Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].[H-].[Na+]>CN(C)C=O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:17]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(OCCCCCn2ccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(OCCCCCn2ccnc2)cc1

Procedure:
To a solution of 2.46 g p-[5-(1-imidazolyl)pentyloxy]phenol and 1.2 ml ethyl bromoacetate in 25 ml anhydrous N,N-dimethylformamide, was added under ice cooling and with stirring 440 mg of 60% sodium hydride in oil, and stirring was continued at room temperature for ten minutes. The solvent was distilled off, the residue was dissolved in chloroform, and the solution was washed with water and dried over anhydrous sodium sulfate. After distilling off the chloroform, the residue was purified by silical gel column chromatography, affording 2.7 g of ethyl p-[5-(1-imidazol-yl)pentyloxy]phenoxyacetate as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[N:26]1[CH2:29][CH:28]([C:30](O)=[O:31])[CH2:27]1.[CH3:33][N:34](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:35].F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CNC>CN(C=O)C.C1COCC1>[CH3:33][N:34]([CH3:35])[C:30]([CH:28]1[CH2:27][N:26]([C:3]2[CH:4]=[CH:5][C:6]([C:8]3[CH2:12][C:11]([C:17]4[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=4)([C:13]([F:16])([F:14])[F:15])[O:10][N:9]=3)=[CH:7][C:2]=2[Cl:1])[CH2:29]1)=[O:31]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Cl)C1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Cl)C1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-{2-Chloro-4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-azetidine-3-carboxylic acid (Preparation 14, 0.1 g, 0.189 mmol) in dry DMF (1 mL) was added HATU (0.108 g, 0.284 mmol) HOBt (0.028 g, 0.207 mmol), DIPEA (0.048 g, 0.378 mmol) and saturated solution of dimethyl amine in THF (2 mL) at 0° C. and stirred at 0° C. for 2 hours and at room temperature for 18 hours. After complete consumption of starting material, reaction mixture was quenched with water (15 mL), extracted with EtOAc (10 mL). Organic layer was washed with saturated solution of lithium chloride (2×20 mL), water (2×20 mL), dried over sodium sulphate and evaporated in vacuo to get crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Further purification by preparative TLC using 5% MeOH in DCM afforded white solid (0.020 g, 19%). 1H-NMR (400 MHz, CDCl3) δ: 2.95 (s, 3H), 2.97 (s, 3H), 3.59 (d, 1H, J=17.08 Hz), 3.67-3.71 (m, 1H), 4.00 (d, 1H, J=17.04 Hz), 4.29-4.38 (m, 4H), 6.48 (d, 1H, J=8.6 Hz), 7.40 (dd, 1H, J1=8.48 Hz, J2=2 Hz), 7.45 (d, 1H, J=1.92 Hz), 7.62 (s, 2H); LC-MS (m/z): [M+H] 554.10.
Reaction SMILES: [CH2:1]([O:6][C:7](Cl)=[O:8])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:25]3[C:24]([NH2:26])=[N:23][CH:22]=[N:21][C:20]=3[N:19]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:18]=2)=[CH:13][C:12]=1[O:32][CH3:33]>N1C=CC=CC=1.ClCCl>[NH2:26][C:24]1[C:25]2[C:17]([C:14]3[CH:15]=[CH:16][C:11]([NH:10][C:7](=[O:8])[O:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])=[C:12]([O:32][CH3:33])[CH:13]=3)=[CH:18][N:19]([CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)[C:20]=2[N:21]=[CH:22][N:23]=1
Reactant: CC(C)(C)COC(=O)Cl
Reactant: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1NC(=O)OCC(C)(C)C
Reaction time: 0.17 h

Procedure:
Neopentylchloroformate (28 uL, 0.186 mmol) was added dropwise to a stirring solution of 5-(4-amino-3-methoxyphenyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 0.155 mmol) in pyridine (1 mL) and dichloromethane (1 mL) under nitrogen at 0° C. After 10 minutes, the ice water bath was removed and the resulting mixture was stirred for 4 hours. The solvent was evaporated and the residue was taken into ethyl acetate. The organic layer was washed, dried and evaporated. The solid was purified by preparative TLC using dichloromethane/methanol (95:5) as the mobile phase to give neopentyl N-[4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate. 1H NMR (CDCl3) δ 1.00 (s 9H), 1.78 (m, 2H), 1.90 (m, 4H), 2.26 (m, 2H), 3.91 (s, 2H), 3.94 (s, 3H), 5.22 (m, 3H), 6.22 (s, 1H), 7.01 (s, 1H), 7.08 (d, J=8 Hz, 1H), 7.25 (s, 1H), 8.17 (br. d, 1H), 8.32 (s, 1H); LC/MS (MH+=438).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:39](O)[CH3:40].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[CH2:39]([O:23][C:22]([C:21]1[N:20]=[C:19]([C:25]([F:27])([F:28])[F:26])[N:16]2[CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:29][C:30]3[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=3[F:38])[CH2:14][C:15]=12)=[O:24])[CH3:40]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Yield: 59.6 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.16 g, 0.29 mmol) was dissolved in 10 mL of dichloromethane under stirring, and ethanol (0.05 mL, 0.87 mmol), triethylamine (0.202 mL, 1.45 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.148 g, 0.58 mmol) were then added to the solution. The reaction mixture was reacted at room temperature for 5 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-7-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid ethyl ester 23a (0.1 g) as a colourness oil.
Reaction SMILES: [Na].[OH:2][CH:3]=[C:4]1[CH2:9][CH2:8][O:7][C:5]1=O.S(O)(O)(=O)=O.[C:15]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)(=[NH:17])[NH2:16]>C(O)C>[CH2:24]([N:21]1[CH2:20][CH2:19][N:18]([C:15]2[N:17]=[C:3]([OH:2])[C:4]([CH2:9][CH2:8][OH:7])=[CH:5][N:16]=2)[CH2:23][CH2:22]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: N=C(N)N1CCN(Cc2ccccc2)CC1
Reactant: O=C1OCCC1=CO
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CCO
Product: OCCc1cnc(N2CCN(Cc3ccccc3)CC2)nc1O
Yield: 28.9 %

Procedure:
10.0 g (73.5 mmoles) of 2-hydroxymethylenebutyrolactone sodium salt [synthesized by the method described in J. O. Fissekis et al., J. Org., Chem. 29, 2670 (1964)] and 19.6 g (73.3 mmoles) of 1-amidino-4-benzylpiperazine sulfate were added to 360 ml of ethanol, and the solution was refluxed for 5 hours. Ethanol was evaporated, and the residue was mixed with water and extracted with chloroform. The chloroform layer was dried, concentrated, and purified by silica gel column chromatography to give 6.66 g (yield 29%) of 2-(4-benzylpiperazino)-4-hydroxy-5-(2-hydroxyethyl)pyrimidine as crystals.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([N:7]1[CH2:11][C:10]2[CH2:12][N:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[CH2:14][C:9]=2[CH2:8]1)=[O:6].Cl.[S:31]1[CH:35]=[C:34]([CH2:36][NH2:37])[N:33]=[CH:32]1>>[S:31]1[CH:35]=[C:34]([CH2:36][NH:37][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([N:13]3[CH2:14][C:9]4[CH2:8][N:7]([C:5](=[O:6])[C:4]5[CH:24]=[CH:25][CH:26]=[CH:27][C:3]=5[C:2]([F:29])([F:28])[F:1])[CH2:11][C:10]=4[CH2:12]3)=[N:16][CH:17]=2)[N:33]=[CH:32]1
Reactant: O=C(O)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Reactant: NCc1cscn1
Agent: Cl
Product: O=C(NCc1cscn1)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Yield: 16 %

Procedure:
6-[5-(2-Trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]nicotinic acid (140 mg, 0.347 mmol) was reacted with C-thiazol-4-ylmethylamine, hydrochloride analogously to example 3d. Yield: 16%, M+H+: 500.40.
Reaction SMILES: CS([O:5][C:6]1[CH:7]=[C:8]([S:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])(=O)=O.[OH-].[Na+]>>[OH:5][C:6]1[CH:7]=[C:8]([S:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(S(=O)(=O)N2CCc3ccccc32)cc1OS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(S(=O)(=O)N2CCc3ccccc32)cc1O
Yield: 100.5 %

Procedure:
A solution of N-(3-methanesulphonyloxy-4-methoxybenzenesulphonyl)-1,2-dihydroindole (1 g) and saturated aqueous sodium hydroxide solution (2 ml) was heated at 85°-90° C. for 2 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (5 ml) and water (10 ml). The aqueous phase was acidified with 2N HCl and extracted with ethyl acetate (2×10 ml). The combined organic phases were dried over magnesium sulphate and concentrated in vacuo to yield a clear oil. Purification by column chromatography eluting with dichloromethane afforded the desired product as a white solid (0.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.I[CH:18]1[CH2:21][O:20][CH2:19]1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH:18]3[CH2:21][O:20][CH2:19]3)[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Nc2cc(Br)cn(C)c2=O)n[nH]1
Reactant: IC1COC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1cc(Nc2cc(Br)cn(C)c2=O)nn1C1COC1
Temperature: 80 °C
Yield: 49.8 %

Procedure:
A mixture of 5-bromo-1-methyl-3-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2(1H)-one 115a (200 mg, 0.71 mmol), 3-iodooxetane (647 mg, 3.53 mmol), Cs2CO3 (1150 mg, 3.53 mmol), and acetonitrile (5 mL) was heated at 80° C. in a sealed tube overnight. The mixture was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 20:1 dichloromethane/methanol to afford the 312a as a yellow solid (120 mg, 50%). MS-ESI: [M+H]+ 339.1
Reaction SMILES: ClC1C=C(C=CC=1)C(O)=[O:6].[Br:11][C:12]1[CH:20]=[CH:19][N:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][NH:16]2>C(Cl)(Cl)Cl>[Br:11][C:12]1[CH:20]=[CH:19][N+:18]([O-:6])=[C:17]2[NH:16][CH:15]=[CH:14][C:13]=12
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: Brc1ccnc2[nH]ccc12
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccc(Br)c2cc[nH]c21
Reaction time: 0.5 h
Yield: 132 %

Procedure:
m-Chlorobenzoic acid (1.0 g) was added to a chloroform (19 ml) solution containing 4-bromo-7-azaindole (760 mg) under ice cooling, followed by stirring for 30 minutes. Then, chloroform (10 ml) was distilled away under reduced pressure, diisopropylether was added, an insoluble precipitate was collected by filtration, and a white solid of 4-bromo-1H-pyrrolo[2,3-b]pyridine 7-oxide (1.085 g) was thus obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[C:14]1([CH3:27])[CH:19]=[CH:18][C:17]([O:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:16][CH:15]=1>>[C:14]1([CH3:27])[CH:15]=[CH:16][C:17]([O:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][S:4]([C:7]3[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=3)(=[O:6])=[O:5])[CH2:23][CH2:22]2)=[CH:18][CH:19]=1
Reactant: O=S(=O)(CCCl)c1ccc(O)cc1
Reactant: Cc1ccc(OC2CCNCC2)cc1
Product: Cc1ccc(OC2CCN(CCS(=O)(=O)c3ccc(O)cc3)CC2)cc1
Yield: 59 %

Procedure:
The title compound was prepared from 4-(2-chloro-ethanesulfonyl)-phenol and 4-p-tolyloxy-piperidine (prepared according to J. Med. Chem., 1978, 21, 309) in 59% yield as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12])=[O:4].[NH2:17][C:18]1[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=[C:22]([Cl:24])[N:23]=1>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15](=[O:16])[NH:17][C:18]1[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=[C:22]([Cl:24])[N:23]=1)(=[O:12])=[O:13])=[O:4]
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: Cn1cc(Cl)nc(N)c1=O
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(Cl)cn(C)c1=O
Yield: 94.9 %

Procedure:
A mixture of 2.41 g of 2-methoxycarbonylphenylsulfonyl isocyanate, 1.6 g of 3-amino-5-chloro-1-methylpyrazin-2-one and 40 ml of absolute dioxane is refluxed for 3 hours. The reaction mixture is evaporated to dryness and the residue is crystallized by treatment with acetone. 3.8 g of 3-[3-(2-methoxycarbonylphenylsulfonyl)-ureido]-5-chloro-1-methylpyrazin-2-one with a melting point of 213°-214° C. are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14]C(NC3C=C(C(F)(F)F)C=CC=3F)=O)=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[C:29]#[N:30].O.NN>C(O)CC>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:5]=[CH:4][C:3]([C:29]#[N:30])=[C:2]([Cl:1])[N:7]=2)=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)nc1Cl
Agent: NN
Solvent: O
Solvent: CCCO
Product: N#Cc1ccc(-c2ccc(N)cc2)nc1Cl
Temperature: 80 °C
Yield: 132.5 %

Procedure:
0.46 mmol (200 mg) of 1-[4-(6-chloro-5-cyanopyridin-2-yl)phenyl]-3-(2-fluoro-5-trifluoromethylphenyl)urea is suspended in 3.2 ml of 1-propanol. 0.13 ml (0.14 g, 2.76 mmol, 6 eq.) of hydrazine hydrate is added. The suspension is heated at 80° C. for 10 h. The mixture is filtered and the solid is dried so as to obtain 140 mg of the expected product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:10])=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[Br:8].CN(C)C1C=CC=CC=1.[Br:20][CH2:21][C:22](Br)=[O:23]>C(Cl)Cl>[Br:10][C:3]1[C:2]([NH:1][C:22](=[O:23])[CH2:21][Br:20])=[C:7]([Br:8])[CH:6]=[C:5]([CH3:9])[N:4]=1
Reactant: Cc1cc(Br)c(N)c(Br)n1
Reactant: O=C(Br)CBr
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: Cc1cc(Br)c(NC(=O)CBr)c(Br)n1
Reaction time: 0.08 h
Yield: 85 %

Procedure:
3-Amino-2,4-dibromo-6-methylpyridine (1.16 g, 4.38 mmol) was dissolved in methylene chloride (10 mL). N,N-dimethylaniline (0.77 g, 6.35 mmol) was added to the solution and then a solution of bromoacetyl bromide (1.03 g, 5.12 mmol) in dichloromethane (2 mL) was added dropwise thereto over 5 minutes with stirring and cooling with ice. After completion of addition, the temperature of the mixture was elevated to room temperature and stirred for 12 hours. The resultant mixture was washed sequentially with water, an aqueous saturated sodium hydrogencarbonate solution, and saturated brine. Subsequently, the mixture was dried over sodium sulfate anhydrate and concentrated under reduced pressure. The residue was crystallized from hexane-acetone, to thereby yield 1.44 g of N-[2,4-dibromo-6-methylpyridin-3-yl]-2-bromoacetamide as colorless crystals (yield 85.3%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][C:8]=1[N+:22]([O-:24])=[O:23])[CH3:2].[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:26]2[CH:30]=[CH:29][N:28]=[CH:27]2)[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][C:8]=1[N+:22]([O-:24])=[O:23])[CH3:2]
Reactant: CCOC(=O)CNc1cc(F)c(OCc2ccccc2)cc1[N+](=O)[O-]
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1cc(-n2ccnc2)c(OCc2ccccc2)cc1[N+](=O)[O-]
Yield: 64.9 %

Procedure:
By using 448 mg of N-(4-benzyloxy-5-fluoro-2-nitrophenyl)glycine ethyl ester, 350 mg of imidazole and 2 ml of DMF, 331 mg (65%) of N-[4-benzyloxy-5-(1H-imidazol-1-yl)-2-nitrophenyl]glycine ethyl ester was obtained.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2.C([Li])CCC.C([O:24][B:25](OC(C)C)[O:26]C(C)C)(C)C.Cl>CCOCC.CCCCCC>[CH:13]1[C:14]2[CH:15]=[C:2]([B:25]([OH:26])[OH:24])[C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: Brc1cc2ccccc2c2ccccc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OB(O)c1cc2ccccc2c2ccccc12
Temperature: -67 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
Under an atmosphere of argon, 9-bromophenanthrene (15 g, 58 mmole) was dissolved into anhydrous ether (150 ml) and the resultant solution was cooled at −35° C. in a dry ice/methanol bath. To the cooled solution, a hexane solution of n-butyllithium (1.50 mole/liter, 43 ml, 65 mmole) was added dropwise and the resultant mixture was stirred at −20° C. for 1 hour. After the reaction mixture was cooled at −67° C., a solution (30 ml) of triisopropoxyborane (37 ml, 0.16 mole, 2.8 eq) in anhydrous ether was added the resultant mixture was stirred at −65° C. for 1 hour and at the room temperature for 2 hours and left standing for one night. To the obtained reaction mixture, a 10% hydrochloric acid (150 ml) was added. After the resultant mixture was stirred at the room temperature for 1 hour, the formed organic layer was separated, washed with a saturated aqueous solution of sodium chloride (50 ml) and dried with anhydrous magnesium sulfate. The solid obtained after removing the solvent by distillation was washed with hexane and a white solid (10 g, 78%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.Cl.[CH3:12][O:13][C:14](=[O:19])[C@H:15]([CH2:17][OH:18])[NH2:16].O.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C1C=CC=CN=1)C.O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:16][CH:15]([CH2:17][OH:18])[C:14]([O:13][CH3:12])=[O:19])=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: COC(=O)[C@@H](N)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(CO)NC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.7 %

Procedure:
To 50 ml of tetrahydrofuran was added 4-fluorobenzoic acid (3.64 g, 26 mmol), L-serine methyl ester hydrochloride (2 g, 13 mmol), 1-hydroxybenzotriazole hydrate (4 g, 26 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (9.9 g, 26 mmol), triethylamine (3.5 ml, 26 mmol) and dimethylaminopyridine (20 mg, 0.16 mmol). The reaction was stirred for 24 hours at room temperature. Solvent was removed under reduced pressure, and the residue dissolved in 150 ml of ethyl acetate. The organic solution was washed in a separatory funnel in the following manner: 3×100 ml 10% aqueous citric acid, 3×100 ml saturated sodium bicarbonate, 3×100 ml water, 1×75 ml saturate sodium chloride solution. The organic layer was concentrated and purified using a Flash40 column (1:2 EtOAc:Hexane, 20 psi) to yield 3 grams of methyl 2-[(4-fluorophenyl)carbonylamino]-3-hydroxypropanoate.
Reaction SMILES: Br[C:2]1[C:6]2[NH:7][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([C:10]#[N:11])[C:5]=2[S:4][C:3]=1[CH3:17].[CH3:18]B1OB(C)OB(C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I.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:10]([C:9]1[C:5]2[S:4][C:3]([CH3:17])=[C:2]([CH3:18])[C:6]=2[NH:7][C:8]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:11]
Reactant: CB1OB(C)OB(C)O1
Reactant: CCOC(=O)c1[nH]c2c(Br)c(C)sc2c1C#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)c1[nH]c2c(C)c(C)sc2c1C#N
Temperature: 150 °C
Reaction time: 2.5 h
Yield: 82 %

Procedure:
To a solution of ethyl 3-bromo-6-cyano-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate (0.2 g) in 1,4-dioxane (4.0 mL) were added 2,4,6-trimethylboroxine (0.64 g), copper(I) iodide (50 mg), tripotassium phosphate (0.27 g) and tetrakis(triphenylphosphine)palladium (0.22 g), and the mixture was stirred at 150° C. for 150 minutes using microwave reactor. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=76/24−55/45) to give the title compound (0.13 g).
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]1[CH3:23])(=[O:16])=[O:15].N1C=CC=CC=1>C(Cl)Cl>[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][N:20]([C:2]([Cl:1])=[O:4])[CH2:19][C@@H:18]1[CH3:23])(=[O:15])=[O:16]
Reactant: C[C@H]1CNCCN1S(C)(=O)=O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H]1CN(C(=O)Cl)CCN1S(C)(=O)=O
Temperature: 25 °C
Yield: 154.7 %

Procedure:
Second step: To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (560 mg, 1.88 mmol) in CH2Cl2 (10 mL) at −78° C., was added a solution of (S)-1-methanesulfonyl-2-methyl-piperazine (838 mg, 4.70 mmol) and pyridine (0.74 mL, 9.4 mmol) in CH2Cl2 (10 mL) over 1 hour. The temperature was raised to RT, and stirring was continued over night. The organic phase was washed with H2O, dried over Na2SO4. Concentration under vacuo and flash chromatography (SiO2, EtOAc/H, 1:1) yielded 0.70 g (62%) of (S)-4-methanesulfonyl-3-methyl-piperazine-1-carbonylchloride as a light yellow solid.
Reaction SMILES: [N+:1]([C:4]([CH3:9])([CH3:8])[CH:5]=[N:6][OH:7])([O-:3])=[O:2].[CH3:10][N:11]([S:15][C:16]([CH3:23])([C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH3:17])[C:12](F)=[O:13].C(N(CC)CC)C>O1CCOCC1>[CH3:10][N:11]([S:15][C:16]([CH3:17])([C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH3:23])[C:12]([O:7][N:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])([CH3:9])[CH3:8])=[O:13]
Reactant: CC(C)C(=O)C(C)(C)SN(C)C(=O)F
Reactant: CC(C)(C=NO)[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)C(=O)C(C)(C)SN(C)C(=O)ON=CC(C)(C)[N+](=O)[O-]
Yield: 7.8 %

Procedure:
Prepared as in Example 1 by reacting 2.78 g (0.021 m) of 2-nitro-2-methylpropionaldoxime, 5.0 g (0.21 m) of N-methyl-N-(2,4-dimethyl-3-oxo-2-pentanesulfenyl)carbamoyl fluoride and 2.13 g (0.021 m) of triethylamine in 50 ml of dioxane. The product was purified by column chromatography to yield 0.55 g of an oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][N:10]([CH3:12])[CH2:9][CH:8]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[CH3:21][NH:22][CH2:23][CH:24]=[CH2:25].O>CN1C(=O)CCC1>[CH2:23]([N:22]([CH3:21])[C:4]1[C:5]2[CH2:11][N:10]([CH3:12])[CH2:9][CH:8]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)[CH:24]=[CH2:25]
Reactant: CN1Cc2c(Cl)nc(Cl)nc2C(c2ccc(F)cc2)C1
Reactant: C=CCNC
Solvent: O
Solvent: CN1CCCC1=O
Product: C=CCN(C)c1nc(Cl)nc2c1CN(C)CC2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
The mixture of 2,4-dichloro-8-(4-fluorophenyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (Preparation V, 408 mg, 1.307 mmol) in NMP (13 mL) was added N-methylprop-2-en-1-amine (465 mg, 6.53 mmol). The resulting reaction mixture was stirred at rt overnight. Water (50 mL) was added to the mixture and stirred for 30 min. The mixture was filtered to get a light tan solid which was dried and purified by flash column chromatography eluting with 30 to 100% EtOAc/Hexane to get N-allyl-2-chloro-8-(4-fluorophenyl)-N,6-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (453 mg, 100% yield). LC-MS (M+H)+=347.1.