Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[N:3]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[C:14]=1[CH:21]1[O:25][CH2:24][CH2:23][O:22]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[N:3]=2)=[C:15]([F:20])[C:14]=1[CH:21]1[O:22][CH2:23][CH2:24][O:25]1
Reactant: Oc1ccc(Br)c(C2OCCO2)c1F
Reactant: COc1nc(Cl)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(Oc2ccc(Br)c(C3OCCO3)c2F)ccc1C#N
Yield: 85 %

Procedure:
A solution of 6-chloro-2-methoxynicotinonitrile (1.16 g, 6.88 mmol), 4-bromo-3-(1,3-dioxolan-2-yl)-2-fluorophenol (1.81 g, 6.88 mmol), potassium carbonate (1.14 g, 8.26 mmol), and N,N-dimethylformamide (35 mL) was stirred at 80° C. overnight. Water was added and the solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel column using Combiflash to give 6-(4-bromo-3-(1,3-dioxolan-2-yl)-2-fluorophenoxy)-2-methoxynicotinonitrile (2.31 g, 85% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:9]=1[S:21][CH3:22].Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>CC(C)=O>[CH3:22][S:21][C:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[CH:19]=[CH:20][C:8]=1[O:7][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]
Reactant: CSc1c(O)ccc2c1[nH]c1ccccc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSc1c(OCC(=O)OC(C)(C)C)ccc2c1[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
135 mg of powdered potassium carbonate was added to a solution of 112 mg of 2-hydroxy-1-methylthiocarbazole, as obtained in Example 2, in 4 ml of acetone. 956 mg of tert-butyl bromoacetate was added to the reaction mixture which was then stirred for 2 hours at room temperature. After this time, the reaction mixture was poured into ice water, and concentrated by evaporation under reduced pressure. The aqueous layer was extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 3 g of silica gel with a 9:1 v/v mixture of hexane and ethyl acetate as the eluent, to yield 140 mg of the title compound as an oil.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[N:10]=2)[CH:7]=1.[CH2:20](C([Sn])=C(CCCC)CCCC)[CH2:21]CC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[C:14]1([NH:13][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([CH:20]=[CH2:21])=[CH:7][N:6]3[CH:8]=2)=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Nc1ccccc1)c1cn2cc(I)ccc2n1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Temperature: 130 °C

Procedure:
A mixture of 0.73 g of 6-iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide, 209 mg of tetrakis(triphenylphosphine)palladium(0), 587 μl of tributylvinyltin and 17 ml of DMF is heated at 130° C. for 10 minutes in a microwave device and then concentrated to dryness. The residue is taken up in 100 ml of water and extracted with two times 70 ml of ethyl acetate. The combined organic phases are washed with a saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The solid is triturated from ethyl acetate, filtered off, washed with ethyl acetate and then with isopropyl ether, and taken up in a mixture of methanol and dichloromethane. The insoluble material is filtered off and washed with methanol. The filtrate is concentrated to dryness under reduced pressure to give 0.29 g of N-phenyl-6-vinylimidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][N:10]2[C:25]2[N:26]([CH:31]3[CH2:34][CH2:33][CH2:32]3)[N:27]=[C:28]([CH3:30])[CH:29]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[NH:35]1[CH:39]=[CH:38][CH:37]=[N:36]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:35]4[CH:39]=[CH:38][CH:37]=[N:36]4)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][N:10]2[C:25]2[N:26]([CH:31]3[CH2:34][CH2:33][CH2:32]3)[N:27]=[C:28]([CH3:30])[CH:29]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: c1cn[nH]c1
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(-n4cccn4)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1

Procedure:
In analogy to the procedure described in example 392, (2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (example 385b) was reacted with pyrazole (CAS Reg. No. 288-11-9) to give the title compound as colorless oil. MS (ESI): m/z=554.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=[O:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.Cl[C:13]1[N:18]=[C:17]([Cl:19])[C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=1>CN(C)C(=O)C.C(N(C(C)C)CC)(C)C>[Cl:19][C:17]1[C:16]([C:20]([F:22])([F:21])[F:23])=[CH:15][N:14]=[C:13]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([P:8]([CH3:9])([CH3:10])=[O:11])=[CH:6][CH:7]=2)[N:18]=1
Reactant: CP(C)(=O)c1ccc(N)cc1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 494 %

Procedure:
A suspension of 4-amino-dimethylphenylphosphine oxide (3.7 g, 2.2 mmol) in 15 mL of N,N-Dimethylacetamide and 3.6 mL of Diisopropylethylamine, was allowed to stirred at room temperature for 15 minutes until a clear solution was obtained. 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (5.7 g, 2.6 mmol) was added in four portions over 5 minutes. The reaction mixture was stirred at 60 degrees for 1 hour. The reaction mixture was cooled to room temperature and filtered to obtain a white solid. The white solid was washed with 50 mL of water three times and followed by 50 mL of Ethyl ether three times. The white solid was dried under vacuum to yield desired product (3.8 g, 49% yield). MS/ES+: m/z=350.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][S:4]([CH2:7][CH2:8][C:9]([NH:11][CH2:12][CH2:13][S:14][CH:15]=[CH2:16])=[O:10])(=[O:6])=[O:5].[OH:17]O>C(O)(=O)C>[Cl:1][CH2:2][CH2:3][S:4]([CH2:7][CH2:8][C:9]([NH:11][CH2:12][CH2:13][S:14]([CH:15]=[CH2:16])=[O:17])=[O:10])(=[O:5])=[O:6]
Reactant: C=CSCCNC(=O)CCS(=O)(=O)CCCl
Reactant: OO
Solvent: CC(=O)O
Product: C=CS(=O)CCNC(=O)CCS(=O)(=O)CCCl

Procedure:
A suspension of 6 g Intermediate 2 in 25 ml acetic acid was treated at 20° C. with 2.5 ml of 30 % hydrogen peroxide and 3 ml acetic acid. After 2 hours the solution was evaporated and the residue stirred with ether. The solid was filtered, dried and recrystallised from ethanol-petrolether. Yield 4.85 g; Mp. 108° to 109° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1.[CH2:16]([Li])[CH2:17][CH2:18]C.C(Br)C=C.[Cl-].[NH4+]>C(OCC)C.CCCCCC.C(OCC)(=O)C>[CH2:8]([C:6]1[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=[C:2]([CH3:1])[CH:7]=1)[CH2:18][CH:17]=[CH2:16]
Reactant: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=CCCc1cc(C)cc(-n2c(C)ccc2C)n1
Temperature: -25 °C
Reaction time: 0.08 h
Yield: 68.7 %

Procedure:
A solution of 213 mg (1.06 mmol) of 4,6-dimethyl-2-(2,5-dimethylpyrrol-1-yl)pyridine in 1.2 mL of ethyl ether was added over a 5 min period to a -25° C. solution prepared from 1.2 mL of ethyl ether and 0.75 mL (1.09 mmol) of 1.45 M n-butyllithium in hexane. The mixture was stirred for 5 min at -25° C. and then allowed to warm to -5° C. over 10 min. Allyl bromide (0.105 mL, 147 mg, 1.21 mmol) was added and the mixture was allowed to warm to 10° C. over 1 h. Saturated aqueous ammonium chloride (10 mL) was added and the mixture was extracted with 20 mL of ethyl acetate. The organic layer was washed with 10 mL of saturated aqueous sodium chloride, dried (sodium sulfate), decanted, and evaporated. Column chromatography on 20 g of silica gel eluting with 5% ethyl acetate in hexane gave 175 mg (68% yield) of 6-(3-buten-1-yl)-4-methyl-2-(2,5-dimethylpyrrol-1-yl)pyridine as a colorless oil.
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][CH:16]([CH2:20][P:21]([OH:32])([CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)=O)(C)(C)C>C(OC(=O)C)C>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][CH:16]([CH2:20][P:21]([OH:32])([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(CP(=O)(O)CCCc2ccccc2)C(=O)O)cn1
Solvent: CCOC(C)=O
Product: Nc1ccc(CC(CP(=O)(O)CCCc2ccccc2)C(=O)O)cn1
Reaction time: 22 h
Yield: 93.2 %

Procedure:
To a mixture of 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-3-[hydroxy-(3-phenyl-propyl)-phosphinoyl]-propionic acid (0.170 g, 0.367 mmol) in ethylacetate (3 mL) at 4° C. was slowly added ethylacetate (4 mL, saturated with HCl(g)). The mixture was then stirred for 22 h. Concentration under reduced pressure gave the title compound (0.124 g, 93%) as the hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:14][CH2:15][CH2:16][CH2:17][Cl:18])=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[N:19]([C:22]1[C:23]([CH3:31])=[N:24][C:25]([O:29][CH3:30])=[N:26][C:27]=1[CH3:28])=[C:20]=S.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O1CCCC1.O>[Cl:18][CH2:17][CH2:16][CH2:15][N:14]1[C:3]2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:2]=2[N:1]=[C:20]1[NH:19][C:22]1[C:27]([CH3:28])=[N:26][C:25]([O:29][CH3:30])=[N:24][C:23]=1[CH3:31]
Reactant: COc1nc(C)c(N=C=S)c(C)n1
Reactant: COC(=O)c1ccc(OC)c(N)c1NCCCCl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(OC)c2nc(Nc3c(C)nc(OC)nc3C)n(CCCCl)c12
Temperature: 40 °C
Reaction time: 72 h
Yield: 57.2 %

Procedure:
A mixture of methyl 3-amino-2-[(3-chloropropyl)amino]-4-methoxybenzoate (965 mg, 3.55 mmol) and 5-isothiocyanato-2-methoxy-4,6-dimethylpyrimidine (1.04 g, 5.32 mmol) in tetrahydrofuran (15 mL) was stirred at 40° C. for 3 days. The solvent was removed in vacuo and the solid was collected by filtration, washed with diisopropyl ether. A mixture of the solid (1.589 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.72 g, 3.76 mmol) and triethylamine (0.52 mL, 3.73 mmol) in tetrahydrofuran (16 mL) was stirred at 50° C. for 3 hr. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (130 mg, 0.678 mmol) and triethylamine (0.095 mL, 0.682 mmol) were added to the reaction mixture at room temperature and the mixture was stirred at 50° C. for 1 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with a mixture of ethyl acetate, THF and N,N-dimethylformamide. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (878.9 mg, 2.03 mmol, 66%) as a pale red solid.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[C:5]([F:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[C:5]([F:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:11]=1[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1c(Cl)nc2c(F)cccc2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2c(F)cccc2c1Cl

Procedure:
Prepared according to procedure E using 2,4-dichloro-8-fluoro-3-methylquinoline (1.0 g, 4.35 mmol), Pd(PPh3)4 (251 mg, 0.22 mmol) and 2-tributylstannylpyridine (1.6 mL, 4.35 mmol) in toluene (15 mL) to give 4-chloro-8-fluoro-3-methyl-2-(pyridin-2-yl)quinoline as a white solid.
Reaction SMILES: [H-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:10]=[C:11]([OH:16])[CH:12]=[C:13]([Cl:15])[CH:14]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](Cl)=[N+:20]([O-:25])[C:19]=1[C:26]([O:28][CH3:29])=[O:27]>C(OCC)(=O)C.O>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([O:16][C:11]2[CH:10]=[C:9]([Cl:8])[CH:14]=[C:13]([Cl:15])[CH:12]=2)=[N+:20]([O-:25])[C:19]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: COC(=O)c1c(Cl)ccc(Cl)[n+]1[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(Cl)ccc(Oc2cc(Cl)cc(Cl)c2)[n+]1[O-]
Yield: 76.5 %

Procedure:
To a dry 3-neck round bottom flask was added 60% NaH (0.432 g, 10.81 mmol), dry THF (30 mL) and 3,5-dichlorophenol (1.76 g, 10.81 mmol). The mixture was stirred until evolution of H2 (g) ceased. Methyl 3,6-dichloropyridine-2-carboxylate N-oxide (2.0 g, 9.00 mmol) was added in one portion and stirred at RT for 3 hr, diluted with ethyl acetate and 100 mL of water. The aqueous phase was extracted with ethyl acetate (2×200 mL). The combined extracts were dried (MgSO4) and concentrated to give 2.40 g of white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:5])[CH3:4].F[C:7]1[N:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=24)[N:20]=[CH:19][N:18]([C@H:28]2[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]2[OH:34])[C:17]3=[O:35])=[CH:9][CH:8]=1>CS(C)=O.C(OCC)(=O)C>[CH2:3]([O:5][C:7]1[N:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=24)[N:20]=[CH:19][N:18]([C@H:28]2[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]2[OH:34])[C:17]3=[O:35])=[CH:9][CH:8]=1)[CH3:4]
Reactant: CCO
Reactant: O=c1c2cc(Cc3ccc(F)nc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOc1ccc(Cc2cc3c(=O)n([C@H]4CCOC[C@@H]4O)cnc3c3ccccc23)cn1
Reaction time: 0.08 h

Procedure:
To a solution of sodium hydride (0.012 g, 0.31 mmol) in 1 mL of DMSO was added ethanol (0.022 mL, 0.37 mmol). After 5 min, 6-[(6-Fluoropyridin-3-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (0.050 g, 0.12 mmol) was added. After 4 h, the reaction was diluted with ethyl acetate, washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 25-75% ethyl acetate in hexanes to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 432.1916 for [M+H]+ [Calc'd for C25H26N3O4, [M+H]+=432.1918]: 1H NMR (400 MHz, CDCl3) δ 8.92-8.89 (m, 1H), 8.26 (s, 1H), 8.00 (s, 1H), 7.89-7.86 (m, 1H), 7.84 (s, 1H), 7.65-7.58 (m, 2H), 7.29 (s, 1H), 6.55 (s, 1H), 4.86-4.79 (m, 1H), 4.29-4.06 (m, 7H), 3.59-3.52 (m, 1H), 3.33-3.29 (m, 1H), 3.16 (d, J=6.5 Hz, 1H), 2.29-2.19 (m, 1H), 2.01-1.97 (m, 1H), 1.30-1.27 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C1(C)C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[N:7]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:17]=2)[C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: O=c1cc(Cl)[nH]c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: N#Cc1ccccc1-c1ccc(Cn2c(Cl)cc(=O)[nH]c2=O)cc1
Temperature: 65 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
A mixture of 6-chloropyrimidine-2,4(1H,3H)-dione (10 g), 4′-(bromomethyl)biphenyl-2-carbonitrile (4.71 g), potassium carbonate (27.8 g) and dimethyl sulfoxide (100 mL) was stirred at 65° C. for 2 hr. To the reaction mixture were added 1N aqueous sodium hydroxide solution (70 mL) and toluene (50 mL), and the mixture was cooled to 0° C. The precipitated solid was recrystallized from methanol to give the title compound as colorless crystals (3.3 g, 14%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][S:8][N:7]=1.[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:11]([NH:19][C:20]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][S:8][N:7]=1)=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NCCSCc1ccsn1
Product: O=C(NC(=S)NCCSCc1ccsn1)c1ccccc1

Procedure:
By the procedure of Example 18, 3-[(2-aminoethyl)thiomethyl]isothiazole is reacted with benzoyl isothiocyanate to give N-benzoyl-N'-[2-(3-isothiazolylmethylthio)ethyl]thiourea. Removing the benzoyl group by the procedure of Example 18 gives N-[2-(3-isothiazolylmethylthio)ethyl]thiourea.
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[P:14](=[O:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:28]1([C:2]2[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[C:5]([O:12][CH3:13])=[CH:4][C:3]=2[P:14](=[O:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1cc(P(=O)(c2ccccc2)c2ccccc2)c(I)c(OC)c1OC
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COc1cc(P(=O)(c2ccccc2)c2ccccc2)c(-c2ccccc2)c(OC)c1OC
Yield: 84.8 %

Procedure:
To a 2 liter Schlenk flask was added (2-iodo-3,4,5-trimethoxyphenyl) diphenylphosphine oxide 21 (30 g, 61 mmol), phenylboronic acid (11.1 g, 91 mmol), and degassed THF (800 ml). A solution of degassed saturated K2CO3 (400 ml) was added afterwards. The whole mixture was degassed with nitrogen for an additional 10 min. Then, Pd(PPh3)4 (1.22 mmol, 1.4 g) was added in the solution through one portion. The mixture was stirred at reflux under nitrogen for 24 hrs. In situ 31PNMR showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove THF and 400 ml of CH2Cl2 was then added. The CH2Cl2 layer was washed with water (200 ml) and brine (200 ml), dried over Na2SO4, and evaporated. The solid residue was recrystallized from EtOAc (100 ml) to give off-white product 22 (23 g). The mother liquid was passed though a silica gel column to give another 4 g of product 22. The total yield was 98%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[F:22][C:23]1[CH:24]=[C:25]([C:32]#[N:33])[CH:26]=[C:27]2[C:31]=1[NH:30][CH:29]=[CH:28]2>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:30]3[C:31]4[C:27](=[CH:26][C:25]([C:32]#[N:33])=[CH:24][C:23]=4[F:22])[CH:28]=[CH:29]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: N#Cc1cc(F)c2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(C#N)cc(F)c43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and 7-fluoro-1H-indole-5-carbonitrile (0.085 g, 44%),
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:36]=[CH:35][C:26]2[NH:27][C:28](=[O:34])[CH2:29][CH2:30][C:31]([CH3:33])([CH3:32])[C:25]=2[CH:24]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)([O-])[O-]>C(O)(C)C>[Cl:21][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:22][C:23]2[CH:36]=[CH:35][C:26]3[NH:27][C:28](=[O:34])[CH2:29][CH2:30][C:31]([CH3:33])([CH3:32])[C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: CN([C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl)S(C)(=O)=O
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: CN([C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl)S(C)(=O)=O
Temperature: 120 °C

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-N-methyl-methanesulfonamide (95 mg, 0.27 mmol) in Isopropyl alcohol (4 mL) was added to 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (56 mg, 0.27 mmol) and 10-Camphorsulfonic acid (64 mg, 0.28 mmol) and was heated in a Microwave vial for 90 min at 120° C. Upon cooling, the mixture was treated with MP-Carbonate (2.69 mmol/g loading; 0.29 g, 0.78 mmol) for 1 h, was filtered and was concentrated in vacuo. The material was taken up in DCM and was chromatographed (ISCO, 12 g silica gel, 50% EtOAc/Hex-non-retained) to afford the N-{(1R,2R)-2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-N-methyl-methanesulfonamide as off white solids (145 mg, 100%). mp=140-145° C.; LCMS: 521 (M+H); 1H-NMR, CDCl3: 7.92 (s, 1H), 7.68 (d, 1H, J=8.5 Hz), 7.46 (s, 1H), 7.39 (s, 1H), 7.11 (s, 1H), 6.89 (d, 1H, J=8.5 Hz), 5.69 (d, 1H, 7.8 Hz), 4.07 (m, 1H), 3.77 (m, 1H), 2.85 (s, 3H), 2.75 (s, 3H), 2.41 (t, 2H, J=7.0 Hz), 2.13 (m, 2H, J=7.0 Hz), 1.90 (m, 4H), 1.44 (s, 6H), 1.37 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[C:12]([CH3:13])=[N:11][NH:10][C:9]=2[OH:14])[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:22]([CH3:34])[C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[CH3:33])=[O:24]>CN(C=O)C>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[C:12]([CH3:13])=[N:11][NH:10][C:9]=2[O:14][CH:22]([CH3:34])[C:23]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=2[CH3:33])=[O:24])[N:3]=1
Reactant: Cc1nc(C)n(-c2c(C)n[nH]c2O)n1
Reactant: COc1ccc(C(=O)C(C)Br)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)C(C)Oc2[nH]nc(C)c2-n2nc(C)nc2C)c(C)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 4-(3,5-dimethyl-[1,2,4]triazol-1-yl)-5-methyl-2H-pyrazol-3-ol (1 g, 5.18 mmol) (Intermediate A) in DMF (25 ml) was added Cs2CO3 (1.771 g, 5.43 mmol). The mixture was left to stir at 50° C. for 30 minutes and then treated with of 2-bromo-1-(4-methoxy-2-methyl-phenyl)-propan-1-one (Intermediate B) (1.397 g, 5.43 mmol) in DMF (10 ml). The mixture was stirred at 50° C. for 1 hour and concentrated in vacuo. The residue was dissolved in water (300 ml) and extracted with EtOAc (3×150 ml). The combined organic extracts were washed with NaHCO3, water, dried (MgSO4) and concentrated in vacuo to yield a pale yellow solid. Purification of the solid by chromatography on silica eluting with 20-100% EtOAc in iso-hexane afforded the title compound as a white solid; LC-MS Rt 1.03 mins; MS m/z 370.3 [M+H]+; Method 2minLC—30_v002.