Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1>>[CH3:11][N:8]1[C:7]([CH2:12][N:13]2[CH2:14][CH2:15][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:17][CH2:18]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([C:31]1[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=1)=[N:3][C:4]=2[N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: OB(O)c1cccnc1
Reactant: Cn1c(CN2CCN(S(C)(=O)=O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCN(S(C)(=O)=O)CC2)nc2c(N3CCOCC3)nc(-c3cccnc3)nc21

Procedure:
4-(2-Chloro-9-methyl-8-((4-(methylsulfonyl)piperazin-1-yl)methyl)-9H-purin-6-yl)morpholine (50 mg) was reacted with pyridin-3-ylboronic acid via General Procedure A and purified via reverse phase HPLC to give 33.4 mg 137 as a white solid. MS (Q1) 473.3 (M)+
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22](=O)[CH3:23])[N:20]=2)[N:15]=[N:14]1.Cl.[CH3:26][O:27][NH2:28]>>[CH3:26][O:27]/[N:28]=[C:22](/[C:19]1[N:20]=[C:21]2[N:13]([CH2:12][C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][C:2]=3[F:1])[N:9]=[CH:8][CH:7]=[CH:6]4)[N:14]=[N:15][C:16]2=[N:17][CH:18]=1)\[CH3:23]
Reactant: CON
Reactant: CC(=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Agent: Cl
Product: CO/N=C(\C)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Yield: 70.2 %

Procedure:
The title compound (22.2 mg, 64%) was synthesized from 1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (15.4) (30.0 mg, 0.09 mmol) and O-methylhydroxylamine hydrochloride (78.0 mg, 0.93 mmol) using the same procedure as described in the synthesis of example 15. 1H-NMR (400 MHz, CDCl3) δ ppm 9.45 (s, 1H), 8.92 (d, 1H), 8.08 (d, 1H), 7.81 (d, 1H), 7.78 (s, 1H), 7.39 (dd, 1H), 6.16 (s, 2H), 4.13 (s, 3H), 2.33 (s, 3H). LCMS (method E): [MH]+=352, tR=5.43 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[N:2]=1.C1N2CCN(CC2)C1.[Cl:16][C:17]1[C:18]([F:28])=[CH:19][C:20]([F:27])=[C:21]([S:23](Cl)(=[O:25])=[O:24])[CH:22]=1.C(#N)C>>[Cl:16][C:17]1[C:18]([F:28])=[CH:19][C:20]([F:27])=[C:21]([S:23]([NH:7][C:3]2[N:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:25])=[O:24])[CH:22]=1
Reactant: Nc1cccnn1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: O=S(=O)(Nc1cccnn1)c1cc(Cl)c(F)cc1F
Reaction time: 18 h
Yield: 24.9 %

Procedure:
Pyridazin-3-amine (1.00 g, 10.5 mmol) and triethylenediamine (1.18 g, 10.5 mmol) was added concurrently to a solution of 5-chloro-2,4-difluorobenzenesulfonyl chloride (2.60 g, 10.5 mmol) in acetonitrile (50 mL, 1000 mmol). The reaction mixture was stirred for 18 h then concentrated. The residue was dissolved in ethyl acetate (30 mL), washed with water, brine, dried over sodium sulfate and concentrated. The residue was purified on automated silica gel chromatography (chloroform to 50% of 10% methanol in chloroform) to give 800 mg of the desired product as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:39])[C@H:5]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[NH:6][C:7](=[O:31])[C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH2:17][C:18]2[CH:29]=[N:28][C:21]3[N:22]=[C:23]([NH2:27])[N:24]=[C:25]([NH2:26])[C:20]=3[C:19]=2[CH3:30])[CH2:15][CH3:16])=[CH:10][CH:9]=1)C.COC(=O)[C@H](CCC(OC)=O)NC(=O)C1C=CC(N(CC2C=NC3N=C(N)N=C(N)C=3C=2C)C)=CC=1.Cl.[OH-].[Na+]>>[NH2:27][C:23]1[N:24]=[C:25]([NH2:26])[C:20]2[C:19]([CH3:30])=[C:18]([CH2:17][N:14]([CH2:15][CH3:16])[C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][C@H:5]([C:4]([OH:39])=[O:3])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:31])=[CH:9][CH:10]=3)[CH:29]=[N:28][C:21]=2[N:22]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N(CC)Cc2cnc3nc(N)nc(N)c3c2C)cc1)C(=O)OCC
Agent: COC(=O)CC[C@H](NC(=O)c1ccc(N(C)Cc2cnc3nc(N)nc(N)c3c2C)cc1)C(=O)OC
Agent: Cl
Agent: [Na+]
Product: CCN(Cc1cnc2nc(N)nc(N)c2c1C)c1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Yield: 97 %

Procedure:
N-[4-[[(2,4-Diamino-5-methylpyrido[2,3-d]pyrimidin-6-yl)methyl]ethylamino]benzoyl-L-glutamic acid (21, 5-Methyl-5-deaza-10-ethylaminopterin) was prepared by saponification of 19 as described for the conversion of 18 to 20; yield 97% (56 mg from 60 mg, 0.109 mmol), of 19·0.6H2O, homogeneous by HPLC. Spectral data: mass, m/e 482 (M+1)+ ; UV, 0.1N HCl, 228 (40.8), 313 (17.1; pH 7, 227 (39.2), 308 (30.2); 0.1N NaOH, 228 (36.0), 308 (29.0).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:16])([F:15])[C:5]1[N:6]=[C:7]([C:10](OCC)=[O:11])[S:8][CH:9]=1>CO>[F:16][C:4]([F:3])([F:15])[C:5]1[N:6]=[C:7]([CH2:10][OH:11])[S:8][CH:9]=1
Reactant: CCOC(=O)c1nc(C(F)(F)F)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1nc(C(F)(F)F)cs1
Reaction time: 2 h
Yield: 83.6 %

Procedure:
Sodium tetrahydroborate (840 mg) was added to a solution of ethyl 4-(trifluoromethyl)-1,3-thiazole-2-carboxylate (2.5 g) in methanol (15 ml) at 0° C., and the mixture was stirred at the same temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (1.7 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:13]2[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:14]=2[O:22][CH3:23])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[O:22][CH3:23])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc([N+](=O)[O-])cc1C(NC(C)c1ccc(F)c(F)c1)c1ccc(F)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(N)cc1C(NC(C)c1ccc(F)c(F)c1)c1ccc(F)cc1

Procedure:
Following a similar procedure to that described in Example (1b), 700 mg of isomer A of N-[1-(3,4-difluorophenyl)ethyl]-N-[(4-fluorophenyl)-(2-methoxy-5 nitrophenyl)methyl]amine [prepared as described in step (a) above], 800 mg of nickel chloride hexahydrate and 258 mg of sodium borohydride were reacted, to obtain 532 mg of isomer A of the title compound as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([C:11]3[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]([S:19][CH3:20])[N:12]=3)=[CH:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:38][F:39])(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[F:39][CH2:38][O:1][C:2]1[C:3]2[N:4]([C:8]([C:11]3[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]([S:19][CH3:20])[N:12]=3)=[CH:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCF)cc1
Reactant: CSc1ncc(C#N)c(-c2cnc3c(O)cccn23)n1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ncc(C#N)c(-c2cnc3c(OCF)cccn23)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 39.6 %

Procedure:
100 mg of the 4-(8-hydroxyimidazo[1,2-a]pyridin-3-yl)-2-(methylthio)pyrimidine-5-carbonitrile [158-1] was dissolved in 3 mL of N,N-dimethylformamide, 146 mg of potassium carbonate and 216 mg of fluoromethyl 4-methylbenzenesulfonate (synthesized according to a method disclosed in page 555 to 566 in J. Labelled Compd. Radio pharm. 2003, 46) were added, and stirred at 80° C. for 5 hours. After cooling the reaction mixture back to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and was extracted with a mixture solvent of chloroform and methanol (chloroform:methanol=9:1). The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The insolubles were filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in a small amount of a mixture solvent of chloroform and methanol (chloroform:methanol=9:1), and solidified by adding diethyl ether, to obtain 44.1 mg of 4-[8-(fluoromethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(methylthio)pyrimidine-5-carbonitrile [160-1] as a brown solid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[CH:9]=2)[N:4]([CH3:14])[N:3]=1.C([Mg]Cl)(C)C.[CH2:20]([Sn:24]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])Cl)[CH2:21][CH2:22][CH3:23]>C1COCC1>[CH:11]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH3:14])[N:3]=[C:2]2[Sn:24]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:20][CH2:21][CH2:22][CH3:23])([CH3:13])[CH3:12]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)c1ccc2c(c1)c(I)nn2C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(C(C)C)cc12
Temperature: -16 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 3-iodo-5-isopropyl-1-methyl-1H-indazole (0.3 g, crude) in 100 mL of dry THF at −16° C. under nitrogen was added i-PrMgCl (0.69 mL, 1.38 mmol, 2M in THF) drop-wise. Then the mixture was stirred at −16° C. for 20 minutes. Tributylchlorostannane (0.39 g, 1.2 mmol) was added slowly and the mixture was stirred at room temperature for 2.5 hours. The solution was quenched by 40 mL of water, extracted with ethyl acetate (2×100 mL), washed with water (2×50 mL), brine (50 mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was evaporated under reduced pressure to give crude 5-isopropyl-1-methyl-3-(tributylstannyl)-1H-indazole as an oil, which was used into next step without further purification.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([O-:3])[NH2:2].[NH4+:6].[S:7](=[O:11])(=[O:10])([OH:9])[NH2:8].O.[OH-].[K+:14]>>[S:1]([NH:2][S:7]([O-:11])(=[O:10])=[O:9])([O-:3])(=[O:5])=[O:4].[NH4+:8].[NH4+:6].[S:1]([NH:2][S:7]([O-:11])(=[O:10])=[O:9])([O-:3])(=[O:5])=[O:4].[K+:14].[K+:14]
Reactant: NS(=O)(=O)O
Reactant: NS(=O)(=O)[O-]
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)([O-])NS(=O)(=O)[O-]

Procedure:
Using the procedure of P. Baumgarten, Ber., 6913, 2929-2937 (1936), diammonium imidodisulfate was prepared by adding 114 grams (1.0 mol) of ammonium sulfamate to 97 grams (1.0 mole) of sulfamic acid in a one liter beaker. The mixture was heated on a hot plate with constant mixing. At about 130° C. a stirrable slurry was obtained, and at about 155° C. an exothermic reaction began, forming a solid. When the solid cooled, it was dissolved in about 375 grams of 45 percent potassium hydroxide. Water was added to bring the total volume to 800 milliliters. The resulting solution was filtered and then heated under vacuum to expel ammonia. The solution was cooled and concentrated hydrochloric acid was carefully added to adjust the mixture to pH 7.5. The resulting precipitate was filtered yielding about 150 grams of dipotassium imidodisulfate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:45])[N:24]([CH2:34][C:35]([O:37]CC1C=CC=CC=1)=[O:36])[CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Pd].CCOC(C)=O>[C:1]([O:5][C:6](=[O:46])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:45])[N:24]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:34][C:35]([OH:37])=[O:36])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N(CCC(=O)OC(C)(C)C)CC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N(CCC(=O)OC(C)(C)C)CC(=O)O
Yield: 80 %

Procedure:
17-[Benzyloxycarbonylmethyl-(2-tert-butoxycarbonyl-ethyl)-carbamoyl]-heptadecanoic acid tert-butyl ester (0.054 g, 0.08 mmol) was dissolved in THF (2 ml). 10% Palladium on Charcoal was added and the mixture was hydrogenated at 1 atm and RT over the week-end. The dry reaction mixture was dissolved in EtOAc and filtered 3 times to remove the carbon. The filtrate was concentrated to give 17-[(2-tert-Butoxycarbonyl-ethyl)-carboxymethyl-carbamoyl]-heptadecanoic acid tert-butyl ester in 80% yield (37 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:29]3[N:30]=[CH:31][N:32]=[C:33]([NH2:34])[C:28]=3[C:27]([C:35](=[O:43])[C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([NH2:42])[CH:37]=3)=[CH:26]2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:29]3[N:30]=[CH:31][N:32]=[C:33]([NH2:34])[C:28]=3[C:27]([C:35](=[O:43])[C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([NH:42][C:10]([NH:9][C:4]4[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=4)=[O:11])[CH:37]=3)=[CH:26]2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)c3cccc(N)c3)c3c(N)ncnc32)CC1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)c3cccc(NC(=O)Nc4cc(Cl)cc(Cl)c4)c3)c3c(N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.7 %

Procedure:
3,5-Dichlorophenyl isocyanate (0.26 g, 1.37 mmol) was added to a solution of 4-[4-amino-5-(3-amino-benzoyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.15 mmol) in pyridine (13 mL). The reaction mixture was stirred at 75 C for 4.5 h and room temperature for 12 h in a sealed tube, quenched with H2O (13 mL), and extracted with EtOAc (4×15 mL). The combined organic extracts were washed with CuSO4 (3×15 mL), H2O (20 mL), and brine (30 mL) and dried (MgSO4), filtered, and concentrated in vacuo. The crude reaction mixture was triturated in CH2Cl2 and filtered to obtain the titled compound as a white solid (0.45 g, 63%). MS: 625.5 (MH+); HPLC Rf: 7.48 min. (HPLC method 4); HPLC purity: 100%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19](=[O:30])[C:20]3[C:25]([N+:26]([O-])=O)=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:29])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32]>C(O)(=O)C.CCOC(C)=O.[Fe]>[NH2:26][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:29])[C:20]=1[C:19]([C:13]1[C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:31]([F:34])([F:33])[F:32])[CH:4]=2)(=[O:10])=[O:9])=[CH:17][C:16]([Cl:18])=[CH:15][N:14]=1)=[O:30]
Reactant: O=C(c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1c(Cl)cccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1cccc(Cl)c1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 50 mL round-bottom flask was charged with 4-chloro-N-(5-chloro-2-(2-chloro-6-nitrobenzoyl)pyridin-3-yl)-3-(trifluoromethyl) benzenesulfonamide (350 mg, 0.63 mmol), iron powder (560 mg, 10 mmol) in acetic acid (30 mL) and stirred at room temperature for 2 h and then at 50° C. for 30 min. After cooling, the reaction mixture was diluted with EtOAc, filtered through Celite and evaporated the solvent in vacuo. The residue was dissolved in EtOAc and washed with NaHCO3 (sat), brine, dried over MgSO4, and concentrated under reduced pressure and was further purified through automated normal-phase chromatography to afford the title compound: 1H NMR (400 MHz, CDCl3) δ 10.60 (s, 1 H), 8.28 (d, 1 H), 8.20 (d, 1 H), 8.16 (d, 1 H), 7.96 (dd, 1 H), 7.60 (d, 1 H), 7.09 (t, 1 H), 6.64 (dd, 2H), 4.40 (bs, 2H); MS (ES) (M+H)+ expected 523.9, found 523.9.
Reaction SMILES: Br[C:2]1[C:3]([NH:16][CH3:17])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[N:6][CH:7]=1.[CH3:18][N:19](C=O)C>[C-]#N.[Zn+2].[C-]#N.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].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH3:15][N:12]1[C:13]([CH3:14])=[C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:16][CH3:17])[C:2]([C:18]#[N:19])=[CH:7][N:6]=2)[CH:10]=[N:11]1
Reactant: CN(C)C=O
Reactant: CNc1nc(Nc2cnn(C)c2C)ncc1Br
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CNc1nc(Nc2cnn(C)c2C)ncc1C#N
Temperature: 105 °C
Yield: 25 %

Procedure:
To a mixture of 5-bromo-N2-(1,5-dimethyl-1H-pyrazol-4-yl)-N4-methylpyrimidine-2,4-diamine (95 mg, 0.32 mmol), zinc cyanide (70 mg, 0.60 mmol), Pd2(dba)3 (11 mg, 0.012 mmol), DPPF (13 mg, 0.023 mmol) was added DMF (3.5 mL). The reaction was then heated in a sealed tube at 105° C. for 18 h. The reaction mixture was filtered and concentrated. The crude product was purified by reverse phase HPLC to give 2-(1,5-dimethyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile (19 mg, 25%). LCMS (Method A): [MH+]=244.1 at 2.53 min. 1H-NMR (DMSO): δ 8.96 (m, 1H), 8.21 (m, 1H), 7.49 (m, 2H), 3.69 (s, 3H), 2.84 (m, 3H), 2.14 (m, 3H). K1=0.025.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH:20]1([CH2:26][NH:27][CH2:28][CH:29]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH2:36])[CH2:30]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(OCC)(=O)C.C(OC(C)C)(C)C>>[CH:20]1([CH2:26][NH:27][CH2:28][CH:29]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH:36][C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:30]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: NCCN1CCC(CNCC2CCCCC2)C1
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCC(CNCC3CCCCC3)C2)c2ccccc21
Yield: 19 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[3-[[(cyclohexyl)methylamino]methyl]-pyrrolidin-1-yl]ethanamine in a yield of 19% of theory. Colourless crystals, m.p. 166°-167° C. (ethyl acetate/methanol 1/1 v/v).
Reaction SMILES: [CH:1]1[C:2]2[C:15]3=[CH:16][C@H:17]([OH:25])[C@H:18]4[O:23][P:21]([OH:24])(=[O:22])[O:20][C@H:19]4[C@@H:14]3[NH:13][C:11](=[O:12])[C:3]=2[C:4]([OH:10])=[C:5]2[O:9][CH2:8][O:7][C:6]=12.CO.O.C([O-])(=O)C.[Mg+2:33].C([O-])(=O)C.C([O-])(=O)C>O>[CH:1]1[C:2]2[C:15]3=[CH:16][C@H:17]([OH:25])[C@H:18]4[O:23][P:21]([O-:24])(=[O:22])[O:20][C@H:19]4[C@@H:14]3[NH:13][C:11](=[O:12])[C:3]=2[C:4]([O-:10])=[C:5]2[O:9][CH2:8][O:7][C:6]=12.[Mg+2:33]
Reactant: O=C1N[C@@H]2C(=C[C@H](O)[C@H]3OP(=O)(O)O[C@H]32)c2cc3c(c(O)c21)OCO3
Agent: CC(=O)[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: O
Product: O=C1N[C@@H]2C(=C[C@H](O)[C@H]3OP(=O)([O-])O[C@H]32)c2cc3c(c([O-])c21)OCO3
Reaction time: 72 h

Procedure:
To a mixture of phosphoric acid (3b, 50 mg, 0.135 mmol) and methanol-water (3:2) was added a solution of magnesium acetate (15 mg, 0.0675 mmol. 0.5 equiv) in water (1 ml). The mixture became opaque immediately upon addition of the metal acetate and was stirred for 3 days while further precipitation occurred. The solution was concentrated to a white residue and water-methanol was added (1.4 ml). The precipitate was collected and dried; grey solid, m.p. 210° C. dec. very insoluble in water, soluble in DMSO; 1H-NMR (DMSO-d6, 300 MHz) δ 13.69 (s, 1H), 8.73 (s, 1H), 6.99 (s, 1H), 6.43 (s, 1H), 6.14 (m, 1H), 6.05 (s, 2H), 5.82 (bs, 1H), 4.41-4.31 (m, 2H), 4.03-3.95 (m, 2H). Each of the divalent cation salts proved to be only sparingly soluble in water.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24](N(OC)C)=[O:25])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:6](/[N:10]=[N:11]/[N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:7]=1[C:8]#[CH:9].[CH3:30][Mg]Cl.Cl.O.[Cl-].[Na+].O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([C:8]#[CH:9])=[C:6](/[N:10]=[N:11]/[N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:4]([C:24](=[O:25])[CH3:30])[CH:3]=1
Reactant: C#Cc1c(Cl)cc(C(=O)N(C)OC)c(-c2cccc(F)c2)c1/N=N/N1CCCC1
Reactant: C[Mg]Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#Cc1c(Cl)cc(C(C)=O)c(-c2cccc(F)c2)c1/N=N/N1CCCC1
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
A solution of 4-chloro-5-ethynyl-3′-fluoro-N-methoxy-N-methyl-6-[(E)-pyrrolidin-1-yldiazenyl]biphenyl-2-carboxamide (930 g, 2.2 mol) in tetrahydrofuran (4.3 L) at 0° C. under nitrogen was treated with 3.0 M methylmagnesium chloride in tetrahydrofuran (2.2 L, 6.7 mol) dropwise over 45 minutes. Gas formation was observed and the internal temperature ranged from 1-8° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 70 minutes. The reaction mixture was cooled to 0-5° C. and treated with 2.0 M hydrogen chloride in water (4.1 L, 8.3 mol) dropwise with gas formation observed. The solution was diluted with ethyl acetate (2 L) and stirred for 10 min. The aqueous layer was separated and extracted with ethyl acetate (1 L). The combined organic layers were washed with brine (0.7 L, 4 mol), dried over sodium sulfate, filtered, and concentrated to an oil. This material was azeotroped with toluene (1 L) to give the desired product. A small sample was purified by silica gel column for spectroscopic analysis. LCMS for C20H18ClFN3O (M+H)+: m/z=370.1; Found: 370.0; 1H NMR (400 MHz, DMSO-d6): δ 7.54 (s, 1H), 7.37-7.31 (m, 1H),7.14-7.09 (m, 1H), 6.94-6.86 (m, 2H), 4.54 (s, 1H), 3.68-3.59 (m, 2H), 3.22-3.13 (m, 2H), 2.11 (s, 3H), 1.89-1.78 (m, 4H).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[O:17]>CN(C=O)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:16](=[O:17])[CH2:15][N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(CBr)c1ccc(F)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.5 %

Procedure:
tert-Butyl piperazine-1-carboxylate (5.00 g, 26.8 mmol) and 2-bromo-1-(4-fluorophenyl)ethanone (6.99 g, 32.2 mmol) were dissolved in DMF (5 mL) and stirred for 10 min at room temperature. The crude material was purified by column chromatography eluting with a mixture of DCM and MeOH to afford the title compound (3.50 g) as an oil. 1H NMR (Acetonitrile-d3, 400 MHz) δ 1.42 (s, 9H) 2.47 (t, J=5.0 Hz, 4H), 3.36 (t, J=5.0 Hz, 4H), 3.77 (s, 2H), 7.20 (t, J=8.8, 2H), 8.07 (td, J=2.0, 8.8 Hz, 2H). Exact mass calculated for C17H23FN2O3: 322.2. Found: LCMS m/z=323.4 (M+H+).
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:9]([CH3:10])[C:8](=[O:11])[N:7]([CH3:12])[C:6](=[O:13])[C:5]=1[CH:14]=O)[CH3:2].Cl.[CH2:17]([O:24][NH2:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][N:25]=[CH:14][C:5]1[C:6](=[O:13])[N:7]([CH3:12])[C:8](=[O:11])[N:9]([CH3:10])[C:4]=1[S:3][CH2:1][CH3:2])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NOCc1ccccc1
Reactant: CCSc1c(C=O)c(=O)n(C)c(=O)n1C
Agent: Cl
Product: CCSc1c(C=NOCc2ccccc2)c(=O)n(C)c(=O)n1C

Procedure:
The process described in Method A was followed. 6-(Ethylthio)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (Example 23, Step 1) (0.070 mg, 0.30 mmol) and O-benzyl-hydroxylamine hydrochloride (0.063 mg, 0.40 mmol) were used to obtain the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][C:3]=1[I:10].[NH2:11][C:12]1[C:13]([CH3:21])=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2>CCO.[O-]S([O-])(=O)=O.[Na+].[Na+]>[I:10][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([C:2]=1[NH:11][C:12]1[C:13]([CH3:21])=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2)[C:8]#[N:9]
Reactant: Cc1c(N)ccc2[nH]ccc12
Reactant: N#Cc1cncc(I)c1Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(Nc2c(I)cncc2C#N)ccc2[nH]ccc12
Temperature: 25 °C
Yield: 74.9 %

Procedure:
A mixture of 4-chloro-5-iodonicotinonitrile (5.0 g, 18.9 mmol) and 5-amino-4-methylindole (3.0 g, 20.8 mmol) in EtOH (100 mL) was heated at reflux for 3 days, cooled to r.t. and diluted with saturated aq. Na2SO4 (300 mL). The precipitated solids were collected by filtration, washed with water and dried to give 5.3 g (75%) of 5-iodo-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile as a grey solid. Melting range: 192-194° C.; MS (M+H+): 375.1.