Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][NH:22][CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C=O.[C:46](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CO>[CH3:46][N:22]1[CH2:23][C@@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C@H:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:21]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CNC[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(C)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 97.4 %

Procedure:
Compound 1 (4.00 g, 6.67 mmol) obtained in Example 1 was dissolved in 1,2-dichloroethane (50 mL) and methanol (50 mL), and stirred at room temperature for 1 hour after adding formaldehyde (4.96 mL, 66.7 mmol) and sodium triacetoxyborohydride (Acros Organics; 7.06 g, 33.3 mmol). The reaction mixture was further stirred at room temperature for 2.5 hours after adding sodium triacetoxyborohydride (Acros Organics; 7.06 g, 33.3 mmol). The aqueous layer was extracted with ethyl acetate after adding a saturated sodium bicarbonate aqueous solution to the reaction solution. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure after filtration. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 95/5) to give compound 10 (3.99 g, 97.4%).
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][NH:8][C:9]([C:11]1[C:16]([OH:17])=[CH:15][C:14]([OH:18])=[CH:13][N:12]=1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:17][C:16]1[C:11]([C:9]([NH:8][CH2:7][C:6]([OH:19])=[O:5])=[O:10])=[N:12][CH:13]=[C:14]([OH:18])[CH:15]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ncc(O)cc1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)c1ncc(O)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
To a solution of [(3,5-dihydroxy-pyridine-2-carbonyl)-amino]-acetic acid tert-butyl ester, 28, (0.10 g, 0.37 mmol) in CH2Cl2 (4 mL) at room temperature is added trifluoroacetic acid (1 mL). The reaction is stirred for 16 hours at room temperature and then concentrated under reduced pressure. The solid that remains is collected by filtration, washed with Et2O to afford 0.070 g (89% yield) of the desired compound as a colorless solid. 1H NMR (250 MHz, DMSO-d6) δ ppm 10.86 (1H, br s), 9.00 (1H, t, J=6.1 Hz), 7.77 (1H, d, J=2.4 Hz), 6.69 (1H, d, J=2.4 Hz), 3.95 (1H, d, J=6.2 Hz). HPLC-MS: m/z 213 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[N:9]=1)[CH2:2][CH2:3][CH3:4].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:27]2[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[CH:43]=[CH:42][C:41]([CH2:44]Br)=[CH:40][CH:39]=3)=[N:30][N:29]=[N:28]2)C=CC=CC=1>>[CH2:1]([C:5]1[N:6]([CH2:44][C:41]2[CH:42]=[CH:43][C:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[C:31]3[NH:27][N:28]=[N:29][N:30]=3)=[CH:39][CH:40]=2)[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-n2cccc2)c(C(=O)OCC)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCc1nc(-n2cccc2)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Using the method described in Example 15, ethyl 2-butyl-4-(1H-pyrrol-1-yl)imidazole-5-carboxylate (Example 21) and N-triphenylmethyl-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole (Example 12) are reacted and deprotected to give the title compound.
Reaction SMILES: Cl[C:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[O:4][N:3]=1.[CH3:9][S-:10].[Na+].O>CN(C=O)C>[CH3:9][S:10][C:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[O:4][N:3]=1
Reactant: CC1(C)CC(Cl)=NO1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSC1=NOC(C)(C)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.8 %

Procedure:
To a solution of 193.0 g (1.07 M) of 3-chloro-5,5-dimethyl-2-isoxazoline dissolved in 500 ml of DMF was dropwise added, with ice-cooling, 1.0 kg (content=15%, 2.14 M) of an aqueous sodium methanethiolate solution. The mixture was stirred at room temperature for 12 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic phase was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 115.0 g (yield: 74.1%) of 3-methylthio-5,5-dimethyl-2-isoxazoline. This residue (141.2 mmoles) was dissolved in 1 liter of chloroform. Thereto was added, with ice-cooling, 392.0 g (1.59 M) of m-chloroperbenzoic acid (purity: 70%), followed by stirring at that temperature for 1 hour and at room temperature for 12 hours to give rise to a reaction. After the completion of the reaction, the precipitated m-chloroperbenzoic acid was removed by filtration. The filtrate was washed with an aqueous sodium hydrogensulfite solution, water, an aqueous sodium hydrogencarbonate solution and an aqueous sodium chloride solution in this order, and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was washed with diisopropyl ether to obtain 77.6 g (yield: 59.1%) of 3-methylsulfonyl-5,5-dimethyl-2-isoxazoline as a white powder (melting point: 82 to 84° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH2:16][CH3:17])[NH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[H-].[Na+].I[CH3:21]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH2:16][CH3:17])[N:13]([CH3:21])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CCc1cc(Nc2cc(Br)cn(C)c2=O)n[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc(Nc2cc(Br)cn(C)c2=O)nn1C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
To a mixture of 122a (598 mg, 2.0 mmol) in DMF (10 mL) was added NaH (64 mg, 1.6 mmol) at 0° C. and the mixture was stirred for 0.5 h. To the mixture was added iodomethane (227 mg, 1.6 mmol) in DMF dropwise at 0° C. The mixture was stirred for 0.5 h and quenched with water (20 mL). It was then extracted with dichloromethane (3×30 mL). The combined extract was concentrated under reduced pressure and the residue was purified with silica-gel column chromatography eluting with petroleum ether/ethyl acetate (5:1 to 2:1) to afford 122b (360 mg, 58%) as a light yellow solid. MS-ESI: [M+H]+ 311.1
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl[CH2:21]Cl.C[Si](C=[N+]=[N-])(C)C>CO.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([O:19][CH3:21])=[O:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: ClCCl
Reactant: O=C(O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a stirred suspension of the 1-(4-fluorophenyl)-1H-indazole-5-carboxylic acid (0.22 g, 0.81 mmol) in methanol (5 mL), THF (5 mL), and dichloromethane (5 mL) was added (trimethylsilyl)diazomethane solution (2M in diethyl ether, 1 mL, 2 mmol) dropwise at rt. The reaction mixture was stirred at rt for 1 hr and carefully quenched by the slow addition of acetic acid. Concentration under reduced pressure and titration with methanol gave methyl 1-(4-fluorophenyl)-1H-indazole-5-carboxylate (0.16 g, 0.59 mmol, 73% yield) as a white solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][S:18](O)(=[O:20])=[O:19]>ClCCl>[Cl:17][S:18]([C:5]1[CH:4]=[CH:3][C:2]([CH2:1][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:7][CH:6]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(O)Cl
Reactant: O=[N+]([O-])c1ccc(Cc2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Cc2ccc(S(=O)(=O)Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
A solution of 4-benzyl-nitrobenzene (4.26 g, 70 mmol) dissolved in dichloromethane (25 mL) was added dropwise to a solution of chlorosulfonic acid (6 mL) in dichloromethane (25 mL) at −30° C. The mixture was stirred for 10 minutes at 0° C., then poured onto ice and shaken. The organic phase was separated and solvents were evaporated. The residue was recrystallized from dichloromethane/hexanes to yield 4-(4-chlorosulfonylbenzyl)-nitrobenzene (5.52 g, 78%) as dichloromethane hemisolvate crystals.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:9]([CH:11]=O)[NH:10][C:6]=2[CH2:5][CH2:4][NH:3]1.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[NH:29][C:30](=[O:33])[CH2:31][OH:32])[NH:25][C:24](=[O:34])[CH2:23]2>>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[NH:29][C:30](=[O:33])[CH2:31][OH:32])[NH:25][C:24](=[O:34])[C:23]2=[CH:11][C:9]1[NH:10][C:6]2[CH2:5][CH2:4][NH:3][C:2](=[O:1])[C:7]=2[C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1[nH]c2c(c1-c1ccccc1)C(=O)NCC2
Reactant: O=C(CO)Nc1cc2c(cc1F)CC(=O)N2
Product: O=C(CO)Nc1cc2c(cc1F)C(=Cc1[nH]c3c(c1-c1ccccc1)C(=O)NCC3)C(=O)N2
Yield: 92 %

Procedure:
The title compound was prepared under the same conditions as described in Example 41 with 4-oxo-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-acetamide as starting materials to give N-[5-fluoro-2-oxo-3-(4-oxo-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene)-2,3-dihydro-1H-indol-6-yl]-2-hydroxy-acetamide (39 mg, 92%) as a red solid.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:30]([O:32]C)=[O:31])[CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([Br:29])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:34]=[CH:35][CH:36]=[CH:37][C:6]=2[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:30]([OH:32])=[O:31])[CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([Br:29])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:34]=[CH:35][CH:36]=[CH:37][C:6]=2[NH:5]1
Reactant: COC(=O)[C@@H](Cc1ccc(C)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 70 mg (2.92 mmol) LiOH in 5 mL water was added to a solution of 1.0 g (1.84 mmol) of (R)-2-(3-bromo-4-methyl-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 20 mL THF and the reaction mixture was stirred for 5 h at RT. The reaction solution was evaporated down i.vac., the residue was combined with DCM, the organic phase was washed with 1 M KHSO4 solution and dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was triturated with DIPE, suction filtered and dried.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:12]([CH2:23][CH3:24])=[N:11][CH:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[C:3]([C:9]2[CH:10]=[N:11][C:12]([CH2:23][CH3:24])=[C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:14]=2)=[CH:4][C:5]([NH:25][C@H:26]2[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28][CH2:27]2)=[N:6][CH:7]=1
Reactant: CCc1ncc(-c2cc(F)ncc2Cl)nc1NCC1CCOCC1
Reactant: NC1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCc1ncc(-c2cc(N[C@H]3CC[C@H](N)CC3)ncc2Cl)nc1NCC1CCOCC1
Temperature: 100 °C
Reaction time: 17 h

Procedure:
6-(5-chloro-2-fluoropyridin-4-yl)-3-ethyl-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazine-2-amine (0.0053 g, 0.015 mmol) was dissolved in DMSO (1 ml). This was treated with 1,4-diaminocyclohexane (0.017 g, 0.151 mmol). The reaction mixture was then heated at 100° C. for 4 hr. Additional 1,4-diaminocyclohexane (0.017 g, 0.151 mmol) and triethylamine (0.0084 ml, 0.012 g, 0.060 mmol) were added. Heating at 100° C. was continued for 17 hr. The reaction mixture was purified using prep HPLC. The material was purified by preparative reverse-phase HPLC to give 0.0040 g of trans-N1-(5-chloro-4-(5-ethyl-6-((tetrahydro-2H-pyran-4-yl)methyl)aminopyrazin-2-yl)pyridin-2-yl)cyclohexane-1,4-diamine as the TFA salt. LCMS (m/z): 445.2 (MH+), retention time=0.54 min.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[OH:16])[NH:12][N:11]=[C:10]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1)=[O:6]>O1CCOCC1>[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[OH:16])[NH:12][N:11]=[C:10]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1)([OH:6])=[O:4]
Reactant: COC(=O)c1cc2c(Cc3cccc(C)c3)n[nH]c2cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cccc(Cc2n[nH]c3cc(O)c(C(=O)O)cc23)c1

Procedure:
4.5 4.23 ml of 2 N NaOH are added to a solution of 523 mg of “4d” in 10 ml of dioxane, and the mixture is heated under reflux for 1.5 hours. The mixture is subjected to conventional work-up, giving 386 mg of 5-carboxy-6-hydroxy-3-(3-methylbenzyl)-1H-indazole (“4e”).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[C:18]([CH3:25])[CH:17]=1>ClCCl>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[O:21])=[C:18]([CH3:25])[CH:17]=1
Reactant: Cc1cc(Cl)ccc1C(=O)Cl
Reactant: O=C1CNCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)ccc1C(=O)N1CCNC(=O)C1
Reaction time: 0.5 h

Procedure:
2-piperazinone (0.701 g, 7 mmol, commercially available from e.g. Sigma-Aldrich) was dissolved in dichloromethane (DCM) (30 mL), and to this was added triethylamine (1.171 mL, 8.40 mmol). The solution was then cooled to 0° C. before 4-chloro-2-methylbenzoyl chloride (I55) (1.456 g, 7.70 mmol) in Dichloromethane (DCM) (5 mL) was added dropwise. The solution was stirred, under argon, for 30 minutes before the solvent was evaporated in vacuo. The remaining residue was then dissolved in DCM (40 mL) and the solution was washed with water (20 mL), a saturated solution of sodium bicarbonate (20 mL) and brine (20 mL). The organic phase was then dried over anhydrous sodium sulphate, and the solid sodium sulphate was then filtered off. The solvent was then evaporated in vacuo, and the remaining solid was stirred in hexane, at 55° C., for 30 minutes. The solid was then filtered off and the remaining solid was further purified by flash chromatography (Biotage SP4, 40S cartridge) with a gradient of 0-10% MeOH in DCM. TLC confirmed product location and the solvent from the combined fractions was evaporated in vacuo to yield the product in 0.798 g.
Reaction SMILES: [C:1](=[O:3])=O.[NH2:4][C:5]1[N:16]=[CH:15][CH:14]=[CH:13][C:6]=1[C:7]([NH:9][CH:10]([CH3:12])[CH3:11])=[O:8].C(Cl)(Cl)=O>>[CH:10]([N:9]1[C:7](=[O:8])[C:6]2[CH:13]=[CH:14][CH:15]=[N:16][C:5]=2[NH:4][C:1]1=[O:3])([CH3:12])[CH3:11]
Reactant: O=C=O
Reactant: CC(C)NC(=O)c1cccnc1N
Agent: O=C(Cl)Cl
Product: CC(C)n1c(=O)[nH]c2ncccc2c1=O

Procedure:
In addition to being useful as discussed above, acid anhydrides produced by the method of the invention are useful as intermediates for the production of pyrimidine diones which can be used as herbicides. For example, 3-azaisatoic anhydride can be dissolved in dimethylformamide and reacted with a substantially stoiciometric amount of isopropyl amine to produce 2-amino-N-isopropylnicotinamide. The reaction is conveniently conducted at a temperature of about 45°-50° until carbon dioxide evolution ceases. The 2-amino-N-isopropylnicotinamide can then be reacted with phosgene to produce 3-isopropyl pyrido[2,3-d]pyrimidine-2,4 (1H,3H)-dione. This reaction can be conducted under ambient pressure in p-dioxane as a solvent, preferably in the presence of triethylamine as an HCl absorber, at a temperature in the vicinity of 100°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=1[CH3:14])=[O:5])[CH3:2].CCN(C(C)C)C(C)C.[CH2:24]([CH2:26][NH2:27])[OH:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:25][CH2:24][CH2:26][NH:27][C:11]([C:9]1[NH:10][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([CH3:14])[CH:8]=1)=[O:13]
Reactant: CCOC(=O)c1[nH]c(C(=O)O)cc1C
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c(C(=O)NCCO)cc1C
Yield: 20.8 %

Procedure:
To a solution of 5-[(ethyloxy)carbonyl]-4-methyl-1H-pyrrole-2-carboxylic acid (0.160 g, 0.812 mmol) in DMF (4 ml) was added DIPEA (0.140 mL, 0.790 mmol). The reaction mixture was stirred and the solution was divided into four equal portions, one of which was added to a glass vial with a stir bar. To the vial was added ethanolamine (0.012 mL, 0.2 mmol) and HATU (0.075 g, 0.197 mmol) and the reaction mixture stirred overnight. Purification was accomplished by RPHPLC (water:acetonitrile with 0.1% TFA). The desired fractions were collected and lypholized to afford ethyl 5-{[(2-hydroxyethyl)amino]carbonyl}-3-methyl-1H-pyrrole-2-carboxylate (0.010 g, 48%) as an oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.63 (br. s., 1H) 8.25-8.42 (m, 1H) 6.61 (s, 1H) 4.25 (q, 2H) 3.48 (t, 2H) 3.28 (q, 2H) 2.25 (s, 3H) 1.30 (t, 3H). MS: m/z 241.4 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:45])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH:42]3[CH2:44][CH2:43]3)=[CH:39][C:40]=2[CH3:41])[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:42]1([C:38]2[N:37]=[CH:36][C:35]([C:31]3[CH:30]=[C:29]([C:27]4[CH2:26][C:25](=[O:45])[NH:24][C:9]5[CH:10]=[C:11]([C:20]([F:21])([F:22])[F:23])[C:12]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[CH:13][C:8]=5[N:7]=4)[CH:34]=[CH:33][CH:32]=3)=[C:40]([CH3:41])[CH:39]=2)[CH2:43][CH2:44]1
Reactant: Cc1cc(C2CC2)ncc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(OCC(F)(F)F)cc2NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C2CC2)ncc1-c1cccc(C2=Nc3cc(OCC(F)(F)F)c(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from [2-{3-[3-(6-cyclopropyl-4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M228) (305 mg, 0.47 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (206 mg, 82%).
Reaction SMILES: C(=O)(OC(C)(C)C)[O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:17]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:18]=[CH:19][C:14]([C:5]2[CH:4]=[C:3]([OH:2])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[N:6]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ccccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
0.5 mmol of Compound 27 prepared in Example C-1 was charged in a 25 mL round-bottom flask and dissolved in methylene chloride (5 mL) to make a solution to which trifluoroacetic acid (TFA, 5 equivalents) was then added, followed by stirring at room temperature for 30 minutes. After completion of the reaction was confirmed by TLC, the reaction liquid was washed three times with distilled water, and the organic layer was dried over anhydrous MgSO4 and concentrated to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][N:32]2[CH2:33][CH2:34][CH:29]([C:25]3[CH:24]=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:35])[CH:28]=[CH:27][CH:26]=3)[CH2:30][CH2:31]2)=[CH:8][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc(Oc2ccc(F)c(F)c2)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(Oc4ccc(F)c(F)c4)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-(3,4-difluorophenoxy)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 465.2 (M+H)+.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8](=[O:10])[CH3:9])=[CH:3][CH:2]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.[OH-].[Na+].C(OCC)C>O>[C:1]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:2]=[CH:3][C:4]([CH:7]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=2)[C:8](=[O:10])[CH3:9])=[CH:5][CH:6]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(=O)Cc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CC(=O)C(Cc1ccc(Cl)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 53.2 %

Procedure:
9.93 g of 1-(4-biphenylyl)-2-propanone, 8.4 g of 4chlorobenzyl chloride and 2.1 g of sodium hydroxide were mixed and heated for 5 hours with stirring on an oil bath of 80° to 90° C. The reaction solution was left to cool to room temperature. Then, ethyl ether and water were added thereto. The organic layer was collected by separation and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was recrystallized from hexane to obtain 8.42 g (yield: 53%) of the above-identified compound as colorless needles having a melting point of from 107 to 108.5° C.
Reaction SMILES: Br[CH2:2][C@H:3]([C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)[O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].C(=O)(O)[O-].[Na+].[NH:25]1[CH2:30][CH2:29][CH2:28][C@H:27]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:26]1>C1COCC1>[Si:5]([O:4][C@@H:3]([C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)[CH2:2][N:25]1[CH2:30][CH2:29][CH2:28][C@H:27]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:26]1)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: CCOC(=O)C[C@H]1CCCNC1
Reactant: CC(C)(C)[Si](C)(C)O[C@H](CBr)c1ccc(C#N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C[C@H]1CCCN(C[C@@H](O[Si](C)(C)C(C)(C)C)c2ccc(C#N)cc2)C1
Yield: 62.1 %

Procedure:
To a mixture of (S)-4-(2-bromo-1-(tert-butyldimethylsilyloxy)ethyl)benzonitrile (7 g, 20.57 mmol) and sodium bicarbonate (2.073 g, 24.68 mmol) in THF (100 mL) was added (R)-ethyl 2-(piperidin-3-yl)acetate (3.52 g, 20.57 mmol). The reaction was heated at reflux for 5 days and then cooled, filtered, and concentrated in vacuo. The crude product was purified on a silica gel cartridge eluting with methanol/dichloromethane gradient (0% for 5 minutes then 0-100% over 20 minutes) to afford 5.5 g of ethyl 2-((R)-1-((S)-2-(tert-butyldimethylsilyloxy)-2-(4-cyanophenyl)ethyl)piperidin-3-yl)acetate. MS (M+1)=431; HPLC RT=1.90 minutes. 1H NMR (400 MHz, CDCl3) δ ppm 7.61 (2H, d), 7.45 (2H, d), 4.76 (1H, m), 4.12 (2H, q), 2.75 (1H, m), 2.69 (1H, m), 2.52 (1H, dd), 2.33 (1H, dd), 2.18 (2H, m), 2.10 (1H, dt), 2.00 (1H, m), 1.88 (1H, tt), 1.72 (1H, m), 1.59 (2H, m), 1.25 (3H, t), 1.0 (1H, m), 0.89 (9H, s), 0.08 (3H, s), −0.07 (3H, s).