][C@H:20]([F:22])[CH2:21][N:15]3[C:14]2=[O:23])[C:10]([F:24])=[CH:9][C:8]=1[Cl:25])[CH2:26][CH3:27])(=[O:5])=[O:4]
Reactant: O=C1[C@H]2C[C@H](F)CN2C(=O)N1c1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(c1cc(N2C(=O)[C@H]3C[C@H](F)CN3C2=O)c(F)cc1Cl)S(=O)(=O)CCl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of the title compound of Example 1, Step H (0.414 g, 1 mmol), diethylsulfate (0.17 g, 1.1 mmol), and potassium carbonate (0.27 g) in acetone (10 mL) was stirred at room temperature for 4 h. After completion of the reaction, the potassium carbonate was filtered off and the solvent was removed on a rotary evaporator. The title compound of Step A, a compound of this invention, was isolated by flash chromatography (0.41 g, 92%) as a white solid melting at 198-200° C. 1H NMR (CDCl3) δ 7.46 (d, 1H), 7.42 (d, 1H), 5.52 (m, 1H), 4.62 (dd, 1H), 4.59 (s, 2H), 4.02 (dd, 1H), 3.80 (m, 4H), 3.60 (dd, 1H), 2.64 (m, 1H), 2.01 (m, 1H), 1.20 (t, 6).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[NH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:12]OS(C)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[N:10]([CH3:12])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2[nH]ccc2n1
Reactant: COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ccc2nc(Cl)nc(Cl)c21
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.1 %

Procedure:
A mixture of 2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (2.67 g, 14.2 mmol), methanesulfonic acid methyl ester (1.26 mL, 14.9 mmol) and cesium carbonate (9.25 g, 28.4 mmol) in anhydrous N,N-dimethylformamide (21 mL) was stirred at RT (room temperature) under N2 for 15 h. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with 1:1 water/brine (3×) and brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give 2.50 g (87.1%) of 2,4-dichloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine as a white solid. MS(ESI) m/z: 202.2/204.1 [M+1]+.
Reaction SMILES: [S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-:4])(=[O:3])=[O:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]2[CH:39]=[CH:38][C:26]([O:27][C:28]3[CH:33]=[CH:32][N:31]=[C:30]([C:34]([NH:36][CH3:37])=[O:35])[CH:29]=3)=[CH:25][CH:24]=2)=[O:21])=[CH:15][C:14]=1[C:40]([F:43])([F:42])[F:41]>CO>[S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([OH:4])(=[O:3])=[O:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]2[CH:39]=[CH:38][C:26]([O:27][C:28]3[CH:33]=[CH:32][N:31]=[C:30]([C:34]([NH:36][CH3:37])=[O:35])[CH:29]=3)=[CH:25][CH:24]=2)=[O:21])=[CH:15][C:14]=1[C:40]([F:43])([F:41])[F:42]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C

Procedure:
3.5 g of the tosylate salt of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)-amino]phenoxy}-N-methylpyridine-2-carboxamide in the polymorph II are suspended in 15 ml of methanol and stirred at room temperature. After one week, the suspension is filtered and the residue dried at room temperature. Subsequently, the product is heat-treated at 150° C. for 30 min. The residue is analyzed by X-ray diffractometry and corresponds to the title compound in the polymorph III.
Reaction SMILES: [F-:1].[K+].[N+:3]([C:6]1[CH:19]=[CH:18][CH:17]=[C:16]([N+]([O-])=O)[C:7]=1[C:8]([NH:10][C@H:11]([CH3:15])[C:12]([OH:14])=[O:13])=[O:9])([O-:5])=[O:4].C1OCCOCCOCCOCCOCCOC1>CS(C)=O>[F:1][C:16]1[CH:17]=[CH:18][CH:19]=[C:6]([N+:3]([O-:5])=[O:4])[C:7]=1[C:8]([NH:10][C@H:11]([CH3:15])[C:12]([OH:14])=[O:13])=[O:9]
Reactant: C[C@@H](NC(=O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-])C(=O)O
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H](NC(=O)c1c(F)cccc1[N+](=O)[O-])C(=O)O
Temperature: 175 °C
Reaction time: 0.75 h
Yield: 64.3 %

Procedure:
A mixture of spray-dried KF (1.02 g, 17.6 mmol), intermediate 14 (500 mg, 1.76 mmol) and catalytic amount of 18-crown-6 in dry DMSO (10 mL) was stirred at 170-180° C. for 45 min. Work-up of the reaction mixture as described in example 1 gave the product as a pale brown color solid (290 mg, 64%), mp 158-160° C. 1H NMR (400 MHz, DMSO-d6): δ 12.72 (1H, br s), 9.10 (1H, d, J=7.2 Hz), 8.01 (1H, d, J=7.2 Hz), 7.70-7.78 (2H, m), 4.46 (1H, pentet, J=7.0 Hz), 1.34 (3H, d, J=7.2 Hz); LC-MS (positive ion mode): m/z 279 (M+Na)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][N:13]([CH3:17])[C:14]=2[CH:15]=O)=[CH:6][CH:5]=1.C(OP([CH2:26][C:27]([O:29]CC)=[O:28])(OCC)=O)C.Cl>CN(C)C=O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][N:13]([CH3:17])[C:14]=2/[CH:15]=[CH:26]/[C:27]([OH:29])=[O:28])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cn1ncc(-c2ccc(F)cc2)c1C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncc(-c2ccc(F)cc2)c1/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.5 %

Procedure:
Sodium hydride (60% in oil, 60 mg) was added to a mixture of 4-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carbaldehyde (168 mg), ethyl diethylphosphonoacetate (400 mg) and N,N-dimethylformamide (3 ml) at 0° C. and the mixture was stirred at room temperature for 15 min. The reaction mixture was poured into a 1N aqueous hydrochloric acid solution and the mixture was extracted with ethyl acetate. The ethyl acetate layer was concentrated and the residue was dissolved in a mixture of 6N hydrochloric acid (18 ml) and acetic acid (2 ml). The mixture was stirred for 1 hr. with heating under reflux. The reaction mixture was concentrated and poured into water. 1N Sodium hydroxide was added for neutralization. The precipitated solids were collected by filtration, washed with water, and dried to give (2E)-3-[4-(4-fluorophenyl)-1-methyl-1H-pyrazol-5-yl]acrylic acid (159 mg, 78%) as colorless crystals.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[N:4][CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.[CH3:17][N:18]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:37].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[CH:14]1([CH2:13][O:12][C:3]2[C:2]([C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19](=[O:37])[N:18]([CH3:17])[CH:27]=3)=[CH:7][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:5][N:4]=2)[CH2:16][CH2:15]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
Reactant: CS(=O)(=O)c1cnc(OCC2CC2)c(Br)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cc(S(C)(=O)=O)cnc2OCC2CC2)c2ccccc2c1=O
Temperature: 70 °C
Yield: 71.8 %

Procedure:
A mixture of 3-bromo-2-(cyclopropylmethoxy)-5-methylsulfonylpyridine (67 mg, 0.22 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one (60 mg, 0.21 mmol), Pd2(dba)3 (6 mg), XPhos (7 mg), and K3PO4 (111 mg, 0.51 mmol) in dioxane (1.2 mL) and water (140 uL) was purged with nitrogen, capped, and heated to 70° C. for 2 h. After the mixture was filtered through a short bed of celite, the filtrate was concentrated in vacuo and purified by prep-HPLC to afford the title compound (58 mg, 73%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.12-0.26 (m, 2H) 0.28-0.47 (m, 2H) 1.02-1.15 (m, 1H) 3.30-3.32 (m, 3H) 3.54-3.62 (m, 3H) 4.02-4.41 (m, 2H) 7.17-7.27 (m, 1H) 7.52-7.59 (m, 1H) 7.60-7.64 (m, 1H) 7.64-7.71 (m, 1H) 8.16-8.22 (m, 1H) 8.26-8.35 (m, 1H) 8.70-8.79 (m, 1H). LCMS (M+H)+=385.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12]([CH3:36])=[C:13]2[C:18]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:21]=3)=[C:17]([C:33]#[N:34])[CH:16]=[N:15][N:14]2[CH:35]=1)=O.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[NH:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[C:11]1[C:12]([CH3:36])=[C:13]2[C:18]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:21]=3)=[C:17]([C:33]#[N:34])[CH:16]=[N:15][N:14]2[CH:35]=1
Reactant: Cc1c(C(=O)Nc2ccccc2N)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: Cc1c(-c2nc3ccccc3[nH]2)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12

Procedure:
3-Cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylic acid (2-amino-phenyl)-amide 371 (4 mg, 0.008 mmol) and a small pinch of 10-camphorsulfonic acid was heated in toluene (1.0 ml) at 110° C. for 5 hrs. The reaction mixture was purified by silica gel flash chromatography to isolate 373 as yellow film (1.9 mg, 33%). [M+H]+=436.1.