Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].CC#N.Cl[C:16]1[N:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=1>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:16]2[CH:17]=[CH:18][C:19]([C:22](=[O:24])[CH3:23])=[CH:20][N:21]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(=O)c1ccc(Cl)nc1
Solvent: CC#N
Product: CCOC(=O)C1CCN(c2ccc(C(C)=O)cn2)CC1
Yield: 89.9 %

Procedure:
To a stirred solution of piperidine-4-carboxylic acid ethyl ester (12.6 g, 0.080 mol) in CH3CN (250 mol), iPr2Net (33.7 mL, 0.193 mol) and 1-(6-chloro-pyridin-3-yl)-ethanone (10 g, 0.064 mol) were added. The reaction mixture was heated at reflux over night, and then volatiles evaporated under high vacuum. Column chromatography (SiO2, EtOAc/heptane, 1:9 to 1:1) yielded 15.9 g (89%) of 5′-acetyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester as a yellow oil. ES-MS m/e: 277.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH3:19])[CH3:18])[CH:12]=1)=O.[C:20]([O:24][C:25](=[O:34])[CH2:26][C:27](OC(C)(C)C)=[O:28])([CH3:23])([CH3:22])[CH3:21].[OH-].[K+]>>[C:20]([O:24][C:25]([C:26]1[C:27](=[O:28])[NH:1][C:2]2[C:3]([C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH3:19])[CH3:18])[CH:12]=1)=[CH:4][C:5]([Cl:8])=[CH:6][CH:7]=2)=[O:34])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: CC(C)c1cccc(C(=O)c2cc(Cl)ccc2N)c1
Agent: [K+]
Agent: [OH-]
Product: CC(C)c1cccc(-c2c(C(=O)OC(C)(C)C)c(=O)[nH]c3ccc(Cl)cc23)c1
Temperature: 110 °C
Reaction time: 16 h
Yield: 43.8 %

Procedure:
To a mixture of (2-amino-5-chloro-phenyl)-(3-isopropyl-phenyl)-methanone (1.1 g, 4.02 mmol), and malonic acid di-tert-butyl ester (1.344 ml, 6.03 mmol) was added potassium hydroxide (113 mg, 2.01 mmol) at 25° C., and the resulting reaction mixture was stirred at 110° C. for 16 h. It was cooled to 0° C., and directly purified by column chromatography over silica gel (20-30% EtOAc/hexane) to afford 6-chloro-4-(3-isopropyl-phenyl)-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid tert-butyl ester (700 mg, 44%) as pale yellow solid. LC-MS (ESI): 398 (M+H)+.
Reaction SMILES: [CH:1]1([N:7]2[C:11](=[O:12])[C:10]([NH:13][C:14]([C:16]3[C:20]([CH3:21])=[C:19]([C:22]4[CH2:27][CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][CH:23]=4)[O:18][N:17]=3)=[O:15])=[C:9]([CH3:30])[N:8]2[CH3:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[CH:1]1([N:7]2[C:11](=[O:12])[C:10]([NH:13][C:14]([C:16]3[C:20]([CH3:21])=[C:19]([CH:22]4[CH2:23][CH2:24][C:25]([CH3:28])([CH3:29])[CH2:26][CH2:27]4)[O:18][N:17]=3)=[O:15])=[C:9]([CH3:30])[N:8]2[CH3:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1C1=CCC(C)(C)CC1
Agent: [Pd]
Solvent: CCO
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1C1CCC(C)(C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of N-(2-cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-5-(4,4-dimethylcyclohex-1-en-1-yl)-4-methylisoxazole-3-carboxamide (Example 2.2) (40 mg, 0.094 mmol) in ethanol (20 mL) was flushed with nitrogen and treated with 10% Pd—C, 50% wet (Alfa Aesar, 38303) (14.97 mg, 0.141 mmol). The reaction mixture was stirred at room temperature under an atmosphere of hydrogen for 3 hours. The resulting mixture was filtered through Celite®, washing with ethanol followed by DCM. The filtrate was concentrated under reduced pressure and the residue was passed through a 500 mg silica-TMT cartridge, eluting with ethanol:ether (1:1). The filtrate was collected and the solvent removed under reduced pressure to afford the title compound;
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[I:9])[NH2:5].C(N(C(C)C)CC)(C)C.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][N:21]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([I:9])=[C:2]([CH3:1])[CH:3]=2)=[O:25])=[CH:22][N:21]=1
Reactant: Cc1cc(N)ccc1I
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Yield: 86 %

Procedure:
A solution of 3-methyl-4-iodoaniline (660 mg 2.84 mmol), diisopropylethyl amine (1.2 mL 8.52 mmol) and a catalytic amount of DMAP in CH2Cl2 (15 mL) was treated with 6-chloronicotinoyl chloride (500 mg, 2.84 mmol). Upon completion of the reaction, as judged by TLC, the mixture was partitioned between CH2Cl2 and water. The EtOAc layer was dried over Na2SO4 filtered and concentrated. The solid residue was washed with hexanes and then was passed through a silica gel plug with 50% EtOAc in hexanes as the elution solvent to afford the product, 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide. (910 mg, Yield 86%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([NH:20][C:21]([C:23]1[N:24]=[C:25]([N:28]2[CH2:31][CH:30]([OH:32])[CH2:29]2)[S:26][CH:27]=1)=[O:22])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH:10]([NH:20][C:21]([C:23]1[N:24]=[C:25]([N:28]2[CH2:31][CH:30]([O:32][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:29]2)[S:26][CH:27]=1)=[O:22])[CH2:11][O:12][Si:13]([C:16]([CH3:18])([CH3:19])[CH3:17])([CH3:15])[CH3:14])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCC(CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC(CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 106.3 %

Procedure:
To a solution of 1-{4-[2-(t-butyldimethylsilyloxy)-1-(t-butyldimethylsilyloxymethyl)ethylcarbamoyl]-1,3-thiazol-2-yl}-3-hydroxyazetidine (1.27 g, 2.53 mmol) (obtained as described in Reference Example 39(5)) in methylene chloride (64 ml) were added methanesulfonyl chloride (587 μl, 7.59 mmol) and triethylamine (1.06 ml, 7.59 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (3:1→1:2) as the eluant to afford 1-{4-[2-(t-butyldimethylsilyloxy)-1-(t-butyldimethylsilyloxymethyl)ethylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (1.56 g, yield 100%) as a pale yellow solid.
Reaction SMILES: [Na].C(O[C:5](=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH:12]1([C:17](=[O:19])C)[CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C>[CH2:9]([O:8][C:6](=[O:7])[CH2:5][C:17]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:19])[CH3:10]
Reactant: CC(=O)C1CCCC1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC(=O)C1CCCC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Sodium pellets (3.1 g, 135 mmol) were dissolved in ethanol (100 ml) under nitrogen at room temperature and a solution of diethyloxalate (18.4 ml, 135 mmol) and 1-cyclopentylethanone (16.7 g, 149 mmol) was added dropwise at room temperature over 30 minutes. The reaction was diluted with ethanol (100 ml), heated to 60° C. and stirred at this temperature for 2 hours. After cooling to room temperature the reaction was poured onto ice-cold 2N HCl (200 ml) and extracted with diethylether (300 ml) and ethyl acetate (300 ml). The combined organic extracts were dried over MgSO4, concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with pentane:ethyl acetate (6:1, by volume) to give 3-cyclopentyl-3-oxo-propionc acid ethyl ester (23.8 g) as an orange oil. 1H NMR (400 MHz, CDCl3): δ=14.38-14.65 (1H, brs), 6.83 (1H, s), 4.30-4.39 (2H, quart), 2.82-2.92 (1H, quin), 1.83-1.96 (2H, m), 1.57-1.83 (6H, 2×m), 1.33-1.40 (3H, t) ppm. LRMS (electrospray): m/z [M−H]+ 211.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)N)=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH:21]1[CH3:27].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:19][N:20]1[CH:21]([CH3:27])[CH2:22][C:23]2[N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=3[C:24]=2[CH2:25]1
Reactant: CC1CC(=O)CCN1C
Reactant: Cc1ccc(N(N)CCc2ccc(C)nc2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CC(C)N(C)C1
Temperature: 85 °C
Reaction time: 1 h
Yield: 10.3 %

Procedure:
To a solution of N-[2-(6-methyl-pyridin-3-yl)-ethyl]-N-p-tolyl-hydrazine (200 mg, 0.829 mmol) in dioxane (7 mL) was added 1,2-dimethyl-piperidin-4-one (137 mg, 1.078 mmol) in dioxane (3 mL) at RT. To this mixture was added sulfuric acid (0.1 mL) at RT. After complete addition the mixture was stirred at 85° C. for 1 h. The reaction was monitored by TLC. After completion of reaction, the mixture was basified with NaHCO3 solution and extracted with EtOAc (300 mL). The organic layer was dried over sodium sulfate, concentrated under vacuum and purified by HPLC to obtain 28.5 mg of desired compound as the TFA salt. 1HNMR (CD3OD, TFA salt) d (ppm): 8.20 (s, 1H), 8.05 (d, 1H), 7.63 (d, 1H), 7.25 (s, 1H), 7.10 (d, 1H), 6.95 (d, 1H), 4.70 (m, 1H), 4.45 (t, 2H), 4.36 (m, 1H), 4.05 (m, 1H), 3.75 (m, 1H), 3.20 (m, 2H), 3.0 (m, 3H), 2.90 (m, 1H), 2.62 (s, 3H), 2.40 (s, 3H), 1.50 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[CH2:8][C:9]([C:11]1[C:16]2[CH:17]=[C:18]([C:20]([OH:22])=O)[O:19][C:15]=2[C:14]([O:23][CH3:24])=[CH:13][CH:12]=1)=[O:10].O.ON1C2C=CC=CC=2N=N1.[NH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[CH2:8][C:9]([C:11]1[C:16]2[CH:17]=[C:18]([C:20]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[O:22])[O:19][C:15]=2[C:14]([O:23][CH3:24])=[CH:13][CH:12]=1)=[O:10]
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2cc(C(=O)O)oc12
Reactant: C1CNCCN1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2cc(C(=O)N3CCNCC3)oc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
Compound M (4.12 g) obtained in Reference Example 3 was dissolved in DMF (150 ml), 1-hydroxybenzotriazole monohydrate (5.8 g) and N-ethyl-N-′3-dimethylaminopropylcarbodiimide monohydrochloride (8.2 g) were added thereto, and the mixture was stirred at room temperature for 10 minutes. The mixture was dropwise added to a solution of piperazine (18.6 g) in DMF (300 ml) and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure and the residue was extracted with chloroform. The extract was washed a saturated aqueous sodium chloride solution and dried over sodium sulfate, and the solvent was distilled off. The resulting residue was suspended in ethanol and the precipitated crystals were collected by filtration to give the desired compound (3.54 g, 73%) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([C:15]([CH3:19])([CH3:18])[C:16]#[CH:17])[C:9]2=[O:20])=[N:5][N:4]=1.[C:23]1(C)C(S(O)(=O)=O)=CC=CC=1>CO>[F:22][C:2]([F:1])([F:21])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][CH3:23])[CH2:12][CH2:11][N:10]([C:15]([CH3:18])([CH3:19])[C:16]#[CH:17])[C:9]2=[O:20])=[N:5][N:4]=1
Reactant: C#CC(C)(C)N1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O
Reactant: Cc1ccccc1S(=O)(=O)O
Solvent: CO
Product: C#CC(C)(C)N1CCC(OC)N(c2nnc(C(F)(F)F)s2)C1=O

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-(1,1-dimethylprop-2-ynyl)-6-hydroxy-2(1H)-pyrimidinone (7 grams), methyl alcohol (50 ml) and toluenesulfonic acid (0.2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 24 hours. After this time the mixture is stripped of unreacted alcohol under reduced pressure to yield a solid product. This product is then recrystallized to yield the desired product tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-(1,1-dimethylprop-2-ynyl)-6-methoxy-2(1H)-pyrimidinone.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](O)=[O:9])=[CH:6][CH:7]=1>CO>[C:2]1([CH3:1])[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1
Solvent: CO
Product: Cc1ccc(C=O)cc1

Procedure:
Esterification of methanol is carried out with 100 g of per-p-toluic acid crystals obtained by distilling off acetone from the per-p-toluic acid product solution, obtained by autooxidizing p-tolualdehyde with air in the absence of catalyst in acetone as a solvent.
Reaction SMILES: [CH2:1]([NH:4]C(=O)OC(C)(C)C)[C:2]#[CH:3].[N:12]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N+:13]=[N-:14].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].Cl.[Na+].[Cl-]>C(O)(C)(C)C.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[CH2:15]([N:12]1[CH:3]=[C:2]([CH2:1][NH2:4])[N:14]=[N:13]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: NCc1cn(Cc2ccccc2)nn1

Procedure:
A reaction mixture comprising of tert-butyl prop-2-yn-1-ylcarbamate (219 mg, 1.411 mmol), (azidomethyl)benzene (188 mg, 1.411 mmol), copper (II) acetate (25.6 mg, 0.141 mmol) and sodium L-ascorbate (55.9 mg, 0.282 mmol) in tert-butanol (20 ml)/water (20 ml) was stirred for 18 hours at room temperature. The reaction mixture was acidified to pH1 using 6M HCl, then saturated with solid NaCl. The reaction mixture was concentrated under pressure to yield a green aqueous solution. The mixture was diluted with ethyl acetate and the organics were removed and dried (MgSO4). Concentration under reduced pressure afforded an orange oil. The oil was loaded on to a 10 g SCX2 cartridge, and this was washed with water and methanol. The product was then eluted with 2M ammonia in methanol. The solution was then concentrated to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]([CH:8](C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.CS(C)=O.[Cl-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncc(Cl)cc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1ncc(Cl)cc1F
Temperature: 138.5 °C
Reaction time: 0.67 h
Yield: 72.2 %

Procedure:
5.83 g of diethyl (5-chloro-3-fluoro-2-pyridyl)malonate and 25 ml of dimethyl sulfoxide were mixed. To the mixture were added 1.29 g of sodium chloride and 0.72 g of water. The mixture was stirred for about 40 minutes at an inner temperature of 135 to 142° C. The reaction mixture was allowed to cool to room temperature, then, to the reaction mixture was added water, and extracted with ethyl acetate. The organic layer was washed with saturated brine twice, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 4.03 g of the resultant residue was subjected to silica gel column chromatography, to obtain 3.16 g of ethyl (5-chloro-3-fluoro-2-pyridyl)acetate.
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([O:14][P:15](COS(C(F)(F)F)(=O)=O)([O:17]CC)=[O:16])C.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[P:15]([C:10]1[CH:11]=[CH:2][CH:3]=[CH:4][C:5]=1[C:6]([O:8][CH3:9])=[O:7])([OH:17])([OH:16])=[O:14]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCOP(=O)(COS(=O)(=O)C(F)(F)F)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1P(=O)(O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 139.8 %

Procedure:
A solution of methyl 4-hydroxybenzoate 111 (0.977 g, 6.42 mmol) and trifluoro-methanesulfonic acid diethoxy-phosphorylmethl ester (2.12 g, 7.06 mmol) in THF (50 mL) was treated with Cs2CO3 (4.18 g, 12.84 mmol). The resulting reaction mixture was stirred for 1 h at room temperature before it was partitioned between EtOAc and sat. aqueous NH4Cl and extracted with EtOAc (3×). The organic phase was washed with brine, dried over Na2SO4, and evaporated under reduced pressure. Purification of the crude product on silica gel (eluted with 60-90% EtOAc/hexane) provided 1.94 g (quantitative) of methyl phosphonobenzoate compound 112 as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:19]=[C:18]([NH:20]CC4C=CC(OC)=CC=4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:19]=[C:18]([NH2:20])[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(CNc2cc3c(Nc4ccc(Cl)c(Cl)c4)ncnc3cn2)cc1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cn1
Temperature: 25 °C
Reaction time: 43 h
Yield: 98.1 %

Procedure:
To a stirred heterogeneous mixture of compound 213 (2.50 g, 5.86 mmol) and DCM (60 ml) was added trifluoroacetic acid (4.49 ml, 58.6 mmol), followed by anisole (1.28 mL, 11.7 mmol), and the mixture was stirred further at room temperature for 43 h. It was poured into petroleum ether (600 mL) and stirred at room temperature for ca. 20 min. Petroleum ether layer was decanted and discarded. The process was repeated with more petroleum ether (300 mL). To the solid left behind was added 5M NH3 (80 mL) at 0° C. and stirred at room temperature for 15 min. The solid was collected and washed successively with water (6×10 mL), petroleum ether-ethyl acetate=3:1 (3×20 mL), and dried to give N4-(3,4-dichlorophenyl)pyrido[3,4-d]pyrimidine-4,6-diamine (222) (1.76 g, 98%), mp 277-280° C.; 1H NMR δ [(CD3)2SO] 9.83 (s, 1H), 8.73 (s, 1H), 8.42 (s, 1H), 8.34 (d, J=2.5 Hz, 1H), 7.92 (dd, J=8.8, 2.5 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.14 (s, 1H), 6.30 (s, 2H). Anal. Calcd for C13H9Cl2N5.0.5H2O: C, 49.54; H, 3.20; N, 22.22. Found C, 49.70; H, 3.08; N, 22.28.
Reaction SMILES: [K].[CH2:2]([C:6]1[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:8]([CH2:12][OH:13])=[C:9]([Cl:11])[N:10]=1)[CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[C:39](Cl)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl.O>[CH2:2]([C:6]1[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:39]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:8]([CH2:12][OH:13])=[C:9]([Cl:11])[N:10]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 90.9 %

Procedure:
To a solution of 0.600 g of 2-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol mono potassium salt in 40 ml of methylene chloride is added 0.218 ml of triethylamine and 0.381 g of trityl chloride. The solution is heated at reflux for 8 hours, cooled and diluted with 30 ml of water. The organic layer is separated and the aqueous layer extracted with methylene chloride. The combined extracts are washed with water, dried with potassium carbonate, filtered and concentrated in vacuo to give 0.785 g of the desired product as a solid. FAB MASS SPEC 665(M+H).
Reaction SMILES: [CH2:1]([O:8][N:9]([C:21](=[O:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:10]1[N:20]=[CH:19][CH:18]=[CH:17][C:11]=1[C:12]([O:14]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]CC.[Na+]>C(O)C>[CH2:1]([O:8][N:9]1[C:10]2[C:11](=[CH:17][CH:18]=[CH:19][N:20]=2)[C:12]([OH:14])=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:21]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)N(OCc1ccccc1)c1ncccc1C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(O)c2cccnc2n(OCc2ccccc2)c1=O
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
A solution of the product of Example 157B (0.386 g, 1.0 mmol) in ethanol (5 mL) was treated with 21% sodium ethoxide in ethanol (0.324 g, 1.0 mmol), stirred for 30 minutes and partitioned between ethyl acetate and 5% aqueous HCl and the layers were separated. The ethyl acetate layer was washed with brine, dried (Na2SO4), and concentrated to provide the title compound (0.28 g, 82%). MS (DCI) m/z 341(M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:20])[CH:12]([NH2:19])[CH2:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[S:8][CH:9]=1)=[O:4].C(OC(N[C@H](C1C=CC=CC=1)C(O)=O)=O)(C)(C)C.COC(C1N=C(NC(=O)[C@@H](N)CC2C=CC=CC=2)SC=1)=O.C(OC(N[C@@H](CC1SC=CN=1)C(O)=O)=O)(C)(C)C>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:20])[C@@H:12]([NH2:19])[CH2:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)C(N)Cc2nccs2)n1
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1nccs1)C(=O)O
Agent: COC(=O)c1csc(NC(=O)[C@@H](N)Cc2ccccc2)n1
Product: COC(=O)c1csc(NC(=O)[C@@H](N)Cc2nccs2)n1

Procedure:
Prepared as described in example 10 except that (R)—N-(tert-butyloxycarbonyl)-4-methyoxyphenylglycine and 2-(2-amino-3-thiazol-2-yl-propionylamino)-thiazole-4-carboxylic acid methyl ester were used in place of (R)-tert-butoxycarbonylamino-phenylacetic acid and 2-((S)-2-amino-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester respectively in step 1. 2-((S)-2-Amino-3-thiazol-2-yl-propionylamino)-thiazole-4-carboxylic acid methyl ester was prepared as described in example 3 except that (S)-2-tert-butoxycarbonylamino-3-thiazol-2-yl-propionic acid was used in place of (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid in step 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](=O)[C:8]2=O.COC1C=CC=C2C=1CCCC2=O.[Se](=O)=O.C(O)(=O)C.C(O)(=O)C.[NH2:39][C:40]1[C:48]([NH2:49])=[CH:47][CH:46]=[CH:45][C:41]=1[C:42]([OH:44])=[O:43].Cl>C(O)C>[CH3:1][O:2][C:3]1[C:4]2=[CH:5][CH:6]=[C:7]3[C:8]([N:39]=[C:40]4[C:48]([CH:47]=[CH:46][CH:45]=[C:41]4[C:42]([OH:44])=[O:43])=[N:49]3)=[C:9]2[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc2c1C=CC(=O)C2=O
Reactant: Nc1cccc(C(=O)O)c1N
Agent: COc1cccc2c1CCCC2=O
Agent: Cl
Agent: O=[Se]=O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cccc2c1ccc1nc3cccc(C(=O)O)c3nc12

Procedure:
A mixture of 5-methoxy-[1,2]naphthoquinone (prepared by treatment of 5-methoxytetralone with selenium dioxide, A. Bekaert et al Tetrahedron Letters 38, 24, 4219–4220, 1997) (1.98 g), 2,3-diamino-benzoic acid, diacetate salt, (J. Chem. Soc. Perkin. Trans I, 1984, p2019) (4.03 g) and conc. hydrochloric acid (2.2 mL) was heated to reflux in ethanol (20 mL) for 4 hours. The reaction mixture was cooled and the precipitate collected by filtration, and washed with ethanol and ether to yield the title compound as a beige solid (2.74 g).