Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17]2[N:21]=[C:20]([CH2:22][N:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)[O:19][N:18]=2)=[O:8])=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:21]=[C:20]([CH2:22][N:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]3)[O:19][N:18]=2)[N:9]([C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:2][CH:3]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](c2noc(CN3CCN(C(=O)OC(C)(C)C)CC3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CON=C1C[C@@H](c2noc(CN3CCNCC3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 85 %

Procedure:
tert-butyl 4-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)-1-piperazinecarboxylate (100 mg, 1.80 mmol) was treated with a 25% TFA/DCM solution at 0° C. for 1 hour. The reaction was then made basic with a sodium carbonate solution (10%) and extracted with DCM. The organic phases were combined and dried over magnesium sulfate and solvent removal afforded a residue, which was purified by flash-chromatography using dichloromethane/methanol as eluent to give the desired product, (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(1-piperazinylmethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone O-methyloxime, as a mixture of E-/Z-isomers in a 85% yield (94.3% purity by HPLC).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.Cl.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])=[CH:21][CH:20]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CN1CCOCC1.[OH-].[Na+]>CO.C(Cl)(Cl)Cl>[CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:9]=[CH:10][C:11]([C:12]([N:30]2[CH2:31][CH2:32][CH:27]([C:25](=[O:26])[C:22]3[CH:21]=[CH:20][C:19]([CH3:18])=[CH:24][CH:23]=3)[CH2:28][CH2:29]2)=[O:14])=[CH:15][CH:16]=1
Reactant: Cc1ccc(C(=O)C2CCNCC2)cc1
Reactant: C[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)C2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a mixture of (R)-4-(4-methyl-2-oxooxazolidin-3-yl)benzoic acid (633 mg) described in Preparation Example 37, (4-methylphenyl)piperidin-4-ylmethanone hydrochloride (719 mg) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (1.2 g) were added chloroform (3 mL), methanol (3 mL) and N-methylmorpholine (330 μL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1N aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (989 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[OH:14][CH2:15][C@@H:16]1[O:20][C:19]([C:21]2[NH:25][C:24]([C:26]3[CH:27]=[C:28]([OH:38])[CH:29]=[C:30]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])[CH:31]=3)=[CH:23][CH:22]=2)=[N:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:11]1([S:8]([C:5]2[N:6]=[CH:7][C:2]([O:38][C:28]3[CH:27]=[C:26]([C:24]4[NH:25][C:21]([C:19]5[O:20][C@@H:16]([CH2:15][OH:14])[CH2:17][N:18]=5)=[CH:22][CH:23]=4)[CH:31]=[C:30]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])[CH:29]=3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:13][CH2:12]1
Reactant: O=S(=O)(c1ccc(Cl)cn1)C1CC1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)C3CC3)nc2)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
5-Chloro-2-(cyclopropylsulfonyl)pyridine (168 mg, 0.77 mmol) synthesized in Example (125c) and 3-{5-[(5R)-5-(Hydroxylmethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenol (401 mg, 1.16 mmol) synthesized in Example (125g) were dissolved in N,N-dimethylformamide (2 mL), and potassium carbonate (213 mg, 154 mmol) was added, followed by stirring at 100° C. for 3 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (30 mL) was added, and extraction was carried out twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0.5%-5%) to afford the desired compound (139 mg, yield 34%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:9].C1([Si](C2C=CC=CC=2)(C2C=CC=CC=2)[O:17][C:18]2[C:19]#[C:20][CH:21]=[CH:22][CH:23]=2)C=CC=CC=1>>[OH:17][C:18]1[CH:23]=[C:22]([CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[C:3]2=[O:9])[CH:21]=[CH:20][CH:19]=1
Reactant: CN1CCCCCC1=O
Reactant: c1cccc(O[Si](c2ccccc2)(c2ccccc2)c2ccccc2)c#1
Product: CN1CCCCC(c2cccc(O)c2)C1=O

Procedure:
Following the procedure of Example 3, reaction of the lithium anion of N-methylcaprolactam with m-triphenylsiloxybenzyne (from o-chlorotriphenylsilyloxybenzene and lithium tetramethylpiperidide) followed by workup with aqueous acid gives the title compound m.p. 192°-3° C. (ethylacetate).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:12][C:13](=[O:27])[C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:29][CH2:30][C@@H:31]([C:33]1[CH:34]=[CH:35][C:36]([OH:44])=[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:38]=1)[OH:32]>>[CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:12][C:13](=[O:27])[C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:25][CH2:24][CH:23]([NH:29][CH2:30][C@H:31]([OH:32])[C:33]3[CH:34]=[CH:35][C:36]([OH:44])=[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:38]=3)[CH2:22][CH2:21]2)=[CH:18][CH:19]=1)[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from (2S)-2-[4-(4-oxo-piperidine-1-yl)-benzoylamino]-3-phenyl-propionic acid methyl ester(which was obtained in Example 164) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 180 as an off-white solid; mp >98° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.80-1.90 (m, 2H), 2.05-2.90 (m, 5H), 2.91 (s, 3H), 3.00-3.20 (m, 2H), 3.70-3.80 (m, 2H), 4.47 (dd, J=8.0, 4.3 Hz, 1H), 4.50-4.65 (m, 1H), 6.81 (d, J=8.2 Hz, 1H), 6.92 (d, J=8.9 Hz, 2H), 7.00 (dd, J=8.2, 2.0 Hz, 1H), 7.10-7.30 (m, 6H), 7.67 (d, J=8.9 Hz, 2H), 8.47 (d, J=7.8 Hz, 1H); MS (ES) m/z: 611.2 (MH+); HRMS Calcd. for C31H39N4O7S(MH+): 611.2534. Found: 611.2525.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1.[CH3:24][Si:25]([CH3:28])([CH3:27])Cl>O1CCCC1.CCCCCC>[CH3:24][Si:25]([CH3:28])([CH3:27])[O:22][C:21]([O:23][Si:25]([CH3:28])([CH3:27])[CH3:24])=[CH:20][C:17]1[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][CH:18]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)OC(=Cc1ccc(Cl)cc1)O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A cooled (0°-5° C.) solution of 41.4 g (0.41 mol) of diisopropylamine in 300 ml of tetrahydrofuran was treated slowly with butyllithium in hexane (250 ml of a 1.6 M solution, 0.4 mol). A solution of 34.12 g (0.2 mol) of p-chlorophenylacetic acid in 200 ml of tetrahydrofuran was added dropwise and the reaction mixture was stirred 30 minutes at 0° C. Trimethylchlorosilane (100 g) was added and the mixture was allowed to warm to room temperature and was stirred for 1.5 hours. The contents of the flask were filtered under nitrogen and the filtrate was evaporated under reduced pressure. The residue was dissolved in 80 ml of diethyl ether; the solution was filtered and the filtrate was evaporated. The resultant residue was distilled in a Vigreux column, maintaining the pot temperature below 130° C. to prevent decomposition of the product. The product β,β-bis(trimethylsiloxy)p-chlorostyrene, 32.56 g (52% yield), was obtained as a colorless liquid, bp 110° C. (0.1 mm); 1H NMR (CDCl3) δ7.0-7.4 (m, 4H), δ4.52 (s, 1H); δ0.22 (s) and δ0.26 (s) together 18H. The moisture sensitive product was stored under nitrogen.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([CH3:9])=[N:6][C:7]=1[NH2:8].O.[CH:21]([CH:23]=O)=O.C1(C)C=CC=CC=1>O>[CH2:16]([NH:15][C:3]1[C:2]2[C:7](=[N:8][CH:21]=[CH:23][N:1]=2)[N:6]=[C:5]([CH3:9])[C:4]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCNc1c(N)c(N)nc(C)c1C(=O)OCC
Reactant: O=CC=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCNc1c(C(=O)OCC)c(C)nc2nccnc12
Reaction time: 3 h
Yield: 70 %

Procedure:
13.3 g. of 5,6-Diamino-4-butylamino-2-methylpyridine-3-carboxylic acid, ethyl ester (0.05 Mol.) of Example 1 d and 4g. of glyoxal monohydrate, dissolved in 100 ml. of toluene, are refluxed, while the water formed is removed by means of a water separator. After about 3 hours, the reaction is complete and the solution is concentrated. The remaining oily residue is extracted twice with 50 ml. portions of gasoline and addition of activated charcoal. The gasoline extracts are cooled and the crystalline 8-butylamino-6-methylpyrido[2,3-b]pyrazine-7-carboxylic acid, ethyl ester is filtered off, yield 70%; m.p. 56°-58°.
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([CH2:15][CH2:16][CH:17]([OH:21])[CH:18]([CH3:20])[CH3:19])=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[F:22][C:23]1[CH:24]=C(N)[CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[F:22][C:23]1[CH:24]=[C:14]([N:12]2[C:3](=[O:4])[C:5]3[S:6][C:7]([CH2:15][CH2:16][CH:17]([OH:21])[CH:18]([CH3:19])[CH3:20])=[CH:8][C:9]=3[N:10]=[CH:11]2)[CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH2:31][N:32]1[CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: COC(=O)c1sc(CCC(O)C(C)C)cc1N=CN(C)C
Reactant: Nc1ccc(OCCN2CCCC2)c(F)c1
Product: CC(C)C(O)CCc1cc2ncn(-c3ccc(OCCN4CCCC4)c(F)c3)c(=O)c2s1

Procedure:
3-(Dimethylaminomethyleneamino)-5-(3-hydroxy-4-methylpentyl)thiophene-2-carboxylic acid methyl ester was reacted with 3-fluoro-4-(2-pyrrolidin-1-ylethoxy)phenylamine by method A. The product with the molecular weight of 459.58 (C24H30FN3O3S) was obtained in this way; MS (ESI): 460 (M+H+).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)[CH:22]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[CH:28]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1cccc(-c2cccnc2)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2cccnc2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 3-(pyridin-3-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.61 min.; [M+H]+: 403.00 g/mol.
Reaction SMILES: O[CH2:2][C:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:12])([CH3:11])[CH3:10])[CH2:5][CH:4]=1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[OH:12][C:9]([CH:6]1[CH2:7][CH2:8][C:3]([CH2:2][N:17]2[C:13](=[O:23])[C:14]3[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16]2=[O:18])=[CH:4][CH2:5]1)([CH3:11])[CH3:10]
Reactant: CC(C)(O)C1CC=C(CO)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: CC(C)(O)C1CC=C(CN2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Yield: 55.9 %

Procedure:
To a stirred solution of 2-(4-Hydroxymethyl-cyclohex-3-enyl)-propan-2-ol (5.765 grams, 34.270 mmole), Phthalimide (6.50 grams, 44.208 mmole), and triphenyl phosphene (11.60 grams, 44.208 mmole) in tetrahydrofuran (200 ml) at room temperature was added DIAD (9.010 grams, 44.552 mmole) dropwise, and the peach mixture was stirred at room temperature over night. The mixture was quenched with 150 ml water and extracted with 2×100 ml ethyl acetate. It was then concentrated to a yellow residue. This was taken up in diethyl ether, diluted with hexane, chilled and filtered. The crude product was purified via flash chromatography on silica using 50% ethyl acetate/hexane as eluent to give a yellow gum (5.73 g). MW 299.373; MS (m/e) 279 (M+−18).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[OH:18])[C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.N1(C(OC(C)(C)C)=O)CCNCC1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]3[O:18][C:9]2=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(c1cccc(Cl)c1)C1CCCCC1O
Agent: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1OC2CCCCC2C1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (3-chlorophenyl)(2-hydroxycyclohexyl)acetic acid (Reference Example 2-d) (1.25 g, 4.66 mmol), benzotriazol-1-yloxytris(dimethylaminop)phosphonium hexafluorophosphate (3.1 g, 7.0 mmol), and tert-butyl 1-piperazinecarboxylate (0.87 g, 4.66 mmol) in methylene chloride (12 mL) was treated with triethylamine (0.98 mL, 7.0 mmol). The reaction was stirred at 25° C. for 16 h, after which time the solvent was removed in vacuo and the product was purified via Biotage Horizon (FLASH 40 M, silica, gradient from 0% EtOAc/hexane to 25% EtOAc/hexane) to yield 0.97 g (83%) the lactone, 3-(3-chlorophenyl)hexahydro-1-benzofuran-2(3H)-one as a clear oil. HRMS: calcd for C14H15ClO2+H, 251.0861. found (ESI, [M+H]+), 251.0844.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[CH:12][C:11]2[N:10]([CH2:14][CH:15]([OH:22])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:9]3[CH2:23][CH2:24][N:25]([CH3:27])[CH2:26][C:8]=3[C:7]=2[CH:6]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:2][CH2:3][C:5]1[CH:13]=[CH:12][C:11]2[N:10]([CH2:14][CH:15]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[OH:22])[C:9]3[CH2:23][CH2:24][N:25]([CH3:27])[CH2:26][C:8]=3[C:7]=2[CH:6]=1
Reactant: COC(=O)c1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCN(C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCc2c(c3cc(CO)ccc3n2CC(O)c2ccncc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(2-hydroxy-2-pyridin-4-yl-ethyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylic acid methyl ester (180 mg, 0.493 mmol) in dry THF (12 mL) was portionwise added LAH (56 mg, 1.479 mmol) under nitrogen atmosphere, and the reaction mixture stirred at RT for 2 h. The reaction mixture was cooled to −78° C. and quenched with ice water (0.6 mL), 10% NaOH (0.6 mL) and water (1.8 mL), and the solid filtered. The filtrate was concentrated and the residue was purified by reverse phase HPLC to yield 2-(8-hydroxymethyl-2-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol. 1H NMR (CD3OD, freebase) δ (ppm): 8.4 (d, 2H), 7.4 (s, 1H), 7.27-7.38 (m, 3H), 7.18 (d, 1H), 5.1 (t, 1H), 4.62 (s, 2H), 4.3 (d, 2H), 4.0 (dd, 2H), 3.2 (m, 1H), 3.1 (m, 2H), 2.73 (m, 1H), 2.7 (s, 3H). Separation by chiral HPLC provides enantiomers II-60a-b.
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>COCCOC>[C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[C:10]1[C:11]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: C1COCCN1
Reactant: Cc1cc2nc(OS(=O)(=O)C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Solvent: COCCOC
Product: Cc1cc2nc(N3CCOCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 80 °C

Procedure:
A mixture of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate (12 mg, prepared as in Example 26) and morpholine (0.2 mL) in DME was heated at 80° C. for 12 hours. Concentration in vacuo gave (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethyl pivalate (15 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C31H40ClN2O4: 539.3. Found: 539.4.
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: CC(C)NC(=O)c1cccnc1N
Reactant: O=C=O
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 stoichiometric 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: C(O[C:4]([C:6]1[NH:7][N:8]=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1)=O)C.C(OC(=O)[NH:25][CH2:26][CH:27](O)[CH3:28])(C)(C)C.C(OC(C1N(CC(NC(OC(C)(C)C)=O)C)N=C(COC2C=CC=CC=2)C=1)=O)C.CC1CN2N=C(COC3C=CC=CC=3)C=C2C(=O)N1.CC1CN2N=C(COC3C=CC=CC=3)C=C2CN1>>[CH3:28][CH:27]1[N:7]2[N:8]=[C:9]([CH2:11][O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:10]=[C:6]2[CH2:4][NH:25][CH2:26]1
Reactant: CC(O)CNC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Agent: CC1Cn2nc(COc3ccccc3)cc2C(=O)N1
Agent: CC1Cn2nc(COc3ccccc3)cc2CN1
Agent: CCOC(=O)c1cc(COc2ccccc2)nn1CC(C)NC(=O)OC(C)(C)C
Product: CC1CNCc2cc(COc3ccccc3)nn21

Procedure:
The compound was prepared from 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester and rac-2-hydroxy-propyl-carbamic acid tert-butyl ester using the methods described in the preceding examples 11 (rac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester), 12 (rac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one), and 13 (rac-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine).
Reaction SMILES: Br[C:2]1[C:3]([C:11]#[N:12])=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>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>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[C:2]1[C:3]([C:11]#[N:12])=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: N#Cc1cc2nccn2cc1Br
Reactant: OB(O)c1ccc(Cl)cc1Cl
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: [Na+]
Solvent: CCOC(C)=O
Product: N#Cc1cc2nccn2cc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 38.2 %

Procedure:
A mixture of 6-bromo-imidazo[1,2-a]pyridine-7-carbonitrile (1.5 g, 6.8 mmol), 2,4-dichloro-benzeneboronic acid (1.9 g, 10.1 mmol), Pd(PPh3)4 (390 mg, 0.34 mmol) and Na2CO3 (2.0 M solution in water, 12 mL) in OME (30 mL) was refluxed for 14 h under an inert atmosphere of argon. The reaction mixture was cooled to RT, diluted in AcOEt (200 mL) and washed with water (200 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by Combi-Flash Companion™ (isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→1:1) to yield the title compound (750 mg, 2.6 mmol, 39%) as an orange foam. MS. 289 [M+1]+; HPLC: AtRet=1.50; TLC: RF 0.16 ([hexane/DCM 1:1]/TBME 3:7).
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22]>CN(C=O)C>[OH:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1
Reactant: Nc1ccccc1O
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Nc2ccccc2O)[nH]c1=O
Temperature: 110 °C
Reaction time: 18 h
Yield: 56.4 %

Procedure:
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (40 g) and 2-aminophenol (22.4 g) are added to DMF (80 ml), and the mixture is heated with stirring at 110° C. for 18 hour. After cooling, the precipitate is collected by filtration and recrystallized from DMF to give ethyl 1,6-dihydro-2-(2-hydroxyanilino)-6-oxo-5-pyrimidinecarboxylate (29 g). M.p. 289°-291° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[CH3:11][NH2:12]>C1COCC1>[CH3:11][NH:12][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: CN
Reactant: N#Cc1cccc(CBr)c1
Solvent: C1CCOC1
Product: CNCc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.4 %

Procedure:
In a 3 necked round bottom flask (250 ml), put under nitrogen atmosphere, a solution of 3-(bromomethyl)benzonitrile (5 g; 25.5 mmol; 1 eq.) in anhydrous THF (20 ml) was added dropwise into methylamine (63.76 ml; 2 M; 127.52 mmol; 5 eq.) (2M solution in THF) over 1 hour. The reaction mixture was stirred at RT for 2 hours. Some bis-benzylation was observed (7%). The reaction mixture was filtered to remove the salt. The filtrate was evaporated under reduced pressure. The residue was taken up with DCM and evaporated again to give the title compound as a yellow oil (3.78 g, quantitative yield). It was used in the next step without any further purification. LC/MS (Method B) 146.8 (M+H)+.