Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)Cl.[C:6]([C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])(=O)[NH2:7]>ClCCCl>[C:6]([C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])#[N:7]
Reactant: COCCOc1cc(C(N)=O)cc(C(=O)OC)c1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COCCOc1cc(C#N)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.5 %

Procedure:
POCl3 (20 mmol) was added to the solution of methyl 3-carbamoyl-5-(2-methoxyethoxy)benzoate (15 mmol) in 35 ml 1,2-dichloroethane and stirred for 5 h at reflux. Then the solution was cooled to room temperature, poured to the ice-water and extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered, and concentrated to yield methyl 3-cyano-5-(2-methoxyethoxy)benzoate (90.5%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)cc2)CC1

Procedure:
1-(tert-Butoxycarbonyl)-4-piperidone (5.00 g) and 4-chloroaniline (3.05 g) was treated in the same manner as described in Preparation Example 37 to give white powder of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:16][OH:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+].[Cl:24][C:25]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:26]=1[CH2:27]Cl.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:16][O:17][CH2:27][C:26]1[C:25]([Cl:24])=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:33])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: Cc1ccc(C(Cn2cncn2)=NO)c(Cl)c1
Reactant: ClCc1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(Cn2cncn2)=NOCc2c(Cl)cccc2Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 21.4 %

Procedure:
2 g (0.008 mol) of 1-(2-chloro-4-methylphenyl)-1-oximino-2-(1,2,4-triazol-1-yl)-ethane and 1.2 g (0.008 mol) of potassium carbonate in 8 ml of dimethylformamide were heated to 45° C. and 1.7 g (0.008 mol) of 2,6-dichlorobenzylchloride were added dropwise at that temperature. It was stirred for 12 hours at 60° C., cooled and mixed with 50 ml of water. The mixture was twice extracted with 50 ml of methylene chloride, the combined organic phases were washed with water, dried over sodium sulphate and freed of solvent. The residue which crystallized after some time was recrystallized from ethyl ether/ethyl acetate (1:1). 0.7 g (21% of theory) of 1-(2-chloro 4-methylphenyl)-1-(2,6-dichlorobenzyloximino)-2-(1,2,4-triazol-1-yl)-ethane of melting point 97°-99° C. was obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].CC(C)([O-])C.[K+]>O.CN1CCCC1=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:11][C:12]2[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: Nc1ncccc1O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Nc2ncccc2O)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 30.5 %

Procedure:
0.3 g of 4-fluoronitrobenzene, 0.468 g of 2-amino-3-hydroxypyridine, and 0.353 g of K2CO3 were added to a solution of 2.5 ml of N-methylpyrrolidinone. The reaction medium was heated at 60° C. for 1 hour and 0.286 g of potassium tert-butoxide was then added. Heating was then continued for 6 hours and, after cooling to room temperature, the reaction medium was poured into a water and ice mixture. The aqueous phase was extracted with ethyl acetate. The organic phase was dried over MgSO4 and then evaporated to dryness under vacuum. 0.15 g of 2-[(4-nitrophenyl)amino]pyrid-3-ol (3) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:18][C:19]([OH:21])=[O:20])=[O:17])[CH3:15])=[CH:10][CH:9]=1.[CH2:22](N(CC)CC)C.COC(Cl)=O>C(Cl)(Cl)Cl>[CH3:22][O:20][C:19](=[O:21])[CH2:18][S:16]([CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:9][CH:10]=1)[CH3:15])=[O:17]
Reactant: CCN(CC)CC
Reactant: CC(c1ccc(-c2ccccc2F)cc1)S(=O)CC(=O)O
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)CS(=O)C(C)c1ccc(-c2ccccc2F)cc1
Reaction time: 0.5 h

Procedure:
306 mgm (1millimol) of [1-(2'-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid and 0.15 ml of triethylamine were dissolved in 2 ml of chloroform, and 0.15 ml of chloroformic acid methyl ester was added to the solution at room temperature. After 30 minutes of standing, the mixture was washed with water, dried and evaporated, and the residue was recrystallized from 1 ml. of isopropanol. Yield: 200 mgm (62.5% of theory); m.p. 75°-78° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[C:10]([C:11]2[CH:20]=[C:19]3[C:14]([C:15]([OH:21])=[CH:16][CH:17]=[N:18]3)=[CH:13][CH:12]=2)=[C:9]([CH3:22])[O:8][N:7]=1.[C:23](O)(=[O:26])CC>>[CH3:5][C:6]1[C:10]([C:11]2[CH:20]=[C:19]3[C:14]([C:15]([OH:21])=[C:16]([N+:1]([O-:4])=[O:2])[CH:17]=[N:18]3)=[CH:13][C:12]=2[O:26][CH3:23])=[C:9]([CH3:22])[O:8][N:7]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1noc(C)c1-c1ccc2c(O)ccnc2c1
Reactant: CCC(=O)O
Product: COc1cc2c(O)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Temperature: 100 °C
Yield: 82 %

Procedure:
Nitric acid (10 ml) was added slowly to a solution of 7-(3,5-dimethyl-4-isoxazolyl)-4-quinolinol (for a preparation see Intermediate 14 (28 g, 104 mmol) in propanoic acid (450 ml) at room temperature, followed by heating the reaction mixture to 100° C. for 1 h. After cooling with an ice bath, the precipitate was filtered off, washed with pentane to give the title compound as a yellow powder (27 g, 82%). [APCI-MS] m/z: 314 [M−H]−, Rt 2.12 min. 1H NMR (300 MHz, DMSO-d6, ppm) δ: 13.06 (s, 1H), 9.26 (s, 1H), 7.84 (s, 1H), 7.67 (s, 1H), 3.98 (s, 3H), 2.39 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[O:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.O>O1CCCC1.ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:26][C:25]2[CH:24]=[CH:23][C:22]([N:19]3[CH2:20][CH2:21][O:16][CH2:17][CH2:18]3)=[CH:28][CH:27]=2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: Clc1ncc(Cl)c(Nc2ccc(N3CCOCC3)cc2)n1
Reaction time: 8 h

Procedure:
2,4,5-Trichloropyrimidine (1.05 g, 5.73 mmol) was dissolved in tetrahydrofuran (30 mL). Potassium carbonate (1.18 g, 8.55 mmol) was added, followed by 4-morpholinoaniline (1.017 g, 5.71 mmol). After stirring overnight, water (30 mL) and dichloromethane (30 mL) were added, the phases separated and the aqueous layer extracted once with dichloromethane (30 mL). The combined organic fractions were dried over sodium sulfate, concentrated onto silica gel and chromatographed (120 g SiO2, 0-60% EA:Hex). (2,5-Dichloro-pyrimidin-4-yl)-(4-morpholin-4-yl-phenyl)-amine was isolated as a yellow solid (1.29 g, 70%). m.p.=168-172° C.; LCMS (m/e) 325 (M+1); 1H-NMR (DMSO-d6, 400 MHz) δ 9.38 (s, 1H), 8.30 (s, 1H), 7.37 (d, 2H, J=9.0 Hz), 6.96 (d, 2H, J=9.0 Hz), 3.74 (t, 4H, J=4.9 Hz), 3.11 (t, 4H, J=4.9 Hz).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=2)[N:14]=1.CCN(C(C)C)C(C)C.CCOCC>CN(C=O)C>[F:20][C:18]([F:19])([F:21])[C:15]1[N:13]2[N:14]=[C:9]([N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)[CH:10]=[CH:11][C:12]2=[N:17][N:16]=1
Reactant: OC1CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: OC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 125 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
4-Hydroxypiperidine (10.91 g, 107.84 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (20 g, 89.87 mmol) and DIPEA (23.48 mL, 134.80 mmol) in DMF (200 mL). The resulting solution was stirred at 125° C. for 2 hours. The reaction mixture was evaporated to dryness, redissolved in DCM and purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to give a beige solid which was stirred with ether then filtered to afford 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (22.64 g, 88%) as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:22][C:23]2[N:28]=[C:27]([N:29](CC)[CH2:30][C:31]3C=CC(OC)=CC=3)[C:26]3=[N:41][CH:42]=[C:43]([C:44]#[N:45])[N:25]3[N:24]=2)[C:6]([F:21])=[C:7]([N:9]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:19])[O:17][CH3:18])[C@H:11]([OH:20])[CH2:10]2)[CH:8]=1)#[N:2].C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[C:1]([C:3]1[CH:4]=[C:5]([NH:22][C:23]2[N:28]=[C:27]([NH:29][CH2:30][CH3:31])[C:26]3=[N:41][CH:42]=[C:43]([C:44]#[N:45])[N:25]3[N:24]=2)[C:6]([F:21])=[C:7]([N:9]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:19])[O:17][CH3:18])[C@H:11]([OH:20])[CH2:10]2)[CH:8]=1)#[N:2]
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](O)C3)c2F)nn2c(C#N)cnc12
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCCl
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](O)C3)c2F)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.8 %

Procedure:
To methyl ((3R,4R)-1-(5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)-2-fluorophenyl)-3-hydroxypiperidin-4-yl)carbamate (60 mg, 0.098 mmol), in DCE (1.5 mL) was added ANISOLE (0.1 mL, 0.915 mmol) and TFA (1.0 mL, 12.98 mmol); the mixture stirred 2 h at 25° C. and solvent was removed. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 15-100% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min Fractions containing the desired product were combined and dried via centrifugal evaporation to afford methyl ((3R,4R)-1-(5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)-2-fluorophenyl)-3-hydroxypiperidin-4-yl)carbamate (3.8 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]=[CH:8][C:7]2=[O:14])([O-])=O>CO.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]=[CH:8][C:7]2=[O:14]
Reactant: O=c1ccoc2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc2occc(=O)c2c1
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a solution of 6-nitrochromone (2.0 g, 10.5 mmol) in Methanol/Ethyl acetate (100 mL/20 mL) purged with argon, was added 5% Pd/C (Degussa-wet, 0.5 g) catalyst. Hydrogen gas was bubbled through the slurry with stirring until (2 hrs.) LCMS and TLC showed no starting material. The spent palladium catalyst was filtered off through a celite, and the solid was washed with methanol. The combined filtrate and washings were evaporated to produce 6-amino-chromen-4-one as a light yellow solid (1.58 g, 94%). LCMS m/z (%)=162 (M+H, 100), 1H NMR (400 MHz, CDCl3) δ: 7.79-7.81 (d, J=5.96 Hz, 1H), 7.38 (d, J=2.86 Hz, 1H), 7.29-7.31 (d, J=8.88 Hz, 1H), 7.01-7.04 (dd, J=8.80, 2.8 Hz, 1H), 6.26-6.28 (d, J=5.96 Hz, 1H), 5.299 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[C:32]([O:36][C:37](=[O:44])[NH:38][C@@H:39]1[CH2:43][CH2:42][NH:41][CH2:40]1)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37](=[O:44])[NH:38][CH:39]1[CH2:43][CH2:42][N:41]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:31])([F:30])[F:29])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH2:40]1)([CH3:35])([CH3:33])[CH3:34].[NH2:38][C@@H:39]1[CH2:43][CH2:42][N:41]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:31])([F:29])[F:30])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH2:40]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Product: CC(C)(C)OC(=O)NC1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1
Product: N[C@@H]1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1

Procedure:
(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and pyrrolidin-3-(R)-yl-carbamic acid tert-butyl ester following General Procedure C. The compound was used directly following General Procedure H to provide 2-(3-(R)-Amino-pyrrolidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([B:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]2)=[CH:7][C:5]=1[NH2:6])([O-])=O.C1N=CN([C:25](N2C=NC=C2)=[O:26])C=1>C(OCC)(=O)C.C(Cl)Cl.[Pt](=O)=O>[CH3:18][C:13]1([CH3:19])[C:14]([CH3:17])([CH3:16])[O:15][B:11]([C:8]2[CH:9]=[CH:10][C:4]3[NH:1][C:25](=[O:26])[NH:6][C:5]=3[CH:7]=2)[O:12]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])c(N)c2)OC1(C)C
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
Reaction time: 0.5 h

Procedure:
A solution of 2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.35 g, 8.9 mmol) in ethyl acetate (100 mL) was treated with platinum(IV) oxide (0.2 g) and stirred vigorously under a hydrogen atmosphere for 30 minutes. The reaction mixture was degassed with nitrogen and filtered through celite washing with ethyl acetate. This solution was then treated with CDI (1.8 g, 11.1 mmol) and stirred overnight at ambient temperature. The solution was diluted with methylene chloride (100 mL) and the precipate was filtered and washed with cold methanol. The solids were dried in vacuo to yield 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-benzimidazol-2-one as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:13]1[C:17]2=[N:18][CH:19]=[N:20][C:21]([OH:22])=[C:16]2[CH:15]=[N:14]1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34](O)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([O:22][C:21]2[N:20]=[CH:19][N:18]=[C:17]3[N:13]([C:4]4[CH:5]=[CH:6][C:7]([S:9]([CH3:12])(=[O:10])=[O:11])=[CH:8][C:3]=4[N:2]([CH3:23])[CH3:1])[N:14]=[CH:15][C:16]=23)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CN(C)c1cc(S(C)(=O)=O)ccc1-n1ncc2c(O)ncnc21
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CN(C)c1cc(S(C)(=O)=O)ccc1-n1ncc2c(OC3CCN(C(=O)OC(C)(C)C)CC3)ncnc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
1-(2-Dimethylamino-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (66 mg, 0.200 mmol), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (61 mg, 0.300 mmol) and triphenylphosphine (52 mg, 0.200 mmol) were dissolved in toluene (5 mL) and the mixture stirred at 0° C. for 15 min. Diisopropyl azodicarboxylate (28 μL, 0.200 mmol) was then added and the reaction kept going at rt for 16 h. The solvent was removed under reduced pressure and the crude was purified by HPLC. Compound A100 was obtained as a yellowish solid. Exact mass calculated for C24H32N6O5S 516.22, found 517.3 (MH+, 100%). 1H NMR (400 MHz CDCl3) δ (ppm): 8.50 (s, 1H); 8.22 (s, 1H); 7.42 (m, 3H); 5.52 (m, 1H); 3.81 (m, 2H); 3.26 (m, 2H); 3.03 (s, 3H); 2.47 (s, 6H); 2.03 (m, 2H); 1.80 (m, 2H); 1.42 (s, 9H).
Reaction SMILES: N1C=CC=CC=1C([O:9][CH:10]1[C:14]2=[N:15][C:16]3[C:17](=[N:18][CH:19]=[C:20]([NH:22][C:23]([C:25]4[N:26]([CH2:38][C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=5)[C:27]5[C:32]([CH:33]=4)=[CH:31][C:30]([C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=5)=[O:24])[CH:21]=3)[N:13]2[CH2:12][CH2:11]1)=O.CO>C(Cl)(Cl)Cl.ClCCl.N.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[OH:9][CH:10]1[C:14]2=[N:15][C:16]3[C:17](=[N:18][CH:19]=[C:20]([NH:22][C:23]([C:25]4[N:26]([CH2:38][C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=5)[C:27]5[C:32]([CH:33]=4)=[CH:31][C:30]([C:34]([F:36])([F:35])[F:37])=[CH:29][CH:28]=5)=[O:24])[CH:21]=3)[N:13]2[CH2:12][CH2:11]1
Reactant: O=C(OC1CCn2c1nc1cc(NC(=O)c3cc4cc(C(F)(F)F)ccc4n3Cc3cccc(F)c3)cnc12)c1ccccn1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: N
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(Nc1cnc2c(c1)nc1n2CCC1O)c1cc2cc(C(F)(F)F)ccc2n1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A solution of 0.065 g (0.07 mmol) of 3-[[[1-(3-fluorobenzyl)-5-trifluoromethyl-1H-indol-2-yl]carbonyl]amino]-7,8-dihydro-6H-pyrrolo[2′,1′:2,3]imidazo[4,5-b]pyridin-6-yl pyridine-2-carboxylate, prepared in Example 8.1, in 10 ml of chloroform is admixed with 0.022 g (0.7 mmol) of methanol and 0.0127 g (0.07 mmol) of copper acetate. After seven hours of stirring at ambient temperature, the reaction mixture is diluted with 10 ml of dichloromethane and 10 ml of aqueous ammonia, with stirring. The organic phase is separated, washed with 10 ml of water, dried over sodium sulfate and concentrated under reduced pressure. The resulting product is subsequently purified by successive chromatography on a silica column and then on a neutral alumina column. This gives 0.012 g of the expected product.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[OH:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:22][CH2:23][CH2:24][CH2:25]Br.CCOC(C)=O>CN(C=O)C.O>[CH2:7]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[O:21][CH2:25][CH2:24][CH2:23][Br:22])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: BrCCCBr
Reactant: Oc1ccc(Cl)cc1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1ccc(OCCCBr)c(Cc2ccccc2)c1
Temperature: 80 °C
Yield: 72.1 %

Procedure:
Powdered K2CO3 (2.07 g, 15.0 mmol) is added to a stirred solution of 2-benzyl-4-chlorophenol (2.19 g, 10.0 mmol) and 1,3-dibromopropane (3.05 mL, 30.0 mmol) in anhydrous DMF (20 mL) at ambient temperature under nitrogen; The mixture is heated at 80° C. for 1 hour. At ambient temperature, EtOAc (100 mL) and water (150 mL) are added to the mixture. The organic layer is separated, dried over MgSO4, filtered and concentrated. The crude product is chromatographed on silica (gradient 0-2% EtOAc in hexane) to give 2.45 g (7.21 mmol, 72% yield) of the title compound as a white solid. EIMS: m/z 338 (M+, 35Cl, 79Br), 340 (M+, 37Cl, 37Br or 35Cl, 81Br), 342 (M+, 37Cl, 81Br).
Reaction SMILES: [Br:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>O1CCCC1>[BrH:1].[OH:10][C:6]1[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)[O:4][CH:5]=1
Reactant: CN1CCNCC1
Reactant: O=c1cc(CBr)occ1O
Solvent: C1CCOC1
Product: Br
Product: CN1CCN(Cc2cc(=O)c(O)co2)CC1
Temperature: 75 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
2-(Bromomethyl)-5-hydroxy-4H-pyran-4-one 21 (0.5 g, 2.4 mmol), 1-methylpiperazine (0.3 mL, 2.4 mmol) and tetrahydrofurane (12 mL) were charged in a 250 ml round-bottomed flask equipped with a magnetic stirrer. The reaction mixture was stirred for 2 h at 75° C. The reaction mixture was cooled and the precipitate was filtered to give after drying 5-hydroxy-2-((4-methylpiperazin-1-yl)methyl)-4H-pyran-4-one hydrobromide 23 (0.6 g, 83% yield) as a beige solid. A cesium salt was prepared by adding to Cs2CO3 (7.3 g, 22.4 mmol) in water (20 mL). The aqueous phase was washed with CH2Cl2 (200 mL), then water was evaporated at 40° C. and the cesium salt was drying under vacuum to give a white powder.
Reaction SMILES: [NH:1]([C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[C@H:2]([C:10]([NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:36]([OH:38])=[O:37])[CH:33]([CH3:35])[CH3:34])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([CH:53]([C:58]([CH:69]([O:74][SiH](C)C)C(C)(C)C)([CH:60]([O:65][SiH](C)C)C(C)(C)C)[NH-:59])[O:54][SiH](C)C)(C)(C)C>C(O)(=O)C.O>[NH:1]([C:39]([O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])[C@H:2]([C:10]([NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:36]([OH:38])=[O:37])[CH:33]([CH3:35])[CH3:34])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH:54][CH2:53][C:58]([CH2:69][OH:74])([CH2:60][OH:65])[NH-:59]
Reactant: C[SiH](C)OC(C(C)(C)C)C([NH-])(C(O[SiH](C)C)C(C)(C)C)C(O[SiH](C)C)C(C)(C)C
Agent: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)C
Solvent: O
Solvent: CC(=O)O
Product: [NH-]C(CO)(CO)CO

Procedure:
39 mg of Z-Phe-Phe-Leu-Val-tris(tert.-butyldimethylsilyloxymethyl)-methyl amide (Example 62) are stirred for 3 hours in 3 ml of acetic acid/H2O 2:1. After evaporating off the sovent and medium-pressure chromatography (LOBAR® prefabricated column, size B, 40-60 μm, system B8), the title compound is obtained in the form of a colourless powder. Rf (B8)=0.36.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)C.S(=O)(=O)(O)[OH:10].S([O-])([O-])(=O)=O.[Na+].[Na+].[OH2:21]>>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]([OH:10])=[O:21]
Reactant: O=S(=O)(O)O
Reactant: CCc1ccccn1
Reactant: O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: O=C(O)c1ccccn1
Yield: 30 %

Procedure:
The anolyte consisted of the following weight ratios of materials: 2-ethylpyridine (1.0), sulfuric acid (1.5), sodium sulfate (0.1), and water (3.5). The catholyte was 10 wt% sufluric acid. A flow cell as in Example 1 was used having a cation-exchange membrane and a PbO2 packed-bed anode. Charge was passed (6 F/mole) at 25 mA/cm2 current density. The anolyte was worked up as before and gave a 30% yield of picolinic acid and a 40% yield of 2-acetylpyridine. Passing more charge through the anolyte before work up increased the yield of acid significantly. A flow cell with an anion-exchange membrane could also be used where the catholyte was 10 wt% sodium hydroxide. Varying the weight parts of components in the anolyte changed the ratio of ketone to carboxylic acid as did switching from one membrane type to the other. Varying the total charge passed also increased or decreased the ketone yield thereby confirming the aspect of applicant's invention that such intermediates can be produced.