Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](O)[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:25]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Cl:25])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(O)c2ccccc2c1-c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Cl)c2ccccc2c1-c1ccccc1
Reaction time: 1 h

Procedure:
A mixture of 1-hydroxy-4-phenyl-isoquinoline-3-carboxylic acid ethyl ester (1.17 g, 4 mmol; can be obtained according to A. Marsili et al., Ann. Chim. (Rome), 1962, 52, 112-120), and concentrated POCl3 (10 ml) was refluxed with stirring for 1 h. Then the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (50 ml), concentrated aqueous NaHCO3 solution (40 ml) was added and the mixture was stirred vigorously for 1 h. Subsequently, the organic phase was separated, dried over MgSO4 and concentrated in vacuo to give the title compound as a yellowish solid (1.20 g); MS-(+)-ion: M+1=312.0.
Reaction SMILES: N[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[Br:13].N(OC(C)(C)C)=O.B(F)(F)F.CCOCC.[Cu][C:31]#[N:32].[C-]#N.[Na+]>C(Cl)Cl.C(OCC)C.O.CCOC(C)=O>[Br:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[C:31]#[N:32])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1ccc(N)c(Br)c1
Reactant: N#C[Cu]
Agent: CC(C)(C)ON=O
Agent: FB(F)F
Agent: [C-]#N
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C(=O)O)cc1Br
Temperature: 0 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
A solution of ethyl 4-amino-3-bromobenzoate (23.5 g, 96.3 mmol) in methylene chloride at −10° C. is treated dropwise with tert-butyl nitrite (14.0 mL, 118.4 mmol), followed by boron trifluoride diethyl etherate (18.4 mL, 146.5 mmol). The reaction mixture is allowed to come to room temperature, stirred for 4 h, diluted with ethyl ether and filtered. The filtercake is dried, dispersed in toluene, cooled to 0° C., treated with a solution of copper (I) cyanide (11.5 g, 129.2 mmol) and sodium cyanide (15.8 g, 323.1 mmol) in water, stirred at 0° C. for 30 min., warmed to 60° C., stirred for 1 h, cooled to room temperature and diluted with EtOAc and water. The organic phase is separated, dried over MgSO4 and concentrated in vacuo. The resultant residue is crystallized from ethyl ether/hexanes to give the ethyl ester of the title compound as an off-white solid, 18.6 g (76% yield). A solution of this ester (8.5 g, 33.6 mmol) in THF is treated with a solution of NaOH (30 mL, 2.5 N) and ethanol, stirred for 20 h, acidified with 2N HCl and extracted with ethyl ether. The ether extracts are combined, dried over MgSO4 and concentrated in vacuo. The resultant residue is crystallized from ethyl ether/hexanes to afford the title compound as a beige solid, 6.81 g (90% yield), identified by HNMR and mass spectral analyses. MS m/e 223 (M−H)+; 1H NMR (400 MHz, DMSO-d6) δ 8.05 (dd, J=9.76, 1.37 Hz 1H), 8.09 (d, J=8.08 Hz, 1H), 8.29 (d, J=1.37 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](OC)=[O:9])=[N:6][C:5]([Cl:12])=[C:4]([Cl:13])[N:3]=1.NC1C(C(OC)=O)=NC=CN=1.C1N=C2C(NC(NC2=NC=1)=O)=O>>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[N:6][C:5]([Cl:12])=[C:4]([Cl:13])[N:3]=1
Reactant: COC(=O)c1nc(Cl)c(Cl)nc1N
Agent: COC(=O)c1nccnc1N
Agent: O=c1[nH]c(=O)c2nccnc2[nH]1
Product: Nc1nc(Cl)c(Cl)nc1C=O

Procedure:
The 2-amino-5,6-dichloro-3-(methoxycarbonyl)pyrazine (also named methyl 3-amino-5,6-dichloropyrazinecarboxylate) may be prepared by a method described in J. Med. Chem. 10, 66 (1967), from 2-amino-3-carbomethoxypyrazine, reported in J. Am. Chem. Soc. 67, 1711 (1945), which in turn is prepared from lumazine whose preparation from readily available materials is reported in J. Am. Chem. Soc. 67, 802 (1945).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)=[N:9][C:10]([NH:13][C:14]2[CH:15]=[C:16]([NH2:29])[C:17]([C:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH:27]=3)=[CH:18][C:19]=2[O:20][CH3:21])=[N:11][CH:12]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:6][C:7]1[C:8]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH:27]=3)=[C:16]([NH:29][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3c[nH]c4ccccc34)n2)c(OC)cc1C1=CCN(C)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 32.7 %

Procedure:
Acryloyl chloride (0.217 mL, 1M in THF, 0.22 mmol) was added dropwise to a slurry of N′-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)benzene-1,3-diamine (Intermediate 7, 100 mg, 0.22 mmol) and DIPEA (0.057 mL, 0.33 mmol) in THF (3 mL) at −5° C. over a period of 1 minute under N2. The resulting mixture was stirred at 0° C. for 15 minutes and then concentrated in vacuo. The residue was dissolved in CH2Cl2 (5 mL) plus a few drops of CH3OH, and washed with sat. NaHCO3 (2 mL). The organic solution was then dried (MgSO4) and loaded onto silica in vacuo. Purification by FCC, eluting with 5-25% CH3OH in CH2Cl2 and concentration of appropriate fractions in vacuo provided a residue that was washed with CH3OH (0.3 mL) and dried in air to give the title compound (37 mg, 31%) as a beige crystalline solid. 1H NMR: 2.28 (3H, s), 2.38 (2H, m), 2.55 (2H, m), 2.98 (2H, d), 3.85 (3H, s), 5.6-5.72 (2H, m), 6.15 (1H, m), 6.41 (1H, m), 6.88 (1H, s), 7.10 (1H, t), 7.18 (1H, t), 7.47 (1H, d), 7.98 (1H, s), 8.33 (1H, s), 8.36 (1H, d), 8.42 (1H, s), 8.49 (1H, s), 9.29 (1H, s), 11.86 (1H, s); m/z: ES+ MH+ 515.
Reaction SMILES: Cl[C:2]1[C:10]2[C:6](=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:8]([CH2:11][CH2:12][CH3:13])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.Cl.[C:23]1([Mg]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]2[N:8]([CH2:11][CH2:12][CH3:13])[N:9]=[C:10]3[C:6]=2[CH:5]=[CH:4][CH:3]=[C:2]3[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:15][CH:16]=1
Reactant: CCCn1nc2c(Cl)cccc2c1-c1ccc(OC)cc1
Reactant: Br[Mg]c1ccccc1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCCn1nc2c(-c3ccccc3)cccc2c1-c1ccc(OC)cc1
Temperature: 80 °C
Yield: 78.8 %

Procedure:
To a stirred solution of 7-Chloro-3-(4-methoxyphenyl)-2-propyl-2H-indazole (0.200 g, 0.66 mmol) in anhydrous dioxane (6 mL) was added tris(dibenzylideneacetone)-dipalladium(0) (0.0128 g, 0.013 mmol) and 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene.HCl (0.011 g, 0.07 mmol). Phenylmagnesium bromide (0.4 mL, 1.20 mmol, 3M in diethyl ether) was added and the reaction heated to 80° C. for 3 hours. After this time an additional equivalent of reagents was added and the reaction heated for an additional 18 hours. The reaction mixture was treated with 1N aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer washed with water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the organic phase was filtered and the filtrate evaporated in vacuo to yield crude title compound. The oil was purified by silica gel column chromatography eluting with hexane/ethyl acetate (5/1) to provide the title compound as a white solid (0.178 g, 0.52 mmol, 78%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=1[CH2:19][CH2:20][C:21]#[N:22]>>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=1[CH2:19][C:20]1[C:21]([NH2:22])=[N:1][C:2]2[C:3]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: COc1cccc(F)c1CCC#N
Reactant: Nc1ccccc1C=O
Product: COc1cccc(F)c1Cc1cc2ccccc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-aminobenzaldehyde and 3-(2-fluoro-6-methoxyphenyl)propionitrile.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([NH:7][C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([I:17])=[CH:10][N:9]=1)([CH3:6])[CH3:5].O.O.Cl[Sn]Cl>C(O)C>[I:17][C:11]1[CH:10]=[N:9][C:8]2[NH:7][C:4]([CH3:6])([CH3:5])[C:3](=[O:2])[NH:14][C:13]=2[CH:12]=1
Reactant: COC(=O)C(C)(C)Nc1ncc(I)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CC1(C)Nc2ncc(I)cc2NC1=O
Yield: 46 %

Procedure:
2-(5-Iodo-3-nitro-pyridin-2-ylamino)-2-methyl-propionic acid methyl ester (618 mg) was dissolved in ethanol. SnCl2.2H2O (5 eq) was added and the reaction mixture was heated to 80° C. for three (3) hours. The resulting precipitate was filtered and washed with ethanol to give the title compound as an off-white solid (46% yield). M.p.>300° C., LCMS: m/z=304.30 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 1.29 (s, 6H), 7.11 (bs, 1H), 7.16 (d, J=1.8 Hz, 1H), 7.80 (d, J=2.0 Hz, 1H), 10.38 (bs, 1H).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=2[OH:11])[CH2:3][CH2:2]1.CC(C)([O-])C.[Na+].[OH:18][C:19]1[CH:24]=[C:23]([Cl:25])[N:22]=[N:21][C:20]=1Cl.Cl>C1(C)C=CC=CC=1.O.C(O)(C)(C)C>[Cl:25][C:23]1[N:22]=[N:21][C:20]([O:11][C:5]2[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:19]([OH:18])[CH:24]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
A mixture of 114.76 g (purity: 95.9%; 743 mmol) of 2-cyclopropyl-6-methylphenol and 70.0 g of t-butanol was charged into an autoclave, and 72.8 g (purity: 98.0%; 743 mmol) of sodium t-butoxide was added to the mixture over one hour, and then stirred at 70° C. for 30 minutes. The resultant solution was cooled to 40° C., and then 25.0 g (purity: 98%; 148.6 mmol) of 4-hydroxy-3,6-dichloropyridazine was added to the solution. Then, the resultant mixture was heated from 40° C. to 140° C. to effect a reaction for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 750 g of pure water and 574 g of toluene were added to the cooled mixture and stirred for 30 minutes. Then, 41.7 g (400 mmol) of a 35% aqueous hydrochloric acid solution was added dropwise to the mixture, and an organic phase containing 2-cyclopropyl-6-methylphenol added in an excess amount was separated. 287 g of toluene was added to the resultant aqueous phase and stirred at room temperature for 30 minutes, and then an organic phase was separated. Then, the resultant aqueous phase containing a sodium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was added dropwise to 20.5 g (196 mmol) of a 35% aqueous hydrochloric acid solution at 0° C. to deposit solids, followed by filtration. The resultant solids were washed with pure water and dried under a reduced pressure, and dissolved in an organic solvent and quantitatively determined by an HPLC internal standard analysis method, which showed that 41.2 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (purity: 85.4%; yield: 87.0%) and 29 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 1.4%) were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([N+:15]([O-])=O)=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2s1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2cc(N)ccc2s1
Reaction time: 96 h

Procedure:
A suspension of 5-nitro-benzo[b]thiophene-2-carboxylic acid ethyl ester (10.52 g, 41.89 mmol) and 10% Pd/C (1.1 g) in 450 mL of EtOH was hydrogenated under 1 atm of H2 for 4 d at rt. The reaction mixture was filtered and the filtrate was concentrated and dried to give 5-amino-benzo[b]thiophene-2-carboxylic acid ethyl ester as a green solid. A parallel reaction was preformed on 10.61 g of 5-nitro-benzo[b]thiophene-2-carboxylic acid ethyl ester in the same manner. A total of 18.37 g of 5-amino-benzo[b]thiophene-2-carboxylic acid ethyl ester was obtained. MS (EI): cal'd 222.0 (MH+), exp 222.2 (MH+). Procedure for Acylation
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][N:3]=1.S(C)C.C1COCC1>CO>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][NH:8][C:9]=2[CH:10]=1
Reactant: Clc1cc2[nH]ccc2cn1
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: Clc1cc2c(cn1)CCN2
Temperature: 25 °C
Yield: 41.1 %

Procedure:
Under nitrogen, 6-chloro-5-aza indole (500 mg, 3.29 mmol) was dissolved in 2.0 M BH3.SMe2 in THF (6.6 mL, 13.16 mmol) and heated gently to 68° C. for 2 h. After cooling to ambient temperature, MeOH (6.0 mL) was added slowly over 20 min. Once bubbling had stopped, the reaction was heated to 68° C. for 30 min, then cooled to ambient temperature and concentrated in vacuo. Chromatography on silica gel (gradient elution, 0-60% EtOAc/petrol), gave the title compound (209 mg, 41%) as colourless oil. 1H NMR (CDCl3): 7.86 (1H, s), 6.43 (1H, s), 4.33 (1H, s), 3.80-3.65 (2H, m), 3.05 (2H, t).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[O:9])[C:5](=[O:19])[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH2:20][CH2:21][CH3:22])[N:3]=1.O.O.Cl[Sn]Cl.[OH-].[Na+]>C(O)C>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([C:8](=[O:9])[CH2:7][N:6]2[C:5](=[O:19])[C:4]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([CH2:20][CH2:21][CH3:22])[N:3]=[C:2]2[CH3:1])=[CH:15][CH:14]=1
Reactant: CCCC1(c2ccccc2)N=C(C)N(CC(=O)c2ccc([N+](=O)[O-])cc2)C1=O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCC1(c2ccccc2)N=C(C)N(CC(=O)c2ccc(N)cc2)C1=O
Temperature: 80 °C
Yield: 97.1 %

Procedure:
A mixture of (+/−)-2-methyl-3-[2-(4-nitro-phenyl)-2-oxo-ethyl]-5-phenyl-5-propyl-3,5-dihydro-imidazol-4-one (528 mg, 1.4 mmol) and SnCl2.2H2O (1.92 g, 8.4 mmol) in 15 mL ethanol is heated to 80° C. for 2 hours. The reaction mixture is poured on to 1M sodium hydroxide solution and extracted with ethyl acetate. The combined organic phases are tried and evaporated to yield (+/−)-3-[2-(4-amino-phenyl)-2-oxo-ethyl]-2-methyl-5-phenyl-5-propyl-3,5-dihydro-imidazol-4-one (475 mg, 97%). LCIMS at 254 nm; [M+H] 350; Rt 2.506 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[OH-].[Na+].[CH2:19](O)[CH3:20]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:19][CH3:20])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)Cc1cccc(Br)c1
Reaction time: 8 h
Yield: 93 %

Procedure:
3-Bromophenylacetic acid, 35i-a, (50 g, 0.23 mol) was dissolved in ethanol (250 mL) and sulfuric acid was added drop-wise. The mixture was heated to reflux and stirred overnight. The solution was adjusted to about a pH of 7-8 with sodium hydroxide solution and concentrated in vacuo. The water phase was extracted with ethyl acetate (3×150 mL) and the combined organics was washed with brine (50 mL) and dried, concentrated to give the compound, 35i-b, (52.6 g, 93%) as colorless oil. 1H NMR (300 MHz, CDCl3) δ 1.24-1.29 (m, 3H), 3.58 (s, 2H), 4.11-4.19 (m, 2H), 7.18-7.25 (m, 2H), 7.38-7.44 (m, 2H). LC-MS (M+H)+ 243, 245.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]O)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].[Br-].[Li+].P(Br)(Br)[Br:23]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:23])=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: BrP(Br)Br
Reactant: COC(=O)c1ccc(CO)cc1-c1ccccc1C
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CBr)cc1-c1ccccc1C
Temperature: 25 °C
Yield: 96.5 %

Procedure:
To a stirred solution of 4-hydroxymethyl-2-(2-methylphenyl)benzoic acid methyl ester prepared in Example 331A (10.85 g, 42.2 mmol) in dry DMF (40 mL) at 0° C. was added successively lithium bromide (4.00 g, 46.6 mmol, 1.1 eq) and phosphorus tribromide (4.18 mL, 44.5 mmol, 1.05 eq) at a rate such that the temperature did not exceed 5° C. On completion of the addition the mixture was warmed to ambient temperature, and quenched by the addition of ice. The resultant solution was partitioned between water and ether; the ethereal solution was dried (Na2SO4), filtered and the solvent removed under reduced pressure to afford the title compound (13 g, 96%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10](=O)[C:11]([O:13][CH3:14])=[O:12].O.[NH2:18][NH2:19]>CC(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[NH:19][N:18]=1
Reactant: NN
Reactant: COC(=O)C(=O)CC(=O)c1ccccc1Br
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(-c2ccccc2Br)n[nH]1
Temperature: 130 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a solution of methyl 4-(2-bromophenyl)-2,4-dioxobutanoate (540 mg, 0.0019 mol) in AcOH (4 mL) was added hydrazine monohydrate (67 mg, 0.00208 mol). The reaction mixture was allowed to stir at 130° C. overnight and then concentrated. The residue was dissolved in EtOAc, washed with aq. NaHCO3 and brine, dried over Na2SO4, filtered and concentrated to give methyl 3-(2-bromophenyl)-1H-pyrazole-5-carboxylate (0.516 g, 97%) as a white solid. LCMS: (FA) ES+ 283.2, ES-281.2.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8](C)(C)[CH2:7][CH2:6]2.B(Br)(Br)Br.C(Cl)(Cl)Cl>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(C)(C)C2=O
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C1CCCc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
3.69 g of 6-methoxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one was dissolved in 70 ml of anhydrous methylene chloride. The obtained solution was cooled in a dry ice-acetone bath. Thereafter, 36 ml of boron tribromide (a 1.0 M methylene chloride solution) was added thereto, and the obtained mixture was stirred at room temperature overnight. Thereafter, the reaction solution was again cooled in a dry ice-acetone bath. 36 ml of boron tribromide (a 1.0 M methylene chloride solution) was added thereto, and the obtained mixture was stirred at room temperature overnight. Thereafter, the reaction solution was poured into ice, and chloroform was then added thereto. An insoluble precipitate was removed by filtration. The organic layer was separated and then dried over anhydrous sodium sulfate. The obtained solution was passed through a glass filter filled with silica gel, and the solvent was removed under a reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 1.52 g of the subject compound.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[C:22]1[C:23]2[C@H:30]([CH3:31])[CH2:29][CH2:28][C:24]=2[N:25]=[CH:26][N:27]=1.C(OCC)(=O)C>CCCCO>[CH3:31][C@H:30]1[C:23]2[C:22]([N:11]3[CH2:12][CH2:13][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:10]3)=[N:27][CH:26]=[N:25][C:24]=2[CH2:28][CH2:29]1
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Reaction time: 17 h
Yield: 74.1 %

Procedure:
Neat POCl3 (463.9 mL, 5067 mmol) was added slowly by addition funnel to a 0° C. solution of (R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (152.2 g, 1013 mmol) in DCE (1.2 L). After the addition was complete, the reaction mixture was warmed to room temperature, then heated to reflux and stirred for 70 minutes. The reaction was complete as determined by HPLC. The reaction mixture was cooled to room temperature, and the excess POCl3 was quenched in 4 portions as follows: Reaction mixture transferred to separatory funnel and dripped into a beaker containing ice and saturated NaHCO3 solution cooled in an ice bath. Once the addition of each portion of the reaction mixture was completed, the quenched mixture was stirred 30 minutes to ensure complete destruction of POCl3 prior to transfer to separatory funnel. The mixture was transferred to the separatory funnel and extracted twice with DCM. The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel as follows: silica gel (1 kg) was slurried in 9:1 hexane:ethyl acetate onto a 3 L fritted funnel, silica settled under vacuum, topped with sand. The crude was loaded with a DCM/hexane mixture, and the compound was eluted using 1 L sidearm flasks under vacuum. High Rf byproducts eluted first, then (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (104.4 g, 61.09% yield) as an oil. Triethylamine (93.0 mL, 534 mmol) and tert-butyl piperazine-1-carboxylate (34.8 g, 187 mmol) was added to a solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (30.0 g, 178 mmol) in n-BuOH (250 mL). The reaction mixture was heated to reflux under nitrogen and stirred overnight (17 hours), after which it was concentrated on a rotavap. The resulting oil was dissolved in DCM, washed with H2O, dried (Na2SO4), filtered, and was concentrated. The resulting oil was purified on silica gel eluting first with 2:1 hexanes:ethyl acetate until product eluting cleanly, then gradient 1:1 to 1:5 DCM:ethyl acetate to give (R)-tertbutyl 4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (42.0 g, 74.1% yield) as a powder. LC/MS (APCI+) m/z 319.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9]CC(C)(C)N=2)=[C:4]([S:15][CH3:16])[C:3]=1[O:17][CH3:18].Cl.[OH2:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:9])=[O:20])=[C:4]([S:15][CH3:16])[C:3]=1[O:17][CH3:18]
Reactant: COc1c(Cl)ccc(C2=NC(C)(C)CO2)c1SC
Reactant: O
Agent: Cl
Product: COc1c(Cl)ccc(C(=O)O)c1SC

Procedure:
A mixture of 2-[4-chloro-3-methoxy-2-(methylsulphenyl)-phenyl]-4,4-dimethyloxazoline (9.0 g) and hydrochloric acid (5M) was stirred and heated at reflux for 5 hours. After cooling the mixture was diluted with water and extracted with dichloromethane. It was dried (MgSO4), filtered and the filtrate was evaporated to dryness to give 4-chloro-3-methoxy-2-(methylsulphenyl) benzoic acid as a white solid, m.p. 98°-99° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2SC=N[C:8]=2[C:7]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:5])C>OS(O)(=O)=O>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:7]2[C:8]3[CH:9]=[CH:10][N:11]([CH3:6])[C:9]=3[C:10](=[O:13])[N:11]([CH3:12])[C:6]=2[C:4]([OH:3])=[O:5])=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)c2ncsc2c(=O)n1C
Agent: O=S(=O)(O)O
Product: Cn1c(C(=O)O)c(-c2ccc(F)cc2)c2ccn(C)c2c1=O

Procedure:
7-(4-Fluorophenyl)-4,5-dihydro-5-methyl-4-oxo-6-thiazolo[5,4-c]pyridinecarboxylic acid ethyl ester obtained in Step 3 was subjected to hydrolysis in 70% H2SO4 at temperatures ranging from 120° to 130° C. to give the above-titled compound as colorless crystals.