Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])(=O)C.[NH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[NH2:24])[C:18]([OH:20])=[O:19].[C:25]([O-:28])(=O)[CH3:26].[K+].Cl>O1CCOCC1.O>[C:5]([NH:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[NH:24][C:7](=[O:8])[C:6]1[C:5](=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:4])[C:18]([OH:20])=[O:19])(=[O:4])[C:6]1[C:25](=[CH:26][CH:12]=[CH:11][CH:10]=1)[OH:28]
Reactant: CC(=O)[O-]
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(NC(=O)c2ccccc2O)c(NC(=O)c2ccccc2O)c1
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
A solution of 17.2 g of 2-acetoxybenzoylchloride in 20 ml of dioxane was added at one time to a mixture of 4.6 g of 3,4-diaminobenzoic acid, 15.3 g of potassium acetate and 70 ml of water while stirring at a temperature of from 0° to 5°C, followed by stirring at that temperature for 30 minutes. To the mixture was added a solution of 1 g of 2-acetoxybenzoylchloride in 3 ml of dioxane. The resulting mixture was stirred at room temperature for 30 minutes and then at 50°C for 30 minutes. The reaction mixture was added to 200 ml of cold diluted hydrochloric acid and the undissolved mixture of oil and powdery solid was separated. The mixture was dissolved in about 100 ml of 1N aqueous sodium hydroxide solution, and the solution was treated with active carbon and then acidified to precipitate crystals. The crystals were recovered by filtration and washed with water. Recrystallization from a mixture of dioxane and water gave 6.9 g of 3,4-bis(salicylamido)-benzoic acid having a melting point between 305° - 307°C (decomposition).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:30])[C:15](=[O:29])[CH2:16][NH:17][C:18]2[N:23]=[C:22]([CH3:24])[C:21]([N+:25]([O-])=O)=[C:20]([CH3:28])[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[NH2:25][C:21]1[C:22]([CH3:24])=[N:23][C:18]([NH:17][CH2:16][C:15]([N:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)[CH3:30])=[O:29])=[N:19][C:20]=1[CH3:28]
Reactant: Cc1nc(NCC(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1nc(NCC(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.5 %

Procedure:
Compound 62 (93 mg) and zinc (147 mg) were suspended in acetic acid (2 mL) and the suspension was stirred at room temperature (20 to 30° C.) for 3 hours. Subsequently, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate: hexane=5:1 to 3:1) to give 25.4 mg (29% yield) of the desired product as a pale yellow amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[NH:9][C:6]2=[CH:7][N:8]=1.[H-].[Na+].I[CH3:19]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[N:9]([CH3:19])[C:6]2=[CH:7][N:8]=1
Reactant: CI
Reactant: COC(=O)c1cc2cc(OC)ncc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(OC)ncc2n1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.4 %

Procedure:
To a stirred solution of methyl 5-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (910 mg, 4.41 mmol) in N,N-dimethylformamide (35 ml) at room temperature under a nitrogen atmosphere was added slowly sodium hydride (60 w/w % in mineral oil, 177 mg, 4.41 mmol). After 30 minutes iodomethane (0.302 ml, 4.85 mmol) was added and the reaction mixture was stirred at room temperature for 1.5 hours. Then the reaction was quenched in water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (gradient of heptane to heptane/ethyl acetate 1/1) to give methyl 5-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (878 mg).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]([C:7]1[N:8]([CH3:20])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:10]([CH3:12])[CH:11]=1)=[O:6]>C(O)(=O)C.C(OCC)(=O)C>[CH3:3][O:4][C:5]([C:7]1[N:8]([CH3:20])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:10]([CH3:12])[C:11]=1[Br:1])=[O:6]
Reactant: BrBr
Reactant: COC(=O)c1cc(C)c(-c2ccc(Cl)cc2)n1C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1c(Br)c(C)c(-c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.2 %

Procedure:
Bromine (1.69 g, 0.54 ml, 10.54 mmol) was added dropwise to a stirred solution of methyl-5-(4-chlorophenyl)-1,4-dimethyl-1H-pyrrole-2-carboxylate (compound 49α, 1.85 g, 7.03 mmol) in acetic acid (20 ml) at 10° C. The resulting reaction mixture was stirred at room temperature for 15 hr. The progress of the reaction was monitored by TLC. Acetic acid was removed from the reaction mixture under reduced pressure and residue obtained was dissolved in ethyl acetate (150 ml). The mixture so obtained was washed with saturated sodium bicarbonate solution (50 ml) followed by washing with brine (50 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was washed with a mixture of ethyl acetate in hexanes (10:90) to obtain the title compound (2.1 g, 87.5%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:7](=[CH:8][CH:9]=1)[C:6](Br)(Br)[CH2:5]2.S(=O)(=O)(O)[OH:13]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:13])[CH2:5]2
Reactant: Brc1ccc2c(c1)CC2(Br)Br
Reactant: O=S(=O)(O)O
Solvent: O
Product: O=C1Cc2cc(Br)ccc21
Temperature: 75 °C
Reaction time: 108 h

Procedure:
To a suspension of 3-bromo-7,7-dibromo-bicyclo[4.2.0]octa-1,3,5-triene (2) (186.2 g, 0.546 mol, theoretical) in H2O (1000 ml) was added sulfuric acid (97%, 50 ml) at 15° C. The resulting mixture was stirred at 75° C. for 4.5 days.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[Cl:14][CH2:15][C:16]#[N:17].Cl>C(OCC)C>[ClH:14].[Cl:14][CH2:15][C:16]1[N:17]=[C:4]([OH:6])[C:3]2[C:2](=[CH:11][C:10]([O:12][CH3:13])=[CH:9][CH:8]=2)[N:1]=1
Reactant: COC(=O)c1ccc(OC)cc1N
Reactant: N#CCCl
Agent: Cl
Solvent: CCOCC
Product: COc1ccc2c(O)nc(CCl)nc2c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 127.7 %

Procedure:
To a mixture of methyl 2-amino-4-methoxybenzoate (5.4 g, 30.0 mmol) and chloroacetonitrile (2.8 mL, 45.0 mmol) was added anhydrous hydrogen chloride (4M solution in 1,4-dioxane, 20.0 mL, 80 mmol) and the reaction mixture was stirred at 50° C. for 30 minutes. After cooling it to room temperature the resulting slurry was diluted with diethyl ether (100 mL) and the stirring was continued for an additional 30 minutes. The off-white precipitate was collected by filtration, washed with diethyl ether and dried in vacuo to provide 2-(chloromethyl)-7-(methyloxy)quinazolin-4-ol hydrochloride (7.5 g, 96%). MS (EI) for C10H9ClN2O2: 225 (MH+).
Reaction SMILES: [NH:1]([C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4])[NH2:2].[C:18](N1C=CN=C1)(N1C=CN=C1)=[S:19].[CH3:30]I>CN(C=O)C>[CH3:30][S:19][C:18]1[O:4][C:3]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)=[N:1][N:2]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CSc1nnc(C2CCN(C(=O)OC(C)(C)C)CC2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of tert-butyl 4-(hydrazinocarbonyl)piperidine-1-carboxylate (0.97 g) in DMF (8.0 mL) was added 1,1′-thiocarbonyldiimidazole (0.86 g), and the mixture was stirred at room temperature for 1 hr. The mixture was heated at 100° C. for 2 hr, cooled to 0° C., and methyl iodide (0.5 mL) was added. The mixture was stirred at 0° C. for 1 hr, diluted with ice water, and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, water and saturated brine, dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (solvent gradient; 0→60% ethyl acetate/hexane) to give tert-butyl 4-[5-(methylsulfanyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (1.1 g, 91%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:23])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]#[C:20][CH2:21]Cl)[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1.[Na+].[I-].[CH3:26][NH:27][CH2:28][CH2:29][CH3:30]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:23])[N:10]([CH3:11])[CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]#[C:20][CH2:21][N:27]([CH3:26])[CH2:28][CH2:29][CH3:30])[CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: CN(C[C@H]1CC[C@H](C#CCCl)CC1)C(=O)Oc1ccc(F)cc1
Reactant: CCCNC
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CCCN(C)CC#C[C@H]1CC[C@H](CN(C)C(=O)Oc2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of 250 mg (0.63 mmol) of trans-[4-(3-chloro-prop-1-ynyl)cyclohexyl-methyl]-methyl-carbamic acid 4-fluoro-phenyl ester with a catalytic amount of NaI in 7 ml of methanol was treated with 0.65 ml (6.3 mmol) of N-methylpropylamine and stirred over night at room temperature. The solvent was evaporated and the residue extracted with aqueous saturated NaHCO3/ether (3×). The organic phase was dried with sodium sulfate, filtered and evaporated. Purification by flash column chromatography on silica gel (methylenechloride/methanol 98:2) gave 218 mg (93%) of pure trans-methyl-{4-[3-(methyl-propyl-amino)-prop-1-ynyl]-cyclohexylmethyl}-carbamic acid 4-fluoro-phenyl ester as light brown oil, MS: 375 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>C([O-])([O-])=O.[Na+].[Na+].C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([O:19][CH3:18])[CH:25]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Reactant: COc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Yield: 66.1 %

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (150 mg), 66 mg of 3-methoxyphenylboronic acid and 14 mg of bis(triphenylphosphine)palladium(II) dichloride in 1 mL of 1M Na2CO3 aqueous solution and 1 mL of acetonitrile was heated to 100° C. in a sealed microwave reactor for 20 min. The reaction mixture was evaporated. The crude product was purified by flash chromatography eluting with 0-50% EtOAc/hexane to yield 2-chloro-6-(3-methoxyphenyl)-4-morpholinothieno[3,2-d]pyrimidine (94 mg, 66%).
Reaction SMILES: ClC1C=C([N:8]2N=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)C=CC=1.[F:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([F:27])[CH:26]=1)[NH2:23].N1C=CC=CC=1C=O>>[F:19][C:20]1[CH:21]=[C:22]([N:23]2[N:8]=[N:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:11]2)[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Agent: O=Cc1ccccn1
Product: Fc1cc(F)cc(-n2nnc(-c3ccccn3)n2)c1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3,5-difluoroaniline (131 mg, 1.0 mmol) and pyridine-2-carboxaldehyde (109 mg, 1.0 mmol) were employed to obtain 2-[2-(3,5-difluorophenyl)-2H-tetrazol-5-yl]pyridine as an orange solid.
Reaction SMILES: C[Li].[CH3:3][N:4]([CH3:14])[S:5]([N:8]1[CH:12]=[C:11](Br)[CH:10]=[N:9]1)(=[O:7])=[O:6].[B:15](OCC)([O:19]CC)[O:16]CC>C1COCC1>[CH3:3][N:4]([CH3:14])[S:5]([N:8]1[CH:12]=[C:11]([B:15]([OH:19])[OH:16])[CH:10]=[N:9]1)(=[O:7])=[O:6]
Reactant: CCOB(OCC)OCC
Reactant: CN(C)S(=O)(=O)n1cc(Br)cn1
Agent: [Li]C
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(B(O)O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
Methyl lithium (1.6M in Et2O, 12.2 ml, 19.5 mmol) was added to a stirred solution of 4-bromo-pyrazole-1-sulfonic acid dimethylamide (3.18 g, 14.9 mmol) and triethyl borate (3.80 ml, 22.3 mmol) in anhydrous THF (40 ml), such that the internal temperature remained >-60° C. After 30 min, the reaction was allowed to warm to room temperature and stirred for 18 h. The reaction was quenched with 2N HCl (25 ml), then extracted with EtOAc (×3). The organic extracts were combined, dried (Na2SO4), filtered and the solvent removed in vacuo. The material was purified by silica column chromatography to afford a colourless gum (2.1 g). MS: [M+H]+=220
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([F:23])=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:5]=[CH:4][N:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([F:23])=[C:18]([NH:19][S:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH3:24])(=[O:33])=[O:32])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CC(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Product: Cc1ccccc1S(=O)(=O)Nc1cccc(-c2nc(C(C)C)sc2-c2ccnc(Cl)n2)c1F

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-isopropylthiazol-4-yl)-2-fluoroaniline (350 mg, 1.003 mmol) and 2-methylbenzenesulfonyl chloride (0.145 mL, 1.00 mmol) the title compound of Step A was obtained as a yellow solid (140 mg, 28% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.37 (s, 1H), 8.35-8.65 (m, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.11-7.50 (m, 6H), 6.73 (d, J=5.2 Hz, 1H), 3.35-3.41 (m, 1H), 2.54 (s, 3H), 1.34 (d, J=6.9 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]([SH:5])([CH3:4])[CH3:3].Br[C@H:7]([CH3:11])[C:8]([OH:10])=[O:9].O.C(O)(=O)C>CCO>[C:2]([S:5][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:1]
Reactant: C[C@@H](Br)C(=O)O
Reactant: CC(C)(C)S
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: C[C@H](SC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of 483 mg of Na in 10 mL of EtOH was added 10 mL of tert-butylthiol with stirring at room temperature under nitrogen. After 10 min a solution of 1.53 g of (2R)-2-bromopropanoic acid in 3 mL of EtOH was added and the stirring was continued at room temperature for 3 h. The reaction mixture was poured into water and was acidified with acetic acid and extracted with CH2Cl2. The organic layer was dried over Na2SO4 and was evaporated under water aspirator vacuum using a trap containing bleach to give 1.48 g of (2S)-2-(tert-butylthio)propanoic acid as an oil at 92% yield. Characteristic analytical data are as follows: 1H NMR (300 MHz, CDCl3) δ3.44 (q, J=7 Hz, 1H), 1.49 (d, J=7 Hz, 3H), 1.37 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C-:14]#[N:15].[K+].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Na].CCCCCC>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[C:3]([NH:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[N:4][C:5]([C:14]#[N:15])=[N:6][CH:7]=1
Reactant: CC(C)CNc1nc(Cl)ncc1Br
Reactant: [C-]#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Agent: [Na]
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)CNc1nc(C#N)ncc1Br
Temperature: 75 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a solution of (5-bromo-2-chloro-pyrimidin-4-yl)-isobutyl-amine (11.2 mmol) in DMSO (30 ml) is added potassium cyanide (22.5 mmol) and sodium p-toluenesulfonic acid (3.75 mmol) in DMSO(17 ml) at room temperature. The mixture is stirred at 75° C. for 18 h and diluted with AcOEt. The organic layer is washed with water and brine, dried over sodium sulfate and concentrated. Chromatography on silica gel (n-hexane:AcOEt=25:1, 15:1 and 12:1) gives the product in 84% yield. Rf=46 (n-hexane:AcOEt=3:1)
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:26][CH3:27])[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[N:20]=4)=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]2[C@H:28]3[CH2:33][CH2:32][CH2:31][C@H:29]3[N:30]=[C:3]12.[OH:34]OS([O-])=O.[K+]>CC#N.CO>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S@@:26]([CH3:27])=[O:34])[N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[N:20]=4)=[CH:17][CH:18]=3)[N:11]=[C:5]2[N:4]2[C@H:28]3[CH2:33][CH2:32][CH2:31][C@H:29]3[N:30]=[C:3]12
Reactant: CSc1c2c(nn1Cc1ccc(-c3cccc(F)n3)cc1)N1C(=N[C@@H]3CCC[C@@H]31)N(C)C2=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: CN1C(=O)c2c(nn(Cc3ccc(-c4cccc(F)n4)cc3)c2[S@@](C)=O)N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(methylthio)-2-(4-(6-fluoropyridin-2-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (35.2 mg, 0.076 mmol) is dissolved in CH3CN (0.5 mL) and CH3OH (2 mL), and then an aqueous solution of oxone (93.7 mg, 0.152 mmol) is added. The reaction mixture is stirred at room temperature for 20 h, and then purified by a semi-preparative HPLC to give pure product as white solids. MS (ESI) m/z 479.2 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:19]([NH:20][CH:21]([CH3:23])[CH3:22])=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:24]([O:26]C)=[O:25])[CH:16]=2)[N:11]=1.[OH-].[Na+].Cl>CO.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:19]([NH:20][CH:21]([CH3:23])[CH3:22])=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:24]([OH:26])=[O:25])[CH:16]=2)[N:11]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4ccccc4o3)c(NC(C)C)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)Nc1nc2cc(C(=O)O)ccc2nc1-c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a solution of methyl 2-(1-benzofuran-2-yl)-3-[(propan-2-yl)amino]quinoxaline-6-carboxylate (60 mg, 0.17 mmol) in methanol (30 mL) was added sodium hydroxide (60 mg, 1.50 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted pH to 6 with HCl (3N) and filtered to give 2-(1-benzofuran-2-yl)-3-[(propan-2-yl)amino]quinoxaline-6-carboxylic acid as a light yellow solid (30.1 mg, 52%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]([CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18]C)[CH:16]=2)[CH2:11][CH2:10]1)=[O:8].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:5][O:6][C:7]([CH:9]1[C:17]2[C:12](=[CH:13][C:14]([C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10]1)=[O:8]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)C1CCc2ccc(OC)cc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C1CCc2cc(C(=O)c3ccccc3)c(O)cc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
40 g of finely powdered aluminum chloride are added in portions to a stirred solution of 20.6 g of 6-methoxy-indane-1-carboxylic acid methyl ester and 15.5 g of benzoyl chloride in 200 ml of absolute methylene chloride at 20° C, in an anhydrous atmosphere, stirring is continued overnight at room temperature and the reaction solution is then poured onto 500 g of ice and extracted with 3 times 100 ml of methylene chloride. The organic phases are washed successively with 500 ml of saturated sodium bicarbonate solution, 500 ml of 2 N hydrochloric acid and 500 ml of water, dried over anhydrous sodium sulphate and evaporated in vacuo. The evaporation residue, when crystallized from ether-petroleum ether after treatment with active charcoal, gives 5-benzoyl-6-hydroxy-indane-1-carboxylic acid methyl ester of melting point 89°-91° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([NH:20][C:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=2)=[O:22])[C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1.C1COCC1.[Li+].[OH-]>CO>[F:33][C:2]([F:1])([F:34])[C:3]1[CH:4]=[CH:5][C:6]([C@H:9]([NH:20][C:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=2)=[O:22])[C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2C(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
To a solution of (S)-methyl 4-(((4-(trifluoromethyl)phenyl)(3-(trifluoro-methyl)pyridin-2-yl)methyl)carbamoyl)benzoate (135 mg, 0.280 mmol, Example 140) and THF (7 mL):MeOH (3 mL) was added 1M LiOH (1 mL, 1.000 mmol). After 2 h, the reaction was concentrated in vacuo. The off-white solid was taken up in a minimum of DCM and eluted through a Redi-Sep® pre-packed silica gel column (4 g) with EtOAc to provide the title compound as a white solid. 1H NMR (CD3OD, 300 MHz) δ ppm 8.91 (d, J=4.8 Hz, 1H), 8.18 (d, J=7.9 Hz, 1H), 8.03 (d, J=8.3 Hz, 2H), 7.85 (d, J=8.2 Hz, 2H), 7.53-7.66 (m, 5H), 6.93 (s, 1H). MS (ESI pos. ion) m/z: 469.0 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:3])C.[Br:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[S:8][C:7]=1[CH:15]([O:18][Si](C)(C)C)[C:16]#N.C[OH:24]>>[Br:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[S:8][C:7]=1[CH:15]([OH:18])[C:16]([O:3][CH3:1])=[O:24]
Reactant: CC(=O)Cl
Reactant: CO
Reactant: C[Si](C)(C)OC(C#N)c1sc2ncccc2c1Br
Product: COC(=O)C(O)c1sc2ncccc2c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
Acetyl chloride (725 μL, 10.2 mmol) was dropped at 0° C. in methanol (10 mL). After 30 minutes, a solution of 2-{3-bromothieno[2,3-b]pyridin-2-yl}-2-[(trimethylsilyl)oxy]acetonitrile (14e) (290 mg, 0.85 mmol) in methanol (5 mL) was added at 0° C. to the reaction. The mixture was then warmed at room temperature for 20 hours and concentrated in vacuo. A saturated aqueous solution of sodium bicarbonate (20 mL) was added to the residue and extracted with dichloromethane (2×20 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane/ethyl acetate 90/10) to afford the desired hydroxyl-ester (14f) as a white solid (180 mg, 0.6 mmol, 70%).
Reaction SMILES: [CH2:1]([Li])CCC.[CH2:6]([O:13][C:14]1[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CCCCCC>[CH2:6]([O:13][C:14]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:1])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1cc(C=O)ccc1OCc1ccccc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1ccc(OCc2ccccc2)c(C(=O)OC)c1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of methyltriphenylphosphonium bromide (4.1 g) in tetrahydrofuran (40 ml) was added 1.56M n-butyl lithium solution in hexane (7.2 ml) at room temperature, and the mixture was stirred for 1 hour. After the reaction mixture was cooled to −70° C., a solution of methyl 2-benzyloxy-5-formylbenzoate (2.82 g) in tetrahydrofuran (40 ml) was added, and the resulting mixture was stirred for 15 hours with gradually warming up to room temperature. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=4/1) gave methyl 2-benzyloxy-5-vinylbenzoate (2.63 g).