Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]([N:9]2[CH2:16][C:15](=[N:17]O)[C:11]3([CH2:14][CH2:13][CH2:12]3)[C:10]2=[O:19])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Ni]>[NH2:17][CH:15]1[C:11]2([CH2:14][CH2:13][CH2:12]2)[C:10](=[O:19])[N:9]([C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH3:8])[CH2:16]1
Reactant: C[C@H](c1ccccc1)N1CC(=NO)C2(CCC2)C1=O
Agent: [Ni]
Solvent: CO
Product: C[C@H](c1ccccc1)N1CC(N)C2(CCC2)C1=O
Reaction time: 14.5 h

Procedure:
To a solution of 8.75 g of 6-[1-(R)-phenylethyl]-8-hydroxyimino-5-oxo-6-azaspiro[3.4]octane in 300 ml of methanol there was added 26 ml of Raney nickel, and reduction was carried out under a hydrogen atmosphere at room temperature for 14.5 hr. The catalyst was removed by filtration and the solvent was removed under reduced pressure. By the same procedure, 1.65 g of 6-[1-(R)-phenylethyl]-8-hydroxyimino-5-oxo-6-azaspiro-[3.4]octane was reduced using 5 ml of Raney nickel. The crude products were combined and purified by column chromatography using a column containing 380 g of silica gel. From a fraction of an eluant of 1% (v/v) methanolic chloroform, 3.2 g of the less polar isomer of the titled compound was obtained and 1.8 g of the more polar isomer thereof along with 4.4 g of a mixture of the two isomers.
Reaction SMILES: [C:1]12[C:7](=[N:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[CH:13]([NH2:16])([CH3:15])[CH3:14]>CN(C)C=O>[NH2:6][C:7]1[N:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:16][CH:13]([CH3:15])[CH3:14])=[O:4]
Reactant: CC(C)N
Reactant: O=c1[nH]c2ncccc2c(=O)o1
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cccnc1N

Procedure:
In addition to being useful as discussed above, acid anhydrides produced by the method of the invention are useful as intermediates for the production of pyrimidine diones which can be used as herbicides. For example, 3-azaisatoic anhydride can be dissolved in dimethylformamide and reacted with a substantially stoiciometric amount of isopropyl amine to produce 2-amino-N-isopropylnicotinamide. The reaction is conveniently conducted at a temperature of about 45°-50° until carbon dioxide evolution ceases. The 2-amino-N-isopropylnicotinamide can then be reacted with phosgene to produce 3-isopropyl pyrido[2,3-d]pyrimidine-2,4 (1H,3H)-dione. This reaction can be conducted under ambient pressure in p-dioxane as a solvent, preferably in the presence of triethylamine as an HCl absorber, at a temperature in the vicinity of 100°.
Reaction SMILES: Cl[CH:2]1[CH2:6][CH2:5][CH:4]=[CH:3]1.[NH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1>CO>[CH:4]1[CH2:5][CH2:6][CH:2]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:3]=1
Reactant: C1CNCCN1
Reactant: ClC1C=CCC1
Solvent: CO
Product: C1=CC(N2CCNCC2)CC1
Yield: 21.5 %

Procedure:
3-chlorocyclopentene (306 mmoles, 36.9 g) was added dropwise to a solution of anhydrous piperazine (496 mmoles, 36.9 g) in dry methanol (350 mL) at -13° C. The final solution was stirred at -13° C. for 15 minutes and at room temperature for one hour. The solvent was evaporated to dryness, and the residue was first taken up with chloroform and then filtered to eliminate the precipitate. After elimination of chloroform by evaporation the filtrate give 10 g of 1-(cyclopenten-3-yl) piperazine (yellow oil).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](Cl)=[N:6][S:5][N:4]=1.CS(C)=O.[S:13]([NH2:23])(=[O:22])([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3]1[C:7]([NH:23][S:13]([C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)(=[O:14])=[O:22])=[N:6][S:5][N:4]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: COc1nsnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1nsnc1NS(=O)(=O)c1ccc(N)cc1
Yield: 96.8 %

Procedure:
150.6 g of 3-methoxy-4-chloro-1,2,5-thiadiazole (1 mole) were suspended in 390.65 g (5 mole) of dimethyl sulfoxide, and 258.31 g of sulfanilamide (1.5 mole) and 414.63 g of potassium carbonate (3 mole) were added. The mixture was left to react for 10 days at temperatures of 28°-30° C., and was then worked up according to Example 1. 277.2 g of crude 3-methoxy-4-(4'-aminobenzenesulfonamido)-1,2,5-thiadiazole were obtained, corresponding to a yield of 96.82% of theory. Melting point: 144°-147° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CN(C=O)C.O>[N:20]1([C:2]2[S:3][C:4]3[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1cccc2nc(Br)sc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc2nc(N3CCOCC3)sc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.7 %

Procedure:
To 0.200 g (0.77 mmol) of 2-bromo-7-nitro-1,3-benzothiazole in 2 mL of DMF was added 0.21 g (1.5 mmol) of potassium carbonate and 81 μL (0.93 mmol) of morpholine. The mixture was stirred at room temperature for 72 h and diluted with water. The precipitate that formed was collected by filtration and purified by flash chromatography eluting with a 33% ethyl acetate/hexanes mixture to give 0.075 g (37%) of the title compound as a cream colored powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH3:17])[C:4]=1[NH:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[Cl:18][CH2:19][C:20](Cl)=[O:21].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:18][CH2:19][C:20]([N:5]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4]1[C:12]([CH2:16][CH3:17])=[CH:13][CH:14]=[CH:15][C:3]=1[CH2:1][CH3:2])=[O:21]
Reactant: CCOC(=O)CNc1c(CC)cccc1CC
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)CN(C(=O)CCl)c1c(CC)cccc1CC
Reaction time: 2 h

Procedure:
23.5 Grams (0.1 mol) of ethyl 2,6-diethylanilinoacetate and 11.3 g (0.1 mol) of monochloroacetic acid chloride were dissolved in 100 ml of benzene, 11.0 g of triethylamine was then added dropwise thereto with stirring maintaining the reaction temperature at 10°-20° C. and, thereafter, stirring was continued for further 2 hours at a room temperature. The reaction solution was washed with successive, 5% sodium hydroxide aqueous solution, 5% hydrochloric acid aqueous solution, and water. Then, the benzene layer was dried over anhydrous sodium sulfate. Thereafter, benzene was removed under reduced pressure to obtain the end product, ethyl N-chloroacetyl-2,6-diethylanilinoacetate. nD26 : 1.5225.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH2:18])=[CH:16][C:15]([C:19](=[O:24])[NH:20][CH:21]3[CH2:23][CH2:22]3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)[CH3:2].[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31]>C(#N)C>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH:18][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([Cl:26])[CH:28]=3)=[CH:16][C:15]([C:19](=[O:24])[NH:20][CH:21]3[CH2:22][CH2:23]3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)CC1CCN(c2ncc(C(=O)NC3CC3)cc2N)CC1
Solvent: CC#N
Product: CCOC(=O)CC1CCN(c2ncc(C(=O)NC3CC3)cc2NC(=O)c2cccc(Cl)c2)CC1
Reaction time: 8 h
Yield: 52.7 %

Procedure:
A mixture of 0.39 g (0.90 mmol) of (3′-amino-5′-cyclopropylcarbamoyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid ethyl ester in acetonitrile (5 mL) is treated with 0.14 mL (1.1 mmol) of 3-chlorobenzoyl chloride. The mixture is stirred overnight and then concentrated under reduced pressure. The residue is taken up into water and extracted with ethyl acetate. The combined organic phase is washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to provide 0.23 g (52%) of [3′-(3-chloro-benzoylamino)-5′-cyclopropylcarbamoyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid ethyl ester as a colorless foam.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]4[OH:32])=[CH:21][C:20]=3[OH:33])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34](Cl)(=[O:46])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:13]1([C:11]2[N:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]4[O:32][C:34](=[O:46])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:21][C:20]=3[OH:33])[N:10]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Oc1cc(OC2CCCCC2O)ccc1-c1nc(-c2ccccc2)nc(-c2ccccc2)n1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC(=O)OC1CCCCC1Oc1ccc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c(O)c1
Reaction time: 20 h

Procedure:
A mixture of 5.0 g (11.3 mmol) of 2,4-diphenyl-6-(2'-hydroxy-4'-(2"- hydroxycyclohexyloxy)phenyl)-1,3,5-triazine, 5.7 g (26 mmol) of dodecanoyl chloride (Fluka, 98%) and 0.1 g (1.3 mmol) of pyridine in 60 ml of toluene is stirred under nitrogen and kept at 50° C. for 20 h.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:18][CH:17]=3)[C:10]=2[CH:30]=1)=[O:5])[CH3:2].[H][H]>[Pd].C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:18][CH:17]=3)[C:10]=2[CH:30]=1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc2nc(C)n(Cc3ccc(C=Cc4ccccc4)cc3)c2c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc2nc(C)n(Cc3ccc(CCc4ccccc4)cc3)c2c1

Procedure:
Five-percent palladium on carbon was added to a solution of 0.320 g of 6-ethoxycarbonyl-2-methyl-1-[4-(2-phenylethenyl)benzyl]benzimidazole in 10 ml of ethanol in a nitrogen atmosphere, and the mixture was stirred in a hydrogen atmosphere for 23 hours. The solid material was separated through filtration, and the filtrate was concentrated to give 6-ethoxycarbonyl-2-methyl-1-[4-(2-phenylethyl)benzyl]-benzimidazole (368). This compound was used in the subsequent reaction at once.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=1.[OH-].[Na+]>O.O.C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:12])/[CH:11]=[CH:19]/[C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccncc1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(/C=C/c1ccncc1)c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 25.3 %

Procedure:
A suspension of 4′-nitroacetophenone (5 g, 30.3 mmol) and 4-pyridinecarboxaldehyde (2.89 mL, 30.3 mmol) in water (45 mL) at room temperature was treated with 6% NaOH in H2O/ethanol (2:1)(0.606 mL), stirred overnight, and filtered. The filter cake was washed with water and small amount of ethanol then triturated with dichloromethane to provide 1.95 g (25%) of the desired product. MS(ESI(+)) m/e 255 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH2:13][C:14](O)=[O:15])[CH2:10][C@@H:9]1[C:17]([O:19][CH3:20])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH2:13][CH2:14][OH:15])[CH2:10][C@@H:9]1[C:17]([O:19][CH3:20])=[O:18])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)[C@H]1C[C@@H](CC(=O)O)CN1C(=O)OC(C)(C)C
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@@H](CCO)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To 0.67 g of cis methyl N-t-butoxycarbonyl-4-(carboxymethyl)-pyrrolidine-2-carboxylate in 1 ml THF is added at 0° 3.5 ml of borane (1M) in THF. After stirring 0.5 hour, 1 ml of water is added, the solvent is evaporated and the residue is flash chromatographed with ethyl acetate/hexane (75:25) to afford cis methyl N-t-butoxycarbonyl-4-(2-hydroxyethyl)-pyrrolidine-2-carboxylate.
Reaction SMILES: [F:1][C:2]([F:15])([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:3](OCC)=[O:4].[NH2:16][NH2:17].O>CCO>[F:1][C:2]([F:15])([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:3]([NH:16][NH2:17])=[O:4]
Reactant: NN
Reactant: CCOC(=O)C(F)(F)Cc1ccccn1
Solvent: CCO
Solvent: O
Product: NNC(=O)C(F)(F)Cc1ccccn1
Reaction time: 1 h

Procedure:
The product of Example 66 (0.18 g, 0.84 mmol) was dissolved in 5 mL of EtOH. To the solution was added NH2NH2.H2O (0.084 g, 1.7 mmol). The reaction was complete in 1 hour. The solvent was removed under vacuum. The structure was confirmed by 1H NMR.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:12][C@@H:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:14])[CH2:10][OH:11])=[CH:5][CH:4]=1)#[N:2].N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].O>C(Cl)Cl>[Si:27]([O:11][CH2:10][CH:9]([NH:12][C@@H:13]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH3:14])[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: C[C@@H](NC(CO)c1ccc(C#N)cc1)C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: C[C@@H](NC(CO[Si](C)(C)C(C)(C)C)c1ccc(C#N)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.7 %

Procedure:
To a solution of tert-butyl N-[1-(4-cyanophenyl)-2-hydroxyethyl]-D-alaninate (2 g, 0.0068 mol) in DCM (30 ml) were added imidazole (0.92 g, 0.0136 mol) and tert-Butyldimethylsilylchloride (1.25 g, 0.0082 mol) at RT. The reaction mixture was stirred at RT for 6 h and portioned between DCM and water, separated the layer and concentrated under reduced pressure. The crude material was purified by column chromatography using petroleum ether and ethyl acetate (80:20) as an eluent to afford (2 g, 74%) of the title compound as brown oil. 1H NMR: (DMSO-d6, 400 MHz) δ 7.80-7.77 (m, 2H), 7.53-7.50 (m, 2H), 4.86-4.85 (t, J=3.9 Hz, 1H), 3.17-3.13 (m, 1H), 2.61-2.55 (m, 1H), 1.95-1.89 (m, 1H), 1.39 (s, 9H), 1.09-1.07 (d, J=7.1 Hz, 3H), 0.80 (s, 9H), 0.04 (s, 3H), −0.12 (s, 3H). LC/MS (Method A): 405.3 (M+H)+. HPLC (Method A) Rt 5.13 min. (Purity: 73.7%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]([OH:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[C:15]([CH3:27])[CH:14]=2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:28].[H-].[Na+].[CH3:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34].C(OCC)(=O)C>CN(C=O)C>[CH3:27][C:15]1[CH:14]=[C:13]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[C:3]([CH3:28])[CH:4]=2)([CH2:9][CH3:10])[CH2:11][CH3:12])[CH:18]=[CH:17][C:16]=1[O:19][CH2:20][CH:21]([OH:26])[C:22]([CH3:23])([CH3:25])[CH3:24]
Reactant: CC(=O)C(C)(C)C
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(OCC(O)C(C)(C)C)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(OCC(O)C(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution of the compound of example 7 (100 mg, 0.26 mmol) in DMF (2.5 mL) was added NaH (7.0 mg, 0.29 mmol). The reaction mixture was stirred at ambient temperature for 30 min, then pinacolone (39 mg, 0.29 mmol) was added. The reaction was stirred at ambient temperature for I h or until judged complete by TLC (20% ethyl acetate in hexanes). The reaction mixture was quenched with water, and diluted with ethyl acetate. The organic fraction was separated, washed with water and brine, dried over MgSO4, and concentrated in vacuo. Chromatography (silica, 10% ethyl acetate in hexanes) afforded 117 mg (0.24 mmol, 92%) of 11. 1HNMR (CDCl3) δ: 6.91 (m, 4 H, Ar—H), 6.69 (d, J=8.3 Hz, 1 H, Ar—H), 6.49 (d, J=8.3 Hz, 1 H, Ar—H), 4.83 (s, 2 H, CH2), 4.09 (dd, J=11.3 Hz, J=3.3 Hz, 1 H, CH2), 3.85 (t, J=11.3 Hz, 1 H, CH2), 3.69 (d, J=11.3 Hz, 1 H, CH2), 2.23 (s, 3 H), Ar—CH3), 2.18 (s, 3 H, Ar—CH3), 2.00 (q, J=7.3 Hz, 4 H, CH2CH3), 1.24 (s, 9 H, t-Bu), 1.00 (s, 9 H, t-Bu), 0.58 (t, J=7.3 Hz, 6 H, CH2CH3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[C:5](I)=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[C:18]([N:25]1[CH2:28][C:27](=[O:29])[CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1COCC1>[C:21]([O:20][C:18]([N:25]1[CH2:28][C:27]([C:5]2[C:4]([CH2:9][OH:10])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)([OH:29])[CH2:26]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: OCc1cc(Br)cnc1I
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(c2ncc(Br)cc2CO)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.2 %

Procedure:
To a stirred solution of (5-bromo-2-iodo-pyridin-3-yl)-methanol (9.5 g, 30.2 mmol, 1 eq) in dry THF (100 mL) was added i-PrMgCl.LiCl complex (1.3M in THF, 55.9 mL, 72.6 mmol, 2.4 eq) at −20° C. in drop wise manner over period of 20 minutes. Predissolved solution of N-boc-3-azetidinone (6.22 g, 36.3 mmol, 1.2 eq) in dry THF (80 mL) was added at −20° C. to above reaction mixture. Resulting reaction mixture was stirred at room temperature for 16 hours under nitrogen atmosphere. After maximum consumption of starting material, reaction mixture was cooled to 0° C. and quenched with 10% citric acid solution (20 mL), diluted with water (150 mL) and extracted with ethyl acetate (3×100 mL). Combined organic phase was washed with brine solution (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get yellowish sticky mass (18.2 g, crude). Crude compound was purified by column chromatography by using silica gel (100-200 mesh). Desired compound was eluted by 35% ethyl acetate in hexane to afford title compound as pale yellow thick oil (4.9 g, 45%). 1H NMR (400 MHz, CDCl3) δ: 1.43 (s, 9H), 3.12 (s, 1H), 4.13 (d, J=9.92 Hz, 2H), 4.54 (bs, 2H), 4.71-4.73 (m, 3H), 7.93 (d, J=2.12 Hz, 1H), 8.53 (d, J=3.00 Hz, 1H). LC-MS (m/z): 358.9 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][C:24]=1[F:31].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][O:20][C:17]2[CH:18]=[CH:19][N:14]([C:11]3[CH:12]=[CH:13][C:6]4[N:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[N:8]([CH3:9])[C:7]=4[CH:10]=3)[C:15](=[O:21])[CH:16]=2)=[CH:25][C:24]=1[F:31]
Reactant: OCc1ccc(Cl)c(F)c1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(Cl)c(F)c4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 16.6 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (4-chloro-3-fluorophenyl)methanol (114 mg) and tributylphosphine (258 μl) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (265 mg). The mixture was stirred under sonication at 60° C. for 2 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (25 mg) as an off-white solid.
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[C:31]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)[CH:30]=[CH:29][C:28]=1[NH2:40].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:25][O:26][C:27]1[CH:32]=[C:31]([N:33]2[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]2)[CH:30]=[CH:29][C:28]=1[NH:40][C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: CN(c1ncccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Reactant: COc1cc(N2CCN(C)CC2)ccc1N
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: COc1cc(N2CCN(C)CC2)ccc1Nc1nc2c(NCc3cccnc3N(C)S(C)(=O)=O)cccn2n1

Procedure:
N-[3-({2-[2-Methoxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-methyl)-pyridin-2-yl]-N-methyl-methanesulfonamide was prepared from N-{3-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyridin-2-yl}-N-methyl-methanesulfonamide (75.0 mg, 0.204 mmol) and 2-methoxy-4-(4-methyl-piperazin-1-yl)-phenylamine (50.0 mg, 0.226 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a brown foam (0.049 g, 43%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.40 (dd, J=4.7, 1.6 Hz, 1H), 8.19 (d, J=8.6 Hz, 1H), 7.85 (dd, J=7.7, 1.6 Hz, 1H), 7.82 (d, J=6.7 HZ, 1H), 7.29-7.25 (m, 1H), 7.17 (s, 1H), 6.65-6.57 (m, 3H), 6.28 (d, J=7.7 Hz, 1H), 5.29 (t, J=6.1 Hz, 1H), 4.76 (d, J=6.3 Hz, 2H), 3.89 (s, 3H), 3.32 (s, 3H), 3.18-3.13 (m, 4H), 3.09 (s, 3H), 2.63-2.58 (m, 4H), 2.37 (s, 3H). MS=552 (MH)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[C:16]3[C:17]([CH3:21])([CH3:20])[CH2:18][O:19][C:15]=3[C:14]([CH3:22])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-])=O>CCO.[Pd]>[CH3:20][C:17]1([CH3:21])[C:16]2[C:11]([O:10][C:7]3[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)=[CH:12][CH:13]=[C:14]([CH3:22])[C:15]=2[O:19][CH2:18]1
Reactant: Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)c2c1OCC2(C)C
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(Oc2ccc(N)cn2)c2c1OCC2(C)C

Procedure:
5-Nitro-2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]pyridine (Intermediate 185, 920 mg, 3.0 mmol) was dissolved in EtOH (13.5 mL) and stirred under hydrogen atmosphere (2 bar) in the presence of Pd/C 10% w/w (46 mg, 5% w/w) at room temperature for 30 minutes. The catalyst was filtered off, washed with THF and the resulting solution evaporated to dryness to afford an orange solid. The crude product was crystallized from MeOH to the title compound (565 mg) as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[C:14](F)[C:11]([C:12]#[N:13])=[C:10]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[C:22]([CH3:27])=[N:23][NH:24][C:25]=3[CH3:26])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.O.[NH2:29][NH2:30]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[C:25]([CH3:26])=[N:24][NH:23][C:22]=3[CH3:27])[C:11]3[C:12]([NH2:13])=[N:29][NH:30][C:14]=3[CH:15]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1n[nH]c(C)c1CCCNc1cc(-c2ccnc(N)n2)cc(F)c1C#N
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1n[nH]c(C)c1CCCNc1cc(-c2ccnc(N)n2)cc2[nH]nc(N)c12
Temperature: 90 °C
Yield: 32 %

Procedure:
To a solution of 4-(2-amino-4-pyrimidinyl)-2-{[3-(3,5-dimethyl-1H-pyrazol-4-yl)propyl]amino}-6-fluorobenzonitrile (22 mg, 0.037 mmol) in EtOH (2 mL) was added hydrazine monohydrate (1 mL). The resulting solution was stirred at 90° C. until the starting material was consumed as judged by LCMS (˜12 hours). The reaction mixture was concentrated, and the resulting yellow solid was dissolved in EtOH and precipitated with hexanes. The filtrate was decanted to afford the title compound (5 mg, 32%) as a light yellow solid. LC-MS (ES) m/z=378 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.91-1.98 (m, 2H), 2.16-2.23 (s, 6H), 2.59 (t, J=7.2 Hz, 2H), 3.24-3.31 (m, 2H), 6.60 (s, 1H), 7.04 (d, J=5.3 Hz, 1H), 7.23 (s, 1H), 8.27 (d, J=5.30 Hz, 1H).