Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:35](O)(=[O:38])[CH2:36][CH3:37].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:15]1[CH:14]=[N:13][C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)=[C:11]([CH:16]=1)[C:10]([NH:9][C@H:6]1[CH2:7][CH2:8][C@@H:3]([NH:2][C:35](=[O:38])[CH2:36][CH3:37])[CH2:4][CH2:5]1)=[O:27]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Reactant: CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2cc(F)cnc2Oc2cccc(SC)c2)CC1
Temperature: 25 °C
Reaction time: 64 h
Yield: 99.2 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1 ml) and triethylamine (100 μl, 0.729 mmol) was added followed by propionic acid (22 μl, 0.291 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg, 0.291 mmol) and 1-hydroxybenzotriazole (39 mg, 0.291 mmol). The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give 5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-(cis-4-propionylamino-cyclohexyl)-nicotinamide (104 mg) as a white solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH:6]=2)[CH2:3][CH2:2]1.[NH:29]1[CH2:35][C:33](=[O:34])[NH:32][C:30]1=[O:31].N1CCCCC1>C(O)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:35]4\[NH:29][C:30](=[O:31])[NH:32][C:33]\4=[O:34])=[C:9]3[N:8]=[C:7]([N:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]3)[CH:6]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(NC3CC3)n3ncc(C=O)c3n2)CC1
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2cc(NC3CC3)n3ncc(/C=C4\NC(=O)NC4=O)c3n2)CC1
Temperature: 80 °C
Yield: 87.4 %

Procedure:
The above product tert-butyl 4-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate (250 mg, 0.645 mmol) was dissolved in 2.0 mL ethanol, added hydantoin (129 mg, 1.288 mmol) and piperidine (127 ul). The reaction was heated to 80° C. for three hours. Cooled the reaction mixture and yellow precipitate was filtered, washed with ethanol, dried to yield (Z)-tert-butyl 4-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate (264 mg, 87% yield). The above product was further dissolved in 1:1 mixture of DCM: TFA and stirred at room temperature for 30 minutes. Mixture was concentrated and dried to yield yellow solid of (Z)-5((7-(cyclopropylamino)-5-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl) methylene) imidazolidine-2,4-dione. LCMS (M+1=369)
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][C:5]=2[C:4](=[O:15])OC1=O)[CH:12]=[CH:11][CH:10]=[CH:9]3.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1>C1(C)C(C)=CC=CC=1.CN(C)C1C=CN=CC=1>[NH2:1][C:6]1[C:5]([C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=2)=[O:15])=[CH:14][C:13]2[C:8]([CH:7]=1)=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: O=c1[nH]c2cc3ccccc3cc2c(=O)o1
Reactant: Nc1ccc(Cl)cn1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Product: Nc1cc2ccccc2cc1C(=O)Nc1ccc(Cl)cn1
Temperature: 150 °C
Reaction time: 13 h
Yield: 8 %

Procedure:
A suspension of 2H-naphth[2,3-d][1,3]oxazine-2,4(1H)-dione (216 mg) and 2-amino-5-chloropyridine (202 mg) in xylene (5 ml) is stirred at 150° C. for 13 hours, and thereto added 4-dimethylaminopyridine (14.4 mg) and the mixture is stirred at 150° C. for another 3 hours. The reaction solution is concentrated under reduced pressure and the resulting residue is suspended in ethyl acetate, and filtered to remove insoluble materials. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1) to give 3-amino-N-(5-chloropyridin-2-yl)-2-naphthamide (24 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=2[NH:6][CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH3:27]I>CN(C)C=O.C(OCC)(=O)C>[CH3:27][N:6]1[C:5]2[CH:23]=[CH:24][CH:25]=[CH:26][C:4]=2[NH:3][C:2]([CH3:1])=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: CI
Reactant: CCOC(=O)C1=C(C)Nc2ccccc2NC1c1cccc([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C)Nc2ccccc2N(C)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A reaction mixture containing 2,5-dihydro-4-methyl-2-(3-nitrophenyl)-1H-1,5-benzodiazepine-3-carboxylic acid, ethyl ester (1,5 g., 4.25 mmole) in dry dimethylformamide (5 ml.) is treated with methyl iodide (581 mg., 5.5 mmole) and then allowed to stir at room temperature for 24 hours. The reaction mixture is diluted with ethyl acetate and is washed with sodium bicarbonate, water, and brine. After drying over magnesium sulfate, the solvent is evaporated and the residue is purified by flash chromatography on silica gel (30% ethyl acetate in hexanes). The yellow foam obtained (701 mg.) is crystallized from ether-hexanes to provide yellow crystalline 2,5-dihydro-1,4-dimethyl-2-(3-nitrophenyl)-1H-1,5-benzodiazepine-3-carboxylic acid, ethyl ester; m.p. 113°-115.5°. TLC (silica gel; ethyl acetate:hexanes, 1:1) Rf =0.5.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1.[CH3:19][C:20]1[C:21]([CH2:27][OH:28])=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:28][CH2:27][C:21]2[C:20]([CH3:19])=[CH:25][C:24]([CH3:26])=[CH:23][N:22]=2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccccn2)c1C#N
Reactant: Cc1cnc(CO)c(C)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1cnc(COc2nc(N)nc(-c3ccccn3)c2C#N)c(C)c1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyridin-2-yl-pyrimidine-5-carbonitrile, 3,5-dimethyl-2-pyridinemethanol and DBU in DME. EI-MS m/e (%): 332 (M+, 100), 303 (34), 120 (31).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH:15]([CH2:19][CH2:20][CH2:21][CH2:22]C)[C:16](O)=O.[Cl-].[NH4+].S(=O)(=O)(O)O.C[CH2:32][O:33]CC>>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH:15]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:16][CH2:32][OH:33]
Reactant: CCCCCC(C(=O)O)c1ccc(Cl)cc1Cl
Reactant: CCOCC
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCC(CCO)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 2.07 g (0.0545 mole) of lithium aluminum hydride in 100 ml of ether is added dropwise a solution of 15 g (0.054 mole) of 2-(2,4-dichlorophenyl) heptanoic acid in 50 ml of ether. The resulting mixture is stirred at room temperature for 3 hours. The excess lithium aluminum hydride is decomposed carefully with 100 ml of saturated ammonium chloride solution followed by 100 ml of dilute sulfuric acid solution. The ether layer is separated from the aqueous layer and the aqueous layer is again extracted with ether. The combined ether layers are washed with 10% sulfuric acid, water, saturated sodium bicarbonate solution, saturated saline solution and dried over magnesium sulfate. Solvent is evaporated under reduced pressure to give 12 g of an oil which is further purified by vacuum distillation (120°-125°/0.1 mm) to give 10.2 g (72%) of desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].S(=O)(O)[O-].[Na+].[C-:17]#[N:18].[K+]>CCOCC>[OH:8][CH:7]([C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:17]#[N:18]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOCC
Product: N#CC(O)c1cccc([N+](=O)[O-])c1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
A mixture of m-nitrobenzaldehyde (27.0 g, 178.7 mmol) and a 10% solution of 24 g of sodium bisulfite was placed in a 2 liter flask and 75 mL of ether was added. The resulting mixture was cooled in an ice-bath to 10° C. and potassium cyanide (15.0 g, 230.3 mmol) in a 20% solution was added over a period of 30 minutes. The mixture was stirred for another 30 minutes after the addition of the potassium cyanide. The ether layer was separated and the aqueous layer was extracted with ether. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 27.81 g (87%) of α-hydroxy-3-nitrobenzeneacetonitrile, a compound of formula (Q), as a pale yellow oil.
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:20][C:21]3[C:22]([CH3:31])=[N:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH2:45][CH2:44][CH2:43][CH:42]([CH2:46][OH:47])[CH2:41]1>O>[CH3:33][O:32][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[O:9][CH2:8][CH2:7][N:40]1[CH2:45][CH2:44][CH2:43][CH:42]([CH2:46][OH:47])[CH2:41]1)[N:17]=[CH:16][CH:15]=[C:14]2[O:20][C:21]1[C:22]([CH3:31])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCl
Reactant: OCC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCN1CCCC(CO)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
N,N-Dimethylformamide (1 ml) was added to 7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 353) (50 mg), potassium carbonate (53 mg), and piperidin-3-yl-methanol (44 mg), and the mixture was stirred at 80° C. overnight. The reaction solution was then stirred at 100° C. for one day, and the reaction solution was cooled to room temperature. Water was added thereto, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (33 mg, yield 55%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH2:15])=[CH:6][C:7]=1OC(F)(F)C(F)F.C1(N)C=CC=CC=1N.BrBr.[Cl:27][C:28]([Cl:34])([Cl:33])[C:29](=N)OC>C(O)(=O)C>[Cl:27][C:28]([Cl:34])([Cl:33])[C:29]1[NH:16][C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=2[N:15]=1
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: Nc1cc(Br)c(OC(F)(F)C(F)F)cc1N
Agent: BrBr
Agent: Nc1ccccc1N
Solvent: CC(=O)O
Product: ClC(Cl)(Cl)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
9.5 Grams of 4-bromo-5-(1',1',2',2'-tetrafluoroethoxy)-1,2-benzenediamine, [i.e. the o-phenylenediamine compound (IV) containing bromine as the substituent X] was dissolved in 100 ml of acetic acid, 5.7 ml of methyl trichloroacetoimidate was added thereto at room temperature, and the resulting mixture was stirred for 20 minutes. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and recrystallized from hexane-ethyl acetate to obtain 5.0 g of 5(6)-bromo-6(5)-(1',1',2',2'-tetrafluoroethoxy)-2-tetrafluoroethoxy)-2-(trichloromethyl)-benzimidazole. 1H-NMR (CDC3 3+DMSO-d6): δ(ppm) (1H, s), 7.45(1H), 5.97(1H, tt, 7.77 (1H, s), 7.45(1H), 5.97 (1H, tt, J=3, 53 Hz)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Si:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.C1[C:36]2[C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[O:33][C:32]=2[C:31](C2C=C(B3OC(C)(C)C(C)(C)O3)C=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.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>[Br:8][C:6]1[CH:5]=[C:4]([Si:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=[C:2]([C:7]2[CH:2]=[CH:3][CH:4]=[C:36]([C:35]3[C:34]4[O:33][C:32]5[CH:12]=[CH:11][CH:10]=[CH:15][C:31]=5[C:40]=4[CH:39]=[CH:38][CH:37]=3)[CH:6]=2)[CH:7]=1
Reactant: Brc1cc(Br)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CC1(C)OB(c2cccc(-c3cccc4c3oc3ccccc34)c2)OC1(C)C
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cc(-c2cccc(-c3cccc4c3oc3ccccc34)c2)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
A solution of (3,5-Dibromophenyl)triphenylsilane (4.27 g, 8.64 mmol), 2-(3-(dibenzo[b,d]furan-4-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.6 g, 4.32 mmol), Pd(PPh3)4 (0.100 g, 0.086 mmol) and K2CO3 (1.792 g, 12.96 mmol) in toluene (100 mL) and water (10 mL) was refluxed under nitrogen overnight. After cooling to room temperature, the organic phase was isolated, and the solvent was evaporated. The residue was purified by column chromatography on silica gel with hexane/DCM (4/1 to 3/1, v/v) as eluent to yield (5-Bromo-3′-(dibenzo[b,d]furan-4-yl)[1,1′-biphenyl]-3-yl)triphenylsilane (1.3 g, 45%) as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1.C(O)(C)(C)C.[CH:22]1([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[NH:34][C:35]([C:37]3[N:41]4[CH:42]=[CH:43][C:44](F)=[CH:45][C:40]4=[N:39][CH:38]=3)=[O:36])[N:27]([CH2:47][C:48]3[C:49](=[O:55])[N:50]([CH3:54])[CH:51]=[CH:52][CH:53]=3)[N:26]=2)[CH2:24][CH2:23]1>O>[CH:22]1([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[NH:34][C:35]([C:37]3[N:41]4[CH:42]=[CH:43][C:44]([O:16][CH2:15][CH2:14][N:11]5[CH2:12][CH2:13][N:8]([CH3:7])[CH2:9][CH2:10]5)=[CH:45][C:40]4=[N:39][CH:38]=3)=[O:36])[N:27]([CH2:47][C:48]3[C:49](=[O:55])[N:50]([CH3:54])[CH:51]=[CH:52][CH:53]=3)[N:26]=2)[CH2:24][CH2:23]1
Reactant: Cn1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(F)ccn45)cccc32)c1=O
Reactant: CN1CCN(CCO)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CN1CCN(CCOc2ccn3c(C(=O)Nc4cccc5c4c(C4CC4)nn5Cc4cccn(C)c4=O)cnc3c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A one dram vial was charged with solid potassium tert-butoxide (54 mg, 0.48 mmol), 2-(4-methylpiperazin-1-yl)ethanol (0.075 g, 0.52 mmol), and tert-butanol (0.3 mL, 3.4 mmol). The mixture was stirred at ambient temperature for 30 minutes. N-(3-cyclopropyl-1-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide (0.032 g, 0.070 mmol) was added in one portion. The mixture was heated at 88° C. with stirring for 16 hours. The mixture was cooled to ambient temperature and diluted with water until a precipitate formed. The precipitate was isolated by filtration and dried under high vacuum. Purification using silica preparative thin layer chromatography plate (20×20 cm, 0.5 mm) developed in a chamber with 10% methanol/dichloromethane with 0.6% concentrated ammonium hydroxide gave the product. MS (APCI), positive scan, m/z=581.2 (M+).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:21])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([CH3:19])[CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:20])[CH:5]=[CH:6][CH:7]=1.[C:22]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([CH3:21])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([CH3:19])[CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:22])[C:9]2=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Br)cccc1-n1c(=O)[nH]c2c(C)cccc2c1=O
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1c(Br)cccc1-n1c(=O)c2cccc(C)c2n(C)c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 104.4 %

Procedure:
A mixture of 3-(3-bromo-2-methylphenyl)-8-methylquinazoline-2,4(1H,3H)-dione (470 mg, 1.36 mmol) and Cs2CO3 (1.33 g, 4.08 mmol) in DMF (8 mL) was treated with iodomethane (0.85 mL, 13.6 mmol) and stirred at room temperature for 1.5 h. The mixture was diluted with EtOAc, washed sequentially with water and two portions of 10% aqueous LiCl. The combined aqueous phases were extracted with EtOAc. The combined organic phases were washed sequentially with 10% aqueous LiCl and water, dried and concentrated to give impure 3-(3-bromo-2-methylphenyl)-1,8-dimethylquinazoline-2,4(1H,3H)-dione as a white solid (510 mg), used without further purification. Mass spectrum m/z 359, 361 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C@@H:5]([C@H:14]1[C:19]([O:20][CH3:21])=[N:18][C@H:17]([CH:22]([CH3:24])[CH3:23])[C:16]([O:25][CH3:26])=[N:15]1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:21][O:20][C:19]1[C@H:14]([C@@H:5]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[CH2:4][CH2:3][OH:2])[N:15]=[C:16]([O:25][CH3:26])[C@@H:17]([CH:22]([CH3:23])[CH3:24])[N:18]=1
Reactant: COC(=O)C[C@H](c1ccc(OC)cc1)[C@@H]1N=C(OC)[C@@H](C(C)C)N=C1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1[C@H](CCO)c1ccc(OC)cc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
In a dry two-necked flask equipped with dropping funnel and thermometer was added 3(R)-[(2S,5R)-2,5-dihydro-3,6-dimethoxy-5-(1-methylethyl)-2-pyrazinyl]-3-(4-methoxyphenyl)propanoic acid methyl ester (17.5 g, 46.48 mmol) and 559 mL of dry THF. The solution was then cooled to −10° C. in an acetone-ice bath under argon. To the solution was added dropwise a solution of lithium aluminum hydride in THF (0.8 M, 60 mL, 48 mmol) at a rate so as to maintain the internal temperature below 0° C. After the addition, the ice bath was removed, and reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of 10 mL of ethyl acetate followed by 25 mL of saturated sodium sulfate solution. The resulting white precipitate was filtered and was washed with ethyl acetate (4×100 mL). The combined filtrate was then concentrated to give 3(R)-[(2S,5R)-2,5-dihydro-3,6-dimethoxy-5-(1-methylethyl)-2-pyrazinyl]-3-(4-methoxyphenyl)propanol, as a colorless oil (17.7 g). TLC (Rf: 0.5, ethyl acetate/hexane=1:1) single spot.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([CH3:37])[CH2:10][C@H:11]([OH:36])[C@@H:12]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@@H:13]([O:26][CH3:27])[CH2:14][C@@H:15]([CH3:25])[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[H-].[Na+].[CH3:40]I>O1CCCC1>[C:1]([O:7][CH2:8][C@H:9]([CH3:37])[CH2:10][C@H:11]([O:36][CH3:40])[C@@H:12]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@@H:13]([O:26][CH3:27])[CH2:14][C@@H:15]([CH3:25])[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:22])[CH3:23])([CH3:19])[CH3:20])(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CO[C@@H](C[C@@H](C)CO[Si](C)(C)C(C)(C)C)[C@H](OCc1ccccc1)[C@@H](O)C[C@@H](C)COC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H](C[C@@H](C)COC(=O)C(C)(C)C)[C@@H](OCc1ccccc1)[C@H](C[C@@H](C)CO[Si](C)(C)C(C)(C)C)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
Pivaloate 22 (3.52 g, 6.50 mmol) was dissolved in 50 ml of tetrahydrofuran at 25° C. and 523 mg of NaH (60% dispersion in mineral oil) and 4.0ml of anhydrous methyl iodide (10 equiv) were added successively. The solution was stirred at 25° C. for 24 hr. The mixture was partitioned between 150 ml of diethyl ether and 50 ml of water. The aqueous phase was extracted with an additional 2×100 ml of ether. The organic phases were combined, washed with 100 ml of saturated sodium chloride solution and dried over magnesium sulfate. Concentration in vacuogave 3.82 g of 23 as a crude oil. The material was purified by column chromatography on 190 g of silica gel eluting with hexanes:ethyl acetate (8:1) to give 3.58 g (99%) of dimethoxy pivaloate 23. This material was homogeneous by 1H and 13C NMR.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[C:4](=[O:19])[N:5]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:6]=[CH:7][C:8]=1[C:9]([O:11][CH3:12])=[O:10].[CH:20]1([C:23]2[C:28]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[C:27]([F:36])[C:26]([O:37][CH:38]([CH3:40])[CH3:39])=[C:25]([CH:41]=O)[CH:24]=2)[CH2:22][CH2:21]1.[Na].C(=O)([O-])O.[Na+]>C1COCC1.O.C(O)(=O)C.C(N(CC)CC)C>[ClH:1].[CH:20]1([C:23]2[C:28]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[C:27]([F:36])[C:26]([O:37][CH:38]([CH3:39])[CH3:40])=[C:25]([CH2:41][N:16]3[CH2:15][CH2:14][CH:13]([N:5]4[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:3]([CH3:2])[C:4]4=[O:19])[CH2:18][CH2:17]3)[CH:24]=2)[CH2:22][CH2:21]1
Reactant: CC(C)Oc1c(C=O)cc(C2CC2)c(-c2ccc(F)cc2)c1F
Reactant: COC(=O)c1ccn(C2CCNCC2)c(=O)c1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccn(C2CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4)c(F)c3OC(C)C)CC2)c(=O)c1C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
Triethylamine (35.3 g) was added to a suspension of methyl 3-methyl-2-oxo-1-(piperidin-4-yl)-1,2-dihydropyridine-4-carboxylate hydrochoride (100 g) in THF (2.00 L) at room temperature. After being stirred at the same temperature for 30 minutes, 6-cyclopropyl-2,4′-difluoro-3-isopropoxybiphenyl-4-carbaldehyde (121 g) was added to the reaction mixture. The mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyhydroborate (111 g) and acetic acid (20.9 g) were added to the reaction mixture. The mixture was stirred at room temperature for 16 hours. Aqueous saturated sodium hydrogen carbonate solution (1.30 L) and water (1.30 L) were added to the mixture at room temperature. The mixture was extracted with ethyl acetate (10 L). The organic layer was separated, washed with brine (4.00 L), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was dissolved in ethyl acetate (1.00 L). 4M hydrogen chloride (ethyl acetate solution, 87 ml) was added to the mixture at room temperature. Then crystalline seeds were added to the mixture. The mixture was diluted with diisopropyl ether (2.00 L) and stirred at room temperature for 1 hour. The precipitate was collected by filtration and washed with diisopropyl ether (1.50 L) to give the title compound (183.7 g).