Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=1)[O:15][CH2:16][CH2:17][NH:18][C:19]([CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:20])#[N:11].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[C:1]([N:25]1[CH2:26][CH2:27][CH:22]([CH2:21][C:19]([NH:18][CH2:17][CH2:16][O:15][C:14]2[CH:28]=[CH:29][CH:30]=[C:12]([C:10]#[N:11])[CH:13]=2)=[O:20])[CH2:23][CH2:24]1)(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1
Reactant: N#Cc1cccc(OCCNC(=O)CC2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(OCCNC(=O)CC2CCN(C(=O)c3ccccc3)CC2)c1

Procedure:
175 mg (1.43 mmol) of benzoic acid, 430 mg (1.58 mmol) of N-[2-(3-cyanophenoxy)ethyl]piperidine-4-carboxyamide, 0.22 ml (1.58 mmol) of triethylamine, 213 mg (158 mmol) of 1-hydroxybenzotriazole and 303 mg (1.58 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were stirred in 10 ml of dimethylformamide at room temperature overnight. After the treatment with ethyl acetate as the extractant in an ordinary manner, the title compound was obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=1[NH:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].CN(C)C=O.[NH2:31][NH:32][C:33]([NH2:35])=[S:34]>C(Cl)Cl.N1C=CC=CC=1>[NH2:35][C:33](=[S:34])[NH:32][NH:31][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=1[NH:16][C:9]1[C:10]([Cl:15])=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[Cl:7]
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(=O)O)c1Cl
Reactant: NNC(N)=S
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1ccc(Cl)c(Nc2ccccc2C(=O)NNC(N)=S)c1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 42.4 %

Procedure:
Oxalyl chloride (2.85 g, 22.5 mmol) in 10 ml of methylene chloride is added dropwise to a 0° C. suspension of 2-[(2,6-dichloro-3-methylphenyl)amino]-benzoic acid (3.17 g, 10.6 mmol) and dimethylformamide (830 μl, 10.6 mmol) in 50 ml of methylene chloride. The clear yellow solution is stirred at 0° C. for 15 minutes and then at room temperature for 30 minutes. The solution is then concentrated in vacuo to give a yellow solid. This solid is added in portions to a suspension of thiosemicarbazide (1.95 g, 21.4 mmol) in 20 ml of pyridine. The suspension is stirred at 0° C for 30 minutes then at room temperature overnight. The reaction mixture is concentrated in vacuo and the residue is partitioned between ethyl acetate and water. The organic layer is concentrated, then slurried with equal volumes of ethyl acetate and hexane. The off-white solid is collected by filtration providing 1.66 g (42%) of 2-[(2,6-dichloro-3-methylphenyl)amino]-benzoic acid, 2-(aminothioxomethyl) hydrazide, mp is undefined.
Reaction SMILES: Cl[Si](C)(C)C.BrCCBr.CN(C)C=O.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19]Br.Br[C:26]1[N:27]=[C:28]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[S:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]>[Zn].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:24][C:23]1[CH:22]=[CH:21][C:18]([CH2:19][C:26]2[N:27]=[C:28]([N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)[S:29][C:30]=2[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:17][C:16]=1[F:15]
Reactant: CCOC(=O)c1sc(N2CCOCC2)nc1Br
Reactant: Fc1cc(CBr)ccc1Cl
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: BrCCBr
Product: CCOC(=O)c1sc(N2CCOCC2)nc1Cc1ccc(Cl)c(F)c1
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
In a 50 ml flame-dried round bottom flask, a suspension of zinc (0.183 g, 0.00280 mol), chlorotrimethylsilane (8.9 uL, 0.000070 mol) and 1,2-dibromoethane (6.0 uL, 0.000070 mol) in N,N-dimethylformamide (2.4 mL, 0.031 mol) was stirred for 15 minutes. To this was added a solution of 3-fluoro-4-chlorobenzylbromide (0.626 g, 0.00280 mol) in N,N-dimethylformamide (4.8 mL, 0.062 mol), and the resulting suspension was stirred overnight at room temperature. To a flame-dried 50 ml round bottom flask containing ethyl 4-bromo-2-morpholin-4-yl-1,3-thiazole-5-carboxylate (0.300 g, 0.000934 mol) and bis(tri-t-butylphosphine)palladium(0) (36 mg, 0.000070 mol) was added the organozinc solution from above, and the reaction was heated with stirring at 60° C. for 60 min. Reaction was quenched with saturated ammonium chloride, and then transferred to a separatory funnel containing water (10 mL) and EtOAc (40 mL). The layers were separated, and the aqueous layer was extracted 2×30 mL with EtOAc. The combined organic layers were washed 1× brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was dissolved in DCM, adsorbed onto silica gel and purified via column chromotography (24 gram Isco column, gradient elution, 0-50% EtOAc/hexanes) to afford ethyl 4-(4-chloro-3-fluorobenzyl)-2-morpholin-4-yl-1,3-thiazole-5-carboxylate (245 mg, yield 68.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[N:3]=1.[N+:25]([O-])([OH:27])=[O:26].O>C(OC(=O)C)(=O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:14])=[O:15])=[CH:9][CH:8]=2)[N:4]([C:17]2[CH:22]=[CH:21][C:20]([N+:25]([O-:27])=[O:26])=[C:19]([O:23][CH3:24])[CH:18]=2)[N:3]=1
Reactant: COc1cccc(-n2nc(Cl)cc2-c2ccc(S(C)(=O)=O)cc2)c1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COc1cc(-n2nc(Cl)cc2-c2ccc(S(C)(=O)=O)cc2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-chloro-1-(3-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole (575 mg) in acetic anhydride (10 ml) and acetic acid (1 ml) was added nitric acid (fuming) (500 ml) at 0° C. After being stirred at 0° C. for 2 hours, the reaction mixture was poured into water, and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, and filtered. The filtrate was evaporated in vacuo, and purified by column chromatography using dichloromethane as eluent to give 3-chloro-1-(3-methoxy-4-nitro-phenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole (590 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]([F:19])=[C:15]([CH3:20])[NH:14][C:13]2=[O:21])=[C:4]([F:22])[CH:3]=1.S(OC)(O[CH3:27])(=O)=O>>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]([F:19])=[C:15]([CH3:20])[N:14]([CH3:27])[C:13]2=[O:21])=[C:4]([F:22])[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1[nH]c(=O)n(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)c1F
Product: Cc1c(F)c(=O)n(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)n1C

Procedure:
using 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5-fluoro-6 methyl-2,4(1H,3H)-pyrimidinedione and dimethyl sulphate there is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-1,6-dimethyl-5-fluoro-2,4(1H,3H)pyrimidinedione, m.p. 139°-141° C.;
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[CH:15]=[C:14]([CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([NH:23][CH3:24])[CH2:19][CH2:18]3)[CH:13]=[CH:12][N:11]=2)=[CH:4][C:3]=1[O:25][CH3:26].[Cl:27][C:28]1[C:33]([O:34][CH3:35])=[CH:32][C:31]([C:36]2[CH:41]=[C:40]([CH2:42]Cl)[CH:39]=[CH:38][N:37]=2)=[CH:30][C:29]=1[O:44][CH3:45]>>[ClH:1].[ClH:27].[ClH:1].[ClH:1].[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[CH:15]=[C:14]([CH2:16][N:17]3[CH2:18][CH2:19][CH:20]([N:23]([CH2:42][C:40]4[CH:39]=[CH:38][N:37]=[C:36]([C:31]5[CH:32]=[C:33]([O:34][CH3:35])[C:28]([Cl:27])=[C:29]([O:44][CH3:45])[CH:30]=5)[CH:41]=4)[CH3:24])[CH2:21][CH2:22]3)[CH:13]=[CH:12][N:11]=2)=[CH:4][C:3]=1[O:25][CH3:26]
Reactant: CNC1CCN(Cc2ccnc(-c3cc(OC)c(Cl)c(OC)c3)c2)CC1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1Cl
Product: COc1cc(-c2cc(CN3CCC(N(C)Cc4ccnc(-c5cc(OC)c(Cl)c(OC)c5)c4)CC3)ccn2)cc(OC)c1Cl
Product: Cl

Procedure:
1-[[2-(4-chloro-3,5-dimethoxyphenyl)pyridin-4-yl]methyl]-4-methylamino-piperidine (195 mg) and 2-(4-chloro-3,5-dimethoxyphenyl)-4-chloromethylpyridine (152 mg) were condensed in the same manner as described in Example 2. A free base obtained was converted to a tetrahydrochloride giving yellow powder.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:7]([N:24]=[C:25]([NH2:27])[N:26]=3)[C:8]([CH2:12][C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=4)[NH:15][CH:14]=3)=[N:9][C:10]=2[CH:11]=1.O1C2C=CC(CC3N4N=C(N)N=C4C4C=CC(F)=CC=4N=3)=CC=2OC1.[OH:53][CH2:54][CH2:55][NH2:56]>>[NH2:27][C:25]1[N:26]=[C:6]2[N:7]([C:8]([CH2:12][C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=4)[NH:15][CH:14]=3)=[N:9][C:10]3[CH:11]=[C:2]([NH:56][CH2:55][CH2:54][OH:53])[CH:3]=[CH:4][C:5]=32)[N:24]=1
Reactant: COc1ccc2[nH]cc(Cc3nc4cc(F)ccc4c4nc(N)nn34)c2c1
Reactant: NCCO
Agent: Nc1nc2c3ccc(F)cc3nc(Cc3ccc4c(c3)OCO4)n2n1
Product: COc1ccc2[nH]cc(Cc3nc4cc(NCCO)ccc4c4nc(N)nn34)c2c1
Yield: 35 %

Procedure:
Operating as in Example 54, but employing 8-fluoro-5-(5-methoxy-1H-indol-3-ylmethyl)-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine, prepared as described in Example 32, instead of 5-benzo[1,3]dioxol-5-ylmethyl-8-fluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine and 2-hydroxy-ethylamine instead of morpholine, the title compound was obtained in 35% yield.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]([C:28]1[N:33]=[CH:32][C:31]([C:34]2[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=2)=[CH:30][N:29]=1)[C@@H:8]1[CH2:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23](O)[CH3:24])[C@H:10]([CH2:26][CH3:27])[CH2:9]1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O.ClCCCl>[F:45][C:43]([F:44])([F:46])[C:41]1[CH:40]=[C:5]([CH:4]=[C:3]([C:2]([F:48])([F:47])[F:1])[CH:42]=1)[CH2:6][N:7]([C@H:8]1[CH2:9][C@@H:10]([CH2:26][CH3:27])[N:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:14]=2[CH2:23][CH3:24])[CH2:12]1)[C:28]1[N:29]=[CH:30][C:31]([C:34]2[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=2)=[CH:32][N:33]=1
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1c1ccc(C(F)(F)F)cc1C(C)O
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(C(F)(F)F)ccc1N1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)C[C@H]1CC
Temperature: 80 °C
Reaction time: 4 h
Yield: 7.5 %

Procedure:
To a mixture of 1-[2-((2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-5-trifluoromethyl-phenyl]-ethanol (29 mg, 0.04 mmol) in TFA (1 mL) and DCE (1 mL) is added triethylsilane (1 mL, 6.3 mmol) The reaction mixture is stirred at 80° C. for 4 hours. After removal of solvent and triethylsilane, the mixture is washed with brine and extracted with EtOAc. The combined organic layer is dried over MgSO4 then concentrated under reduced pressure to give (3,5-bis-trifluoromethyl-benzyl)-[(3S,5R)-5-ethyl-1-(2-ethyl-4-trifluoromethyl-phenyl)-pyrrolidin-3-yl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine as a colorless oil (2 mg, 7%) after purification by silica gel column chromatography (eluent: n-hexane/EtOAc);
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][CH3:11])[CH:3]=1.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1>N1C=CC=CC=1>[OH:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:13]/[C:14]([OH:16])=[O:15])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: COc1cc(O)ccc1C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1cc(O)ccc1/C=C/C(=O)O
Temperature: 80 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
To a stirring solution of 4-hydroxy-2-methoxybenzaldehyde (1.02 g, 6.70 mmol) and malonic acid (728 mg, 7.00 mmol) in pyridine (9.2 mL) at ambient temperature under nitrogen was added piperidine (0.20 mL, 2.02 mmol) drop-wise. The mixture was then heated to 80° C. over 20 mins and then stirred at this temperature for 2 h. The reaction was then quenched with water (50 mL), acidified to pH 1 with concentrated HCl and then partitioned with EtOAc (50 mL) and the layers separated. The aqueous layer was re-extracted with EtOAc (50 mL) and the combined organic layer washed with brine (80 mL) and then concentrated under vacuum to give a bright yellow solid. Purification by SPE (silica, 20 g cartridge) eluting with cyclohexane:EtOAc (gradient 25:1 to 0:1) afforded the title compound (674 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1.CCOCC.[BH4-].[Na+]>C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CN1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: CCOCC
Product: CN1CCC(Nc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 1946.8 %

Procedure:
To a solution of 4-chloroaniline (4.59 g, 30×1.2 mmol) and 1-methyl-4-piperidone (3.39 g, 30 mmol) in benzene (12 ml) is added Molecular Sieve 4A (6 g), and the resultant mixture is heated under reflux over a period of 20 hours. After cooling, the reaction mixture is mixed with ether and filtered to remove the Molecular Sieve. The filtrate is concentrated in vacuo, and the residue is dissolved in 95% ethanol (50 ml). Sodium borohydride (0.6 g, 15 mmol) is added to the solution, which is stirred at room temperature over a period of 5 hours. The reaction mixture is mixed with water and the ethanol is evaporated therefrom. The aqueous residue is shaken with methylene chloride, and the methylene chloride layer is dried over anhydrous potassium carbonate and concentrated in vacuo. The residue is distilled to give crude product (5.89 g) b.p. 130°-150° C./1 mmHg. This substance is recrystallized from ether-petroleum ether to give 4 -(4-chloroanilino)-1-methylpiperidine (5.25 g) as crystals melting at 91° to 92° C. The yield is 78%.
Reaction SMILES: C(OC([NH:8][C:9]1[C:13]([NH:14]C(OC(C)(C)C)=O)=[CH:12][S:11][C:10]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:29][CH:30]=[C:31]([NH:41]C(OC(C)(C)C)=O)[C:32]=2[NH:33]C(=O)OC(C)(C)C)=[CH:24][CH:23]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[NH2:33][C:32]1[C:31]([NH2:41])=[CH:30][S:29][C:28]=1[C:25]1[CH:24]=[CH:23][C:22]([C:10]2[S:11][CH:12]=[C:13]([NH2:14])[C:9]=2[NH2:8])=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)Nc1csc(-c2ccc(-c3scc(NC(=O)OC(C)(C)C)c3NC(=O)OC(C)(C)C)cc2)c1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Nc1csc(-c2ccc(-c3scc(N)c3N)cc2)c1N
Reaction time: 3 h

Procedure:
To the resulting tert-butyl 2-[4-(3,4-bis(tert-butoxycarbonylamino)thien-2-yl)phenyl]-4-tert-butoxycarbonylaminothien-3-ylcarbamate was added 80 equivalents of trifluoroacetic acid, and a reaction was performed at 25° C. for 3 hours. The resulting reaction liquid was dropped slowly to a saturated aqueous sodium carbonate solution to neutralize, thereby stopping the reaction. Ethyl acetate was added to the reaction liquid and stirred, and then the organic layer was taken and the solvent was distilled off, and the residue was purified by silica gel column chromatography using an ethyl acetate/hexane solvent, so that 2-[4-(3,4-diaminothien-2-yl)phenyl]thiophene-3,4-diamine was obtained. The yield based on the charged tert-butyl 2-[4-(3,4-bis(tert-butoxycarbonylamino)thien-2-yl)phenyl]-4-tert-butoxycarbonylaminothien-3-ylcarbamate was 90%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[O:16])[CH2:12][CH:11]([C:22](O)=[O:23])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].O[N:26]=[C:27]([NH2:31])[CH:28]([CH3:30])[CH3:29]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH:11]([C:22]3[O:23][N:31]=[C:27]([CH:28]([CH3:30])[CH3:29])[N:26]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[O:16])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CC(O)C3)C2)cc1C
Reactant: CC(C)C(N)=NO
Product: Cc1ccc(C2CC(c3nc(C(C)C)no3)CN(C(=O)N3CC(O)C3)C2)cc1C

Procedure:
72 mg (0.22 mmol) of the compound from Example 134A and 43 mg (0.33 mmol) of N′-hydroxy-2-methylpropanimidamide were reacted according to the General Method 2. Yield: 17 mg (19% of theory)
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[C:14]([O:21][CH3:22])[N:13]=2)[CH:3]=1.[NH2:23][C@@H:24]1[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]1[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]>CN1C(=O)CCC1.C(OCC)(=O)C.[Cl-].[Na+].O>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:23][C@@H:24]2[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]2[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[C:14]([O:21][CH3:22])[N:13]=1)(=[O:9])[NH2:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Reactant: COc1nc(Nc2cc(Cl)nnc2C(N)=O)ccc1C(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1nc(Nc2cc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)ccc1C(C)C
Temperature: 140 °C
Yield: 36.2 %

Procedure:
To a solution of 6-chloro-4-(5-isopropyl-6-methoxypyridin-2-ylamino)pyridazine-3-carboxamide (250 mg, 777 μmol) in NMP (2.6 mL) was added tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (672 mg, 2.33 mmol) in four portions approximately every 12 h and heated to 140° C. in the periods between additions. After a total of 48 h, the mixture was cooled then diluted with ethyl acetate and brine. The phases were separated then the organic phase was washed with brine (2×), concentrated in vacuo and purified by chromatography (silica, 0 to 4% of a 99.5:0.5 methanol:NH4OH solution in dichloromethane) to give tert-butyl (3R,4R)-4-(6-carbamoyl-5-(5-isopropyl-6-methoxypyridin-2-ylamino)pyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (141 mg, 281 μmol, 36%) as light brown solid. MS (EI/CI) m/z: 502.3 [M+H].
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][OH:13])([O-:5])=O.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=1.Cl>N1C=CC=CC=1>[OH:5][N:3]=[C:6]1[CH:11]=[CH:10][C:9](=[C:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[C:23]#[N:24])[CH:8]=[C:7]1[CH2:12][OH:13]
Reactant: COc1ccc(CC#N)cc1
Reactant: O=[N+]([O-])c1ccccc1CO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COc1ccc(C(C#N)=C2C=CC(=NO)C(CO)=C2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 50.7 %

Procedure:
To a stirred and cooled (<15° C.) mixture of 134 parts of potassium hydroxide and 940 parts of pyridine were added portionwise 92 parts of 2-nitrobenzenemethanol. Next there were added 132.5 parts of 4-methoxybenzeneacetonitrile and stirring was continued for 4 hours at room temperature. The reaction mixture was diluted with 3000 parts of ice-water and the whole was acidified with 1270 parts of hydrochloric acid. The precipitate was filtered off, stirred overnight in methylbenzene and dried in vacuo at 60° C., yielding 128.8 parts (50.7%) of α-[4-(hydroxyimino)-3-(hydroxymethyl)-2,5-cyclohexadien-1-ylidene]-4-methoxybenzeneacetonitrile (interm. 40).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19](B(CC)CC)[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(OCC)(=O)C>[N+:9]([C:5]1[C:4]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[CH:3][C:2]([C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)=[CH:7][C:6]=1[NH2:8])([O-:11])=[O:10]
Reactant: Nc1cc(Br)cc(-n2cccn2)c1[N+](=O)[O-]
Reactant: CCB(CC)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1cc(-c2cccnc2)cc(-n2cccn2)c1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To a solution of 5-bromo-2-nitro-3-pyrazol-1-yl-phenylamine (200 mg, 0.71 mmol) in THF (8 mL) was added, successively, 3-pyridyl-diethyl borane (157 mg), (tetrakistriphenylphosphine) palladium(0) (84 mg), and sodium carbonate (1.1 mL, 2.2 mmom of 2M aqueous). The resulting mixture was stirred at 70° C. overnight then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL), brine (50 mL), dried (MgSO4) then concentrated in vacuo. The resulting residue was purified by column chromatography over silica gel eluted with a gradient of ethyl acetate:hexanes (1:3, 1:2, 1:0, 2:1, 4:1, 8:1), to afford 120 mg (60%) of the title compound as a yellow solid. 1H NMR (DMSO-d6) δ 6.45 (br, s 2H), 6.55 (t, 1H), 7.1 (s, 1H), 7.25 (s, 1H), 7.55 (m, 1H), 7.7 (s, 1H), 8.3 (d, 1H), 8.7 (d, 1H), 8.9 (s, 1H).
Reaction SMILES: C([O:4][C:5]1[C:6](=[O:12])[CH:7]=[CH:8][C:9](=[O:11])[CH:10]=1)C=C.[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH2:19])=[CH:16][CH:15]=1.[CH:22](O)([CH3:24])[CH3:23]>>[CH2:24]([C:10]1[C:9](=[O:11])[C:8]2[CH:19]=[CH:18][C:17]3[C:20]([C:7]=2[C:6](=[O:12])[C:5]=1[OH:4])=[CH:21][C:14]([CH3:13])=[CH:15][CH:16]=3)[CH:22]=[CH2:23]
Reactant: CC(C)O
Reactant: C=Cc1ccc(C)cc1
Reactant: C=CCOC1=CC(=O)C=CC1=O
Product: C=CCC1=C(O)C(=O)c2c(ccc3ccc(C)cc23)C1=O

Procedure:
2-Allyloxy-1,4-benzoquinone (6.56 g, 40 mM) and p-Methylstyrene (17.4 g, 0.10 M) were dissolved in 80 ml of isopropanol to give 2.3 g (8.3 mM) of 2-Allyl-3-hydroxy-6-methyl-1,4-phenanthrenequinone in the same manner as in Example 7.
Reaction SMILES: [CH3:1][C:2]1[N:7]=C(C#N)[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C[C:14]([CH3:17])([O-:16])C.[K+].CC([OH:22])C>O>[CH3:1][C:2]1[N:7]=[C:17]([C:14]([OH:22])=[O:16])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1nc(C#N)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)O
Agent: [K+]
Solvent: O
Product: Cc1nc(C(=O)O)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 6-methyl-5-nitropicolinonitrile (31B, 500 mg, 3.1 mmol) in 2-propanol (1 mL) and water (5 mL) was added potassium tert-butoxide (687 mg, 6.13 mmol). The mixture was stirred at 100° C. overnight, when LCMS indicated that the reaction was complete. The mixture diluted with water, and then extracted with DCM (10 mL×3). The aqueous phase was acidified with 1N HCl solution, and extracted with DCM. The organic layer was dried and concentrated to give the crude product which was used to the next step without further purification. LC-MS: m/z 181 (M−H)+
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.Cl.[C:16]12([NH2:21])[CH2:20][CH:18]([CH2:19]1)[CH2:17]2.CCN(C(C)C)C(C)C>C(O)C.O>[C:16]12([NH:21][C:2]3[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=3)[CH2:20][CH:18]([CH2:19]1)[CH2:17]2
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: NC12CC(C1)C2
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1cnc(SC)nc1NC12CC(C1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
A mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (200 g, 0.86 mol), bicyclo[1.1.1]pentan-1-amine hydrochloride (171 g, 1.11 mol; prepared according to Org. Lett., 13(17): 4746-4748 (2011)) and DIEA (278 g, 2.15 mol) in ethanol (2.4 L) was stirred overnight at room temperature. After completion of the reaction, the solvents were concentrated under reduced pressure to give the crude product, which was diluted with water (1 L). The aqueous layer was extracted with chloroform (2×1 L) and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. Evaporation of the solvents afforded the desired compound (231 g, 0.83 mol, 96% yield) as a pale brown oil which was contaminated with trace amounts of DIEA. This product was used in the next reaction without further purification; 1H NMR (400 MHz, CDCl3) δ ppm 8.61 (s, 2H), 4.30 (q, J=7.2 Hz, 2H), 2.54 (s, 3H), 2.51 (s, 1H), 2.20 (s, 6H), 1.35 (t, J=7.2 Hz, 3H).