Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[Na+].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=1.[Br:15]Br>C(O)(=O)C>[Br:15][C:9]1[C:10]([O:13][CH3:14])=[N:11][CH:12]=[C:7]([Cl:6])[CH:8]=1
Reactant: BrBr
Reactant: COc1ccc(Cl)cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ncc(Cl)cc1Br
Temperature: 80 °C
Reaction time: 64 h

Procedure:
To a stirred suspension of 2.5 g of anhydrous sodium acetate in 10 ml of acetic acid was added 4.3 g of 5-chloro-2-methoxypyridine followed by a solution of 3.1 ml of bromine in 10 ml of acetic acid. The mixture was warmed to 80° C. for 6 hours and then allowed to cool and stirred at 23° C. for 64 hours. It was then partitioned between ether and water and the resulting ether layer was washed with aqueous 1N sodium hydroxide solution and then with aqueous 5% sodium bisulfite solution, dried over potassium carbonate and concentrated at reduced pressure to leave a residual brown solid. This residue was bulb-to-bulb distilled with the material distilling at 140°-150° C. at 20 torr collected to give 3-bromo-5-chloro-2-methoxypyridine as a solid melting at about 45°-47.5° C.
Reaction SMILES: CC(C)(OC([NH:7][CH:8]1[C:15](=[O:16])[N:14]2[CH:9]1[CH2:10][S:11][C:12]([S:20][CH3:21])=[C:13]2[C:17]([OH:19])=[O:18])=O)C.[N+](C)([O-])=O.[ClH:27]>CCOCC>[ClH:27].[NH2:7][CH:8]1[C:15](=[O:16])[N:14]2[CH:9]1[CH2:10][S:11][C:12]([S:20][CH3:21])=[C:13]2[C:17]([OH:19])=[O:18]
Reactant: CSC1=C(C(=O)O)N2C(=O)C(NC(=O)OC(C)(C)C)C2CS1
Agent: Cl
Solvent: C[N+](=O)[O-]
Solvent: CCOCC
Product: CSC1=C(C(=O)O)N2C(=O)C(N)C2CS1
Temperature: 0 °C

Procedure:
1.3 g of (6RS) (7RS) 7-[(1,1-dimethylethyloxy)-carbonylamino]-3-methylthio-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid and 13 ml of nitromethane were stirred together cooled to 0° C., and a current of hydrochloric acid gas was passed through it for 15 minutes. 130 ml of ether were added, and after separating and rinsing with ether, 0.74 g of 7-amino-3-methylthio-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid hydrochloride were obtained.
Reaction SMILES: Br[CH:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]([CH3:16])[CH2:4][CH2:3]1.CS(C)=O.[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>CO>[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][CH:2]2[C:7]3=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]3[CH:5]([CH3:16])[CH2:4][CH2:3]2)=[CH:24][CH:23]=1
Reactant: CC1CCC(Br)c2ncc(C(=O)O)c(=O)n21
Reactant: Nc1ccc(Br)cc1
Solvent: CS(C)=O
Solvent: CO
Product: CC1CCC(Nc2ccc(Br)cc2)c2ncc(C(=O)O)c(=O)n21
Reaction time: 72 h
Yield: 45.2 %

Procedure:
2.9 g. (0.01 mole) of (-)-9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid ([α]D20 =-105°, c=2, methanol) are dissolved in 5 ml. of dimethyl-sulfoxide and 3.8 g. (0.022 mole) of p-bromo-aniline are added. The solution is allowed to stand for 3 days at room temperature in an open vessel. 20 ml. of methanol are then added to the reaction mixture. The precipitated crystals are then filtered and washed with methanol. 1.7 g. (45.2%) of (-)-9-(4-bromo-anilino)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid is obtained. Melting point: 210°-211° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][C:15]([S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19])=[CH:16][CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:29]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:29])=[C:6]2[CH:5]=[N:4]1)=[CH:14][C:15]([S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19])=[CH:16][CH:17]=3)[CH3:2]
Reactant: CCn1nccc1Nc1ccc(S(=O)(=O)C(F)(F)F)cc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: CCn1ncc2c(Cl)c3cc(S(=O)(=O)C(F)(F)F)ccc3nc21

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl)-5-(trifluoromethylsulfonyl)anthranilic acid and POCl3 (30 ml) is heated on a steam bath overnight. The reaction mixture is poured onto ice waterl and then is neutralized with NH4OH. The resulting solid is collected by filtration, washed with water, dissolved in CH2Cl2, dried over MgSO4, filtered and stripped. The residue is purified by column chromatography on silica gel eluting with 10% ethyl acetate/hexane to afford 1.0 g of 1-ethyl-4-chloro-6-(trifluoromethylsulfonyl)-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: [C:1]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=O)[CH:2]([CH3:4])[CH3:3]>O1CCCC1>[CH2:1]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:13]=2)[NH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc2c(C(=O)C(C)C)c[nH]c2c1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(CC(C)C)c[nH]c2c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
To a solution of methyl 3-isobutyrylindole-6-carboxylate (146 mg) in tetrahydrofuran (5 ml) was added 1M solution of brane-tetrahydrofuran complex in tetrahydrofuran (1.8 ml), and the mixture was stirred at 50° C. for 1 hour. The resulting mixture was evaporated in vacuo, and the residue was quenched with aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was washed with brine, and dried over sodium sulfate. After evaporation of solvent, the residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (2:1) to give methyl 3-isobutylindole-6-carboxylate (105 mg) as colorless crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].C([Mg]Cl)(C)C.[CH3:13][C@@:14]1([C:26](OC)=[O:27])[CH2:18][CH2:17][CH2:16][N:15]1C(OC(C)(C)C)=O>C1COCC1>[CH3:13][C@@:14]1([C:26]([NH:7][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[O:27])[CH2:18][CH2:17][CH2:16][NH:15]1
Reactant: COC(=O)[C@]1(C)CCCN1C(=O)OC(C)(C)C
Reactant: Nc1cnccn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: C[C@@]1(C(=O)Nc2cnccn2)CCCN1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of pyrazin-2-amine (1.56 g, 16.44 mmol) in THF (30 ml) was added isopropyl magnesium chloride (7.8 ml, 15.62 mmol) (2.0 M THF solution) dropwise at 0° C. under nitrogen. The resulting suspension was stirred at RT for 30 min. A solution of (S)-1-tert-butyl 2-methyl 2-methylpyrrolidine-1,2-dicarboxylate (1.0 g, 4.11 mmol) solid was added to the reaction mixture. The reaction mixture was stirred at RT for 6 h, quenched with MeOH, and concentrated. The residue was dissolved in EtOAc (120 ml) and washed with 1N HCl to remove the excess pyrazin-2-amine, water, and brine, dried over Na2SO4. The crude product was dissolved in methanol and 4N HCl in dioxane (4 mL) was added. The reaction mixture was stirred at room temperature overnight and the crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[CH:22](Br)([CH3:24])[CH3:23].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([O:17][CH:22]([CH3:24])[CH3:23])[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)Br
Reactant: COc1ccc(-c2cc(=O)n(C)c(=O)[nH]2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(=O)n(C)c(OC(C)C)n2)cc1OC
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6-(3,4-dimethoxyphenyl)-3-methyl-2,4(1H,3H)-pyrimidinedione (3.0 g) in N,N-dimethylformamide (30 ml) was added sodium hydride (60% oil suspension, 0.50 g). The mixture was heated at 60° C. with stirring for 20 minutes and cooled to ambient temperature. To the mixture was added isopropyl bromide (15 ml) with stirring, which was continued at ambient temperature for 5 hours, and at 50° C. for 25 hours. To the reaction mixture was added water, and extracted with ethyl acetate. The organic extract was washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated in diisopropyl ether to give 6-(3,4-dimethoxyphenyl)-2-isopropoxy-3-methyl-4(3H)-pyrimidinone (2.73 g).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)=[O:7])(=[O:3])[CH3:2].[BH4-].[Na+].O>CO>[C:1]([O:4][CH2:5][CH:6]([OH:7])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)c1cccc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)OCC(O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-(3-Nitrophenyl)-2-oxoethyl acetate (20 g) was dissolved in MeOH (200 mL) and cooled to 0° C. Sodium borohydride (6.78 g) was added pinch-wise to the reaction mixture and this was stirred for 2 hours at room temperature. The reaction was quenched by addition of acetone (10 mL) and the mixture concentrated to give a solid. The solid was treated with water (100 mL) and extracted with ethyl acetate (3×100 mL). The crude title compound obtained was used for next step without further purification (18 g, 89%).
Reaction SMILES: C([O:8][C:9]1[C:25]([O:26][CH3:27])=[CH:24][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:11]=2[CH:10]=1)[NH:18][CH:17]=[C:16]([C:21]#[N:22])[C:15]3=[O:23])C1C=CC=CC=1>CN(C)C=O.CCOCC.[Pd]>[OH:8][C:9]1[C:25]([O:26][CH3:27])=[CH:24][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:11]=2[CH:10]=1)[NH:18][CH:17]=[C:16]([C:21]#[N:22])[C:15]3=[O:23]
Reactant: COc1cc2cc3c(=O)c(C#N)c[nH]c3cc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cc2cc3c(=O)c(C#N)c[nH]c3cc2cc1O
Yield: 154.3 %

Procedure:
A solution of 3.6 g (7.3 mmol) of 8-benzyloxy-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile and 0.7 g of 10% Pd/C in 240 mL of dimethyl formamide is hydrogenated in a Parr shaker at 40 psi for 24 hours. The catalyst is filtered through a pad of Celite, Is washed with dimethyl formamide and the solvent is reduced in vacuo to yield a solid. The crude product is suspended in ether, collected by filtration, further washed with ether and dried to yield 3.0 g of 8-hydroxy-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile as a yellow solid, mp>300° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:29][CH2:30][C:31](Cl)=[O:32]>CCOCC.O>[Cl:29][CH2:30][C:31]([N:8]([CH2:7][CH:2]1[O:3][CH2:4][CH2:5][CH2:6][O:1]1)[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16])=[O:32]
Reactant: Cc1cccc(C)c1NCC1OCCCO1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CCOCC
Product: Cc1cccc(C)c1N(CC1OCCCO1)C(=O)CCl
Reaction time: 1 h

Procedure:
N-(1,3-Dioxan-2-ylmethyl)-2,6-dimethylaniline prepared in Example 2 (5 grams), sodium carbonate (3 grams), benzene (30 ml) and water (30 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture was cooled to a temperature of from about 0° to about 5°C and chloroacetyl chloride (2.8 grams) was slowly added over a period of about 15 minutes. After the addition was completed stirring was continued at room temperature for a period of about one hour. Ether (100 ml) was then added to the reaction mixture and the resulting solution was washed with water. The washed solution was dried over anhydrous magnesium sulfate and stripped of solvents leaving a solid residue. The residue was recrystallized from heptane to yield the desired product N-α-chloroacetyl-N-(1,3-dioxan-2-ylmethyl)-2,6-dimethylaniline having a melting point of 100° to 102°C.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[CH2:30][CH2:29][CH:28]([C:31](O)=[O:32])[CH2:27]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:31]([CH:28]5[CH2:29][CH2:30][O:26][CH2:27]5)=[O:32])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)C1CCOC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)C1CCOC1

Procedure:
The title compound, white solid (17.6 mg, 60.3%), MS (ISP) m/z=429.2 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25 mg, 0.0681 mmol) and tetrahydrofuran-3-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7]3[C:14]4[CH:15]=[C:16]([CH3:20])[C:17]([CH3:19])=[CH:18][C:13]=4[NH:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.[CH3:22]I>>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7]3[C:14]4[CH:15]=[C:16]([CH3:20])[C:17]([CH3:19])=[CH:18][C:13]=4[N:12]([CH3:22])[C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: Cc1ccc2c(=O)n3c(nc2c1)[nH]c1cc(C)c(C)cc13
Product: Cc1ccc2c(=O)n3c4cc(C)c(C)cc4n(C)c3nc2c1

Procedure:
3,6,8,9-Tetramethylbenzimidazo[2,1-b]quinazolin-12(6H)-one is prepared with 3,8,9-trimethylbenzimidazo[2,1-b]quinazolin-12(6H)one and methyl iodide.
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:44][CH3:45])[C:32]([O:34][CH2:35][CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])=[O:33])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.C(=O)(O)[O-].[Na+]>Cl.C(OCC)(=O)C>[F:52][C:49]([F:50])([F:51])[C:47]1[CH:46]=[C:5]([CH:4]=[C:3]([C:2]([F:53])([F:1])[F:54])[CH:48]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:44][CH3:45])[C:32]([O:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1
Reactant: CCN(C(=O)OCCC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCN(C(=O)OCCC(=O)O)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
Tert-butyl 3-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamoyloxy]-propionate (114 mg) is dissolved in a 4N-hydrochloric acid in ethyl acetate (5 ml), and the mixture is stirred at room temperature for 1 hour and 30 minutes. Thereto are added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→19:1) to give 3-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamoyloxy]-propionic acid (81 mg). The resulting 3-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamoyloxy]-propionic acid (81 mg) is dissolved in ethanol (1 ml), and thereto is added 1N-aqueous sodium hydroxide solution (115 μl) and concentrated under reduced pressure to give 3-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethylcarbamoyloxy]-propionic acid sodium salt (78 mg). MS (m/z): 722 [M−Na]−
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][CH:10]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]=2[C:13]2[O:14][CH:15]=[C:16]([CH2:18]O)[N:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:27]>C(Cl)Cl>[Br:27][CH2:18][C:16]1[N:17]=[C:13]([C:12]2[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:10][N:9]=[N:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:14][CH:15]=1
Reactant: OCc1coc(-c2c(-c3ccccc3)cnnc2-c2ccccc2)n1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: BrCc1coc(-c2c(-c3ccccc3)cnnc2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 193.1 %

Procedure:
To a solution of (2-(3,5-diphenylpyridazin-4-yl)oxazol-4-yl)methanol (220 mg, 0.66 mmol) in DCM (8 mL), PBr3 (91 mg, 0.33 mmol) was added at 0° C. and the reaction mixture was warmed to rt and stirred for 12 h. After completion of starting material, reaction was quenched with saturated NaHCO3 solution, extracted with ethyl acetate (2×25 mL), washed with brine (1×10 mL). Solvent was removed under reduced pressure to obtain the crude product 4-(bromomethyl)-2-(3,5-diphenylpyridazin-4-yl)oxazole (250 mg) which was carried to next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:32])[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C:28](SC)=[NH:29])=[CH:23][CH:22]=2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:37].[Cl-].[NH4+]>CO.C(Cl)Cl>[NH2:29][C:28](=[NH:37])[CH2:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:13]2[C:12](=[O:32])[C:11]3[C:15](=[CH:16][CH:17]=[CH:18][C:10]=3[NH:9][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:8])[C:14]2=[O:19])=[CH:22][CH:23]=1
Reactant: [NH4+]
Reactant: CSC(=N)Cc1ccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)cc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: N=C(N)Cc1ccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
320 mg (0.661 mmol) of methyl 2-{4-[(4-{[(5-chloro-2-thienyl)carbonyl]amino}-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}ethaneimidothioate are suspended in 40 ml of methanol, and 153 mg (1.98 mmol) of ammonium acetate and 106 mg (1.98 mmol) of ammonium chloride are added. The mixture is stirred at room temperature overnight, diluted with methanol and methylene chloride until a clear solution is formed and adsorbed on silica gel. Chromatography on silica gel (CH2Cl2/EtOH=10/1 to 3/1) gives the desired compound. The product is dissolved in methanol and methylene chloride, and trifluoroacetic acid is added. Removal of the solvent under reduced pressure gives 298 mg (80% of theory) of the desired product as trifluoroacetic acid salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:30]4[C@H:37]([CH3:38])[CH2:36][C:35]([OH:40])([CH3:39])[C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:9][N:10]([CH:18]([CH3:20])[CH3:19])C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.[ClH:41].O1CCOCC1>C(Cl)Cl>[ClH:1].[ClH:41].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:9][NH:10][CH:18]([CH3:20])[CH3:19])[C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[C:30]4[C@H:37]([CH3:38])[CH2:36][C:35]([OH:40])([CH3:39])[C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:27][CH2:28]2)=[O:22])=[CH:4][CH:3]=1
Reactant: CC(C)N(CC(C(=O)N1CCN(c2ncnc3c2[C@H](C)CC3(C)O)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)NCC(C(=O)N1CCN(c2ncnc3c2[C@H](C)CC3(C)O)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A solution of tert-butyl 2-(4-chlorophenyl)-3-(4-((5R)-7-hydroxy-5,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (46 mg, 0.080 mmol) in DCM (6 mL) was added to a 4.0M HCl solution in dioxane (1.4 mL, 5.63 mmol). The mixture was stirred at room temperature for 16 hours. The solvents were removed in vacuo to give 2-(4-chlorophenyl)-1-(4-((5R)-7-hydroxy-5,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one dihydrochloride (49 mg, 100%) as a mixture of diastereomers. Rt: 2.05 and 2.18 min.
Reaction SMILES: O(C)[Na].[CH3:4][O:5][CH:6]([C:11]([O:13]C)=O)[C:7]([O:9]C)=O.[NH2:15][C:16]([NH2:18])=[O:17]>CCO>[OH:13][C:11]1[NH:18][C:16](=[O:17])[NH:15][C:7](=[O:9])[C:6]=1[O:5][CH3:4]
Reactant: COC(=O)C(OC)C(=O)OC
Reactant: NC(N)=O
Agent: CO[Na]
Solvent: CCO
Product: COc1c(O)[nH]c(=O)[nH]c1=O
Temperature: 100 °C
Yield: 99 %

Procedure:
The NaOCH3 (8.5 g, 157 mmole), was added to a stirred solution of dimethyl 2-methoxymalonate (10.2 g, 62.91 mmole), urea (2.5 g, 41.7 mmole), and EtOH (80 ml). The reaction mixture was heated to 100° C. for 4 hrs, then the reaction was evaporated to remove the solvent. Water was added to the mixture and then concentrated HCl was added. The pH of the mixture was adjusted to ca. 3˜4. The mixture was filtered and wash water and acetone. After drying in vacuo, it gave a product (99%).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[N+:7]([C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1)([O-:9])=[O:8].FC(F)(F)S(O[C:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH:26]=1)(=O)=O.[Li+].[Cl-]>O1CCOCC1.CCOC(C)=O.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>[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([C:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH:26]=2)=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 87.5 °C
Reaction time: 4 h
Yield: 49.5 %

Procedure:
A solution of 2 M Na2CO3 (5.66 mL, 11.3 mmol) was added to a mixture of 4-nitrophenylboronic acid (0.831 g, 4.98 mmol), tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (I42) (1.50 g, 4.53 mmol), LiCl (0.384 g, 9.06 mmol) and Pd(PPh3)4 (1.308 g, 1.132 mmol) in 1,4-dioxane (20 mL). The reaction mixture was stirred at 85-90° C. for 4 hours. The resulting mixture was dissolved in EtOAc (100 mL) and the organic layer was washed with H2O (50 mL), brine (50 mL) and dried over Na2SO4 to yield a dark red oil. The oil was purified by column chromatography on silica gel (0-20% EtOAc in petroleum benzine 40-60° C.) to yield the title compound (I43) (0.683 g, 50%) as a pale brown solid; 1H NMR (400 MHz, CDCl3) δ 8.24-8.16 (m, 2H), 7.55-7.47 (m, 2H), 6.23 (s, 1H), 4.14-4.12 (m, 2H), 3.66 (t, J=5.7 Hz, 2H), 2.55 (bs, 2H), 1.50 (s, 9H). LCMS Method C: rt 6.39 min; m/z 249 [M-Boc+2H]+, 205 [M-tButyl+2H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14]([CH2:15]O)=[CH:13][C:12]3[CH:17]=[CH:18][S:19][C:11]=3[S:10]2(=[O:21])=[O:20])=[CH:5][CH:4]=1.C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[CH3:38][O:39][CH2:40][CH2:41][NH:42][CH2:43][CH2:44][O:45][CH3:46].C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:38][O:39][CH2:40][CH2:41][N:42]([CH2:15][C:14]1[N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[S:10](=[O:21])(=[O:20])[C:11]2[S:19][CH:18]=[CH:17][C:12]=2[CH:13]=1)[CH2:43][CH2:44][O:45][CH3:46]
Reactant: COCCNCCOC
Reactant: COc1ccc(N2C(CO)=Cc3ccsc3S2(=O)=O)cc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCN(CCOC)CC1=Cc2ccsc2S(=O)(=O)N1c1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of the product of Step D (1.19 g, 3.68 mmol) and triethylamine (1.24 g, 12.3 mmol) in anhydrous THF (50 mL) was added methanesulfonic anhydride (1.07 g, 6.13 mmol). After 30 min, bis(2-methoxyethyl)amine (3 mL) was added and stirring continued for 18 h at ambient temperature. The reaction mixture was heated at reflux temperature for 1 h, cooled, poured into a saturated solution of sodium bicarbonate (100 mL) and this mixture was extracted with ethyl acetate (2×100 mL). The combined extracts were dried (MgSO4) and evaporated to a residue which was purified by column chromatography (silica, 40% ethyl acetate/hexane) to give a viscous oil (1.16 g, 72%).