Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][C:7]2(C#N)[C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=1.[OH-].[Na+].C1C[O:29]CC1.C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][C:7]2([OH:29])[C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=1
Reactant: C1CCOC1
Reactant: COc1cc(OC)nc(C2(C#N)OC(=O)c3c(Cl)cccc32)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1cc(OC)nc(C2(O)OC(=O)c3c(Cl)cccc32)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1.8 g of 7-chloro-3-cyano-3-(4,6-dimethoxy-2-pyrimidinyl)phthalide, 50 ml of 1% NaOH and 50 ml of THF are stirred at room temperature for 3 hrs. The THF is removed by evaporation and the mixture is diluted with water and extracted twice with ethyl acetate. The aqueous solution is acidified with 2N--H2SO4. The resulting acid solution is extracted with 3×100 ml ethyl acetate and the organic phases combined, dried over Na2SO4 and concentrated to give a pale yellow solid. This residue is taken up in ethyl acetate and treated with activated charcoal until the yellow base line material is removed to give the title product as a white solid m.p. 188°-190° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([Cl:26])[C:24]=1[OH:25])[NH2:21]>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:21][C:20]2[CH:19]=[C:18]([Cl:17])[C:24]([OH:25])=[C:23]([Cl:26])[CH:22]=2)=[N:3][CH:4]=1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Product: Oc1cccc(Nc2nc(Nc3cc(Cl)c(O)c(Cl)c3)ncc2F)c1

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 3,5-dichloro-4-hydroxyaniline were reacted to produce 5-Fluoro-N2-(3,5-dichloro-4-hydroxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.47 (bs, 1H), 9.35 (bs, 1H), 9.22 (bs, 2H), 8.09 (d, 1H, J=3.6 Hz), 7.70 (s, 2H), 7.31 (dd, 1H, J=1.2 and 9.3 Hz), 7.10 (t, 1H, J=7.5 Hz), 7.00 (bs, 1H), 6.48 (dd, 1H, J=1.2 and 6.9 Hz); LCMS: purity: 93%; MS (m/e): 382 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Br:9][CH2:10]/[CH:11]=[CH:12]/[CH2:13]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:13]/[CH:12]=[CH:11]/[CH2:10][Br:9]
Reactant: BrC/C=C/CBr
Reactant: Oc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccccc1OC/C=C/CBr

Procedure:
100 g (0.9 mole) of 2-fluorophenol and 477 g (2.7 moles) of trans-1,4-dibromobut-2-ene were stirred under reflux with 70 g of K2CO3 in 500 ml of acetone for 5 hours. The mixture was filtered, and acetone was evaporated off under reduced pressure, the residue was taken up in methylene chloride, the solution was washed four times with aqueous 1 N NaOH solution, and the methylene chloride phase was dried with sodium sulfate and freed from unreacted 1,4-dibromobutene under reduced pressure. 175 g of trans-1-(2-fluorophenoxy)-4-bromobut-2-ene remained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].[N:21]1([C:26]2[CH:27]=[C:28]([C:32]3[O:37]C(C)(C)[O:35][C:34](=O)[CH:33]=3)[CH:29]=[CH:30][CH:31]=2)[CH:25]=[CH:24][N:23]=[CH:22]1>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:15]=[CH:16][CH:17]=[CH:18]2)=[CH:10][C:9]=1[NH:19][C:34](=[O:35])[CH2:33][C:32]([C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH:27]=1)=[O:37])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1

Procedure:
The title compound was prepared from (2-amino-4-pyrrol-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example J2) (1.37 g, 5.0 mmol) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example L3) (1.28 g, 4.75 mmol) according to the general procedure M. Obtained as a light brown foam (1.78 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH2:23]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26]>C1(C)C=CC=CC=1>[CH2:23]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:35])=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCCCc1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Product: CCCCc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Yield: 45 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (50 mg) was dissolved in toluene (3 ml) with heat, 4-butylphenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 26 minutes. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 36 mg of the title compound (yield: 45%).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]([NH:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][C:15]([S:17](Cl)(=O)=O)=[CH:16][C:10]=2[N:9]=1)=[O:6].COC(NC1N[C:29]2C=CC(S)=[CH:34][C:28]=2N=1)=O>[Fe]>[CH3:3][O:4][C:5]([NH:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][C:15]([S:17][CH2:29][CH2:28][CH3:34])=[CH:16][C:10]=2[N:9]=1)=[O:6]
Reactant: COC(=O)Nc1nc2cc(S(=O)(=O)Cl)ccc2[nH]1
Reactant: COC(=O)Nc1nc2cc(S)ccc2[nH]1
Agent: [Fe]
Agent: Cl
Product: CCCSc1ccc2[nH]c(NC(=O)OC)nc2c1

Procedure:
Into 100 ml. of a 10% aqueous hydrochloric acid solution 10.8 g. (0.033 moles) of 2-[(methoxycarbonyl)amino]-1H-benzimidazole-5-sulfonic acid chloride hydrochloride and 10 g. of Fe powder are added at room temperature. The mixture is stirred at 70° to 80° C. for 5 hours, whereupon the precipitated 2-[(methoxycarbonyl)amino]-1H-benzimidazole-5-thiol is filtered off and converted into 2-[(methoxycarbonyl)amino]-5-propylthio-1H-benzimidazole as described in Example 10. The product melts at 208° to 210° C.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:27][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:38]>C(O)(=O)C.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:14]3[NH:38][C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=4)=[CH:16][CH:15]=3)[CH2:27][CH:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(CCC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)c1ccc(F)cn1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(F)cn3)[nH]2)cc1)C1CC1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 56.1 %

Procedure:
To a solution of 5-[4-(cyclopropylsulfonyl)phenyl]-1-(5-fluoropyridin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (65 mg) in acetic acid (3 mL) was added ammonium acetate (170 mg), and the mixture was stirred at 110° C. for 45 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (35 mg, yield 56%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (3:2, volume ratio). MS: 455 (MH+).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH2:11][CH2:10]1>C1COCC1>[O:15]=[C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: NCc1ccccc1
Reactant: O=C1CCC(=O)O1
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)NCc1ccccc1
Yield: 52.7 %

Procedure:
A mixture of benzyl amine (10.7 g) and succinic anhydride (10 g) was stirred in THF (1 liter) for 2 days. The solid was filtered and dissolved in 1N NaOH (110 mL). the aqueous phase was washed with Et2O and then made acidic with conc HCl while cooling in an ice-water bath. The solid was collected, washed with water and dried under high vacuum. There was obtained 10.9 g (53%) of the title compound as a white powder m.p. 137.5°-138°.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:9]2[CH:10]=[C:11](B3OC(C)(C)C(C)(C)O3)[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:8]=2[O:7][C:6]=1[C:29]1[C:33]([CH3:34])=[CH:32][O:31][N:30]=1)=[O:4].Cl[C:36]1[CH:45]=[CH:44][C:43]2[CH2:42][CH2:41][N:40]3[C:46]4[CH:47]=[CH:48][CH:49]=[C:50]([F:53])[C:51]=4[CH:52]=[C:39]3[C:38]=2[N:37]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>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]>[F:53][C:50]1[C:51]2[CH:52]=[C:39]3[C:38]4[N:37]=[C:36]([C:11]5[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:16])=[O:17])=[CH:13][C:8]6[O:7][C:6]([C:29]7[C:33]([CH3:34])=[CH:32][O:31][N:30]=7)=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[C:9]=6[CH:10]=5)[CH:45]=[CH:44][C:43]=4[CH2:42][CH2:41][N:40]3[C:46]=2[CH:47]=[CH:48][CH:49]=1
Reactant: Fc1cccc2c1cc1n2CCc2ccc(Cl)nc2-1
Reactant: CNC(=O)c1c(-c2nocc2C)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
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: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2nocc2C)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CC4)cc12
Temperature: 85 °C
Reaction time: 3 h
Yield: 48.6 %

Procedure:
To a mixture of N-methyl-2-(4-methylisoxazol-3-yl)-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (60 mg, 0.12 mmol), 2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (50 mg, 0.18 mmol) and K3PO4.3H2O (98 mg, 0.37 mmol) in dioxane/H2O (1.5 mL/0.5 mL) was added Pd2(dba)3 (8 mg, 0.008 mmol) and X-Phos (8 mg, 0.016 mmol) under N2. The mixture was stirred at 85° C. for 3 h. It was concentrated, diluted with water, extracted with EtOAc, and dried over Na2SO4. The residue was purified by prep-TLC (DCM:MeOH=60:1) to get the product (35 mg, yield: 48%). 1H-NMR (CDCl3, 400 MHz) δ 9.12 (d, J=3.6 Hz, 1H), 8.68 (s, 1H), 8.40 (s, 1H), 7.76 (s, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.28˜7.26 (m, 1H), 7.21˜7.12 (m, 2H), 6.85˜6.75 (m, 1H), 4.36 (t, J=6.4 Hz, 2H), 3.46 (s, 3H), 3.33 (t, J=6.4 Hz, 2H), 3.03 (d, J=4.8 Hz, 3H), 2.60 (s, 3H), 2.40 (s, 3H). MS (M+H)+: 600.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][CH:17]([CH3:19])[CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].O([C:27]1[N:32]=[CH:31][N:30]=[C:29]2[N:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]([F:45])([F:44])[F:43])[N:34]=[CH:35][C:28]=12)C1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH:17]([O:16][CH2:15][C@H:4]([O:3][C:27]1[N:32]=[CH:31][N:30]=[C:29]2[N:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]([F:45])([F:44])[F:43])[N:34]=[CH:35][C:28]=12)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6])([CH3:19])[CH3:18]
Reactant: FC(F)(F)c1ccccc1-n1ncc2c(Oc3ccccc3)ncnc21
Reactant: Cc1ccc(NC(=O)[C@@H](O)COC(C)C)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)[C@H](COC(C)C)Oc2ncnc3c2cnn3-c2ccccc2C(F)(F)F)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 54.5 %

Procedure:
Sodium hydride (10.78 mg, 0.27 mmol) was added to (S)-2-hydroxy-3-isopropoxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate C7) (53.5 mg, 0.22 mmol) in anhydrous THF (50 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-phenoxy-1-(2-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate Z1) (80 mg, 0.22 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (2×100 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 50 to 100% ethyl acetate in isohexane. The residue was purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents to afford the product (60.0 mg, 53.4%). 1H NMR (400 MHz, CDCl3) δ 1.17-1.20 (6H, m), 2.30 (3H, s), 3.69-3.75 (1H, m), 4.09 (2H, d), 6.01 (1H, t), 7.52-7.56 (2H, m), 7.69 (1H, t), 7.76 (1H, t), 7.91 (1H, d), 8.10-8.15 (2H, m), 8.42 (1H, s), 8.56 (1H, s), 8.72 (1H, s); m/z (ES+) (M+H)+=501; HPLC tR=2.70 min.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[Cl:25][C:26]1[CH:27]=[C:28]([C:33]2[CH:40]=[CH:39][C:36](CO)=[CH:35][CH:34]=2)[CH:29]=[C:30]([Cl:32])[CH:31]=1>C(OCC)C.C(Cl)Cl>[Cl:25][C:26]1[CH:27]=[C:28]([C:33]2[CH:40]=[CH:39][C:36]([CH2:20][Br:24])=[CH:35][CH:34]=2)[CH:29]=[C:30]([Cl:32])[CH:31]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccc(-c2cc(Cl)cc(Cl)c2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: Clc1cc(Cl)cc(-c2ccc(CBr)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of triphenylphospine (636 mg, 2.42 mmol) and carbon tetrabromide (830 mg, 2.50 mmol) in diethyl ether (5 mL) was added a solution of 4-(3',5'-bis-chlorophenyl) benzyl alcohol (50 mg, 1.98 mmol) in CH2Cl2 (12 mL). The reaction was stirred at ambient temperature for 16 hours, silica gel was than added and the solvent evaporated in vacuo. The product was isolated by chromatography (Silica gel, 10-30% EtOAc in hexanes) and obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:22]2[N:26]=[N:25][C:24](=[S:27])[N:23]=2)[CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[O:11]COCCOC)([CH3:4])[CH3:3]>C(Cl)Cl.[Br-].[Zn+2].[Br-]>[CH3:21][C:18]([C:9]1[CH:8]=[C:7]([C:22]2[N:26]=[N:25][C:24](=[S:27])[N:23]=2)[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:19])[CH3:20]
Reactant: COCCOCOc1c(C(C)(C)C)cc(C2=NC(=S)N=N2)cc1C(C)(C)C
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(C)(C)c1cc(C2=NC(=S)N=N2)cc(C(C)(C)C)c1O

Procedure:
Anhydrous zinc bromide (6.6 g, 0.0292 mole) is added to a suspension of 5-[3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]phenyl]-3H-1,2,4-triazole-3-thione (2.4 g, 0.0058 mole) in methylene chloride (6.0 m). After 18 hours the mixture is diluted with methylene chloride (30 ml), washed with water (15 ml), saturated aqueous NaHCO3 (15 ml), saturated aqueous NaCl (10 ml), and dried over MgSO4. Filtration and concentration gives a solid which is recrystallized from ethyl acetate/isopropyl ether to provide 0.8 g (1.8 g theor., 44%) of product, mp >250° C.
Reaction SMILES: [Na].[F:2][C:3]1[C:4]([CH3:18])=[C:5]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[NH:11])[CH:6]=[CH:7][CH:8]=1.C([O:21][CH:22]=[C:23]([C:29](OCC)=O)[C:24]([O:26]CC)=[O:25])C.O.C(=O)(O)[O-].[Na+]>C(#N)C>[F:2][C:3]1[C:4]([CH3:18])=[C:5]([N:9]2[C:22](=[O:21])[C:23]([C:24]([OH:26])=[O:25])=[CH:29][N:11]=[C:10]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(F)cccc1NC(=N)c1ccccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CC#N
Solvent: O
Product: Cc1c(F)cccc1-n1c(-c2ccccc2)ncc(C(=O)O)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-(3-fluoro-2-methylphenyl)benzenecarboximidamide sodium salt (1:1) (i.e. the product from Example 5, Step A) (51.0 g, 200 mmol) in acetonitrile (300 mL) was added diethyl ethoxymethylenemalonate (44.04 g, 200 mmol). The reaction was stirred at room temperature for 30 min followed by the addition of water (3.6 mL, 200 mmol). The reaction was then stirred for another 30 min Water (100 mL) was added to the residue, followed by a saturated solution of sodium bicarbonate (300 mL), and the mixture was extracted with ethyl acetate. The aqueous layer was acidified with concentrated hydrochloric acid until the pH was 1-2, and the mixture was extracted with dichloromethane. The organic layer was dried (MgSO4) and concentrated under reduced pressure to provide a solid, which was washed with diethyl ether and dried under reduced pressure to afford the title product as a off-white solid (18 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:18]=3)=[CH:15][C:14]([CH2:43][N:44]3[CH2:49][CH2:48][N:47]([S:50]([CH3:53])(=[O:52])=[O:51])[CH2:46][C@@H:45]3[CH3:54])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].FC(F)(F)S(O)(=O)=O>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:15][C:14]([CH2:43][N:44]3[CH2:49][CH2:48][N:47]([S:50]([CH3:53])(=[O:52])=[O:51])[CH2:46][C@@H:45]3[CH3:54])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)C[C@@H]4C)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc(CN3CCN(S(C)(=O)=O)C[C@@H]3C)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 70 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
A solution of (S)-4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (9.6775 g, 12.77 mmol) in TFA (65 mL) was treated dropwise with trifluoromethanesulfonic acid (5.67 mL, 63.8 mmol) and the mixture was stirred for 1 h at 70° C. The volatile material was removed in vacuo, and the residual sticky oil was cooled to 0° C. (external ice bath). About 100 g ice was added, and the mixture was carefully quenched with 1 N NaOH(aq) until slightly basic. The mixture was stirred overnight, and the resulting yellow precipitate was collected by filtration and washed with isopropanol (100 mL). The collected yellow solid was purified by column chromatography (silica gel, 0% to 5% (2.0M ammonia in MeOH)/DCM, followed by repurification on silica gel, DCM to 40% EtOAc/DCM to EtOAc) to provide a yellow solid. This solid was washed with hot toluene several times to give (S)-4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (3.808 g, 58%) as a yellow solid. m/z (ESI, +ve ion) 518 (M+H); 1H NMR (400 MHz, d6-DMSO) δ 11.95 (s, 1H), 8.67-8.75 (m, 1H), 8.41 (s, 1H), 8.38 (d, J=12.91 Hz, 1H), 8.27 (s, 1H), 7.90 (br s, 1H), 7.76 (br s, 1H), 3.93 (s, 3H), 3.91 (br s, 1H), 3.12-3.30 (m, 3H), 2.90 (d, J=14.28 Hz, 1H), 2.85 (s, 3H), 2.65-2.78 (m, 2H), 2.55-2.64 (m, 1H), 2.44 (s, 3H), 2.13-2.28 (m, 1H), 1.16 (d, J=6.06 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)=[CH:5][C:4]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[N:3]1.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:14]3[N:18]=[C:17]([CH3:19])[O:16][N:15]=3)[CH:5]=2)=[CH:12][N:11]=1)=[O:24]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Cc1nc(-c2cc(-c3ccc(N)nc3)n(C)n2)no1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(-c2cc(-c3ccc(NC(=O)c4ccccc4Cl)nc3)n(C)n2)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.7 %

Procedure:
To a solution of crude 5-[1-methyl-3-(5-methyl(1,2,4-oxadiazol-3-yl))pyrazol-5-yl]-2-pyridylamine (74) (27 mg, 0.1 mmol) in 2 ml DCM was added 2-chlorobenzoyl chloride (25 μl, 2 eq) followed by addition of DIEA (70 μl). The resulting solution was stirred at r.t. for 3 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (250 μl) at r.t. for 1 h before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished 7 mg (2-chlorophenyl)-N-{5-[1-methyl-3-(5-methyl(1,2,4-oxadiazol-3-yl))pyrazol-5-yl](2-pyridyl)}carboxamide (75) as light yellow solid. (yield: 17.7%, purity>95%).
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.N>O.CO>[NH2:6][C:5]1[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:18]=[CH:3][C:4]=1[N:7]=[O:8]
Reactant: NNc1ccccc1
Reactant: COC(OC)C(C#N)=NO
Agent: Cl
Agent: N
Solvent: O
Solvent: CO
Product: Nc1c(N=O)cnn1-c1ccccc1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To a flask having an inner volume of 25 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged, 2.97 g (20 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 96.9% by weight synthesized in the same manner as in Example 1, 2.32 g (21 mmol) of phenylhydrazine with a purity of 98% by weight, 10 ml of methanol and 3.0 ml (36 mmol) of conc. hydrochloric acid, and the mixture was reacted at 50 to 52° C. for one hour. After completion of the reaction, 10 ml of water was added to the mixture to cool the same up to 10° C., then, 2.3 ml (37.9 mmol) of 28% by weight aqueous ammonia was gradually added dropwise to the mixture, and the resulting mixture was stirred for 30 minutes while maintaining the liquid temperature to 5° C. or lower for 30 minutes. Precipitated crystals were collected by filtration, and the crystals were washed with 5 ml of cold water and dried under reduced pressure to obtain 3.19 g of 5-amino-4-nitroso-1-phenylpyrazole (Isolation yield: 63.4%) as an ocherous solid with a purity of 74.9% by weight (absolute calibration curve method by high performance liquid chromatography).
Reaction SMILES: C([O:8][C:9]([C:11]1([N:19]([CH:37]=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:17][CH:16]2[O:18][CH:13]([CH2:14][CH2:15]2)[CH2:12]1)=[O:10])C1C=CC=CC=1>C(O)C.O>[CH2:42]([O:41][C:39]([CH2:38][CH2:37][N:19]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:29][C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)=[CH:27][CH:28]=1)(=[O:22])=[O:21])[C:11]1([C:9]([OH:10])=[O:8])[CH2:17][CH:16]2[O:18][CH:13]([CH2:14][CH2:15]2)[CH2:12]1)=[O:40])[CH3:43]
Reactant: CCOC(=O)C=CN(C1(C(=O)OCc2ccccc2)CC2CCC(C1)O2)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCN(C1(C(=O)O)CC2CCC(C1)O2)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 48 h

Procedure:
A solution of (4.4 mmol) of the product of step D in 25 mL of ethanol is treated with 2.5 g of 50% water wet 10% palladium on carbon catalyst and shaken under 53 psi olF hydrogen for 48 hours. The catalyst is removed by filtration and washed with ethanol (4×25mL). The filtrate and washings are combined and concentrated under vacuum to crude product.