Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.N1C=CC=CC=1.[C:17](Cl)(=[O:19])[CH3:18]>O1CCCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:17](=[O:19])[CH3:18])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-5-nitropyridine (13.9 g, 100 mmol) and pyridine (24 ml, 300 mmol) in tetrahydrofuran (300 ml) was added dropwise acetyl chloride (10.7 ml, 150 mmol) with ice-cooling, the mixture was stirred at room temperature for 1 hour. To the mixture was added dropwise acetyl chloride (10.7 ml, 150 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice-water and the desired product (14.5 g, 80.1%) as a solid was collected by filtration.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.Cl.[NH2:15][C@@H:16]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([NH:15][C@@H:16]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:13])=[CH:7][CH:8]=1
Reactant: CCOC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CCC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)CCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 40.1 %

Procedure:
Then, 3-(4-methoxyphenyl)propionic acid (330 mg, 1.83 mmol) and ethyl (S)-2-amino-3-(4-nitrophenyl)propionate hydrochloride (500 mg, 1.82 mmol) were dissolved in N,N-dimethylformamide (30 ml). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (384 mg, 2.00 mmol), 1-hydroxy-1H-benzotriazole (270 mg, 2.00 mmol) and N-methylmorpholine (0.25 ml, 2.27 mmol) were added, and the mixture was stirred at room temperature for 21 hours. Water (500 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1) to give 292 mg of ethyl (S)-2-[3-(4-methoxyphenyl)propionylamino]-3-(4-nitrophenyl)propionate as a colorless solid (40%). This solid (280 mg, 0.699 mmol) was dissolved in ethanol (30 ml) and 10% palladium-carbon (100 mg) was added. The mixture was refluxed under heating for 14 hours under a hydrogen atmosphere. The reaction mixture was cooled to room temperature and filtrated. Low boiling matters were distilled away from the filtrate under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1-3/7) to give 171 mg of ethyl (S)-3-(4-aminophenyl)-2-[3-(4-methoxyphenyl)propionylamino]propionate as a colorless solid (66%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:18][CH2:17][C:10]3([NH:14]C(=O)N[C:11]3=[O:16])[CH2:9]2)=[CH:4][CH:3]=1.[OH-:19].[Na+].Cl>O1CCOCC1>[NH2:14][C:10]1([C:11]([OH:19])=[O:16])[CH2:17][CH2:18][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:9]1
Reactant: [OH-]
Reactant: O=C1NC(=O)C2(CC[C@@H](c3ccc(Br)cc3)C2)N1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: NC1(C(=O)O)CC[C@@H](c2ccc(Br)cc2)C1

Procedure:
A solution of (7R)-7-(4-bromophenyl)-1,3-diazaspiro[4.4]nonane-2,4-dione (I-2B, 6.80 g, 22 mmol) in dioxane (20 mL) and NaOH (2N aq) (120 mL, 240 mmol) was heated in an oil bath set to 95° C. The resulting clear, pale yellow solution was left to stir over the weekend. The solution was cooled in an ice bath and neutralized to approximately pH 7 with 6 N HCl resulting in the formation of a precipitate. The solids were collected and left to air dry overnight. The white solid was slurried in hot ethanol (˜100 mL) and re-collected by filtration and the solid was air-dried then placed under high vacuum. (5.8 g, 20.41 mmol). HPLC retention time=0.64 min (Condition G); LC/MS M+1=284/286. 1H NMR (500 MHz, methanol-d4) δ 7.52-7.38 (m, 2H), 7.31-7.17 (m, 2H), 3.55-3.40 (m, 1H), 2.68 (dd, J=13.3, 6.7 Hz, 1H from single diastereomer), 2.58-2.39 (m, 1H), 2.26-2.15 (m, 1H), 2.10-1.98 (m, 1H), 1.98-1.81 (m, 1H), 1.70 (dd, J=13.2, 11.8 Hz, 1H from single diastereomer).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([N:14]1[C:20](=[O:21])[CH2:19][CH2:18][N:17]([C:22](=[O:33])/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:16][CH2:15]1)[CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[BH4-].[Na+].OS([O-])(=O)=O.[K+]>C(O)C>[Cl:32][C:27]1[CH:26]=[C:25](/[CH:24]=[CH:23]/[C:22]([N:17]2[CH2:18][CH2:19][C:20](=[O:21])[N:14]([CH:4]([CH2:3][OH:2])[CH2:5][CH2:6][CH2:7][N:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[CH2:15][CH2:16]2)=[O:33])[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: COC(=O)C(CCCN1CCCCC1)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Agent: [K+]
Solvent: CCO
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(C(CO)CCCN2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A solution of 0.041 g (0.08 mmol) of (rac)-2-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-5-piperidin-1-yl-pentanoic acid methyl ester in 0.5 ml of ethanol was treated at 0° C. with 0.006 g (0.16 mmol) of sodium borohydride in 0.5 ml of ethanol during 5 min. The reaction was stirred for 21 h at RT, cooled (0° C.) and treated again with 0.006 g (0.16 mmol) of sodium borohydride in 0.5 ml ethanol. After 5 h at RT the reaction was neutralized with cold aqueous 10% KHSO4 and extracted with cold saturated NaHCO3/EtOAc (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na2SO4, evaporated and purified by flash silica gel column (CH2Cl2/MeOH 9:1 to 4:1 and then, to elute the product, with CH2Cl2/MeOH/25% NH4OH 9:1:0.1) to yield after precipitation with CH2Cl2/n-penatne 0.022 g (57%) of the title compound as white foam. MS: 482.3 (MH+, 2Cl).
Reaction SMILES: [CH3:1][C:2]1[C@@H:7]2C(C)(C)[C@@H](C2)C[CH:3]=1.[B:11]([CH:22]1[CH:27]([CH3:28])[CH:26]2[C:29]([CH3:31])([CH3:30])[CH:24]([CH2:25]2)[CH2:23]1)[CH:12]1[CH:17]([CH3:18])[CH:16]2[C:19]([CH3:21])([CH3:20])[CH:14]([CH2:15]2)[CH2:13]1.C1CCC=CC=1.C[N+]([O-])(C)C.C1(O)CCCC=C1.C1(O)CCC=CC1>O1CCCC1>[B:11]([CH:12]1[CH:17]([CH3:18])[CH:16]2[C:19]([CH3:20])([CH3:21])[CH:14]([CH2:15]2)[CH2:13]1)[CH:22]1[CH:27]([CH3:28])[CH:26]2[C:29]([CH3:31])([CH3:30])[CH:24]([CH2:25]2)[CH2:23]1.[CH3:3][C:2](=[CH2:1])[CH3:7]
Reactant: CC1=CC[C@@H]2C[C@H]1C2(C)C
Agent: CC1C([B]C2CC3CC(C2C)C3(C)C)CC2CC1C2(C)C
Agent: C[N+](C)(C)[O-]
Agent: OC1C=CCCC1
Solvent: C1CCOC1
Solvent: C1=CCCC=C1
Product: C=C(C)C
Temperature: -25 °C
Reaction time: 12 h

Procedure:
Diisopinocampheylborane was prepared by the method of H. C. Brown et al., Israel J. Chem. 15, 12 (1977) from (+)-α-pinene. To the stirred suspension of diisopinocampheylborane (25 mmol) in tetrahydrofuran at -25° C. was added dropwise 2.4 mL (25 mmol) of 1,3-cyclohexadiene. Monohydroboration of the diene was complete after stirring the reaction mixture at -25° C. for 12 hours, as indicated by the disappearance of the solid diisopinocampheylborane and 11B NMR (δ+80) examination of the solution. The reaction mixture was oxidized with trimethylamine-N-oxide, giving a 92:8 mixture of (-)-2-cyclohexen-1-ol (94% ee) and 3-cyclohexen-1-ol. A second reaction mixture at -78° C. was treated with 25 mm of lithium tert-butyl. Isobutylene was formed and the organoborane was converted into the corresponding borohydride as represented by the following reaction scheme.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:32]2[N:41]=[CH:40][C:39]3[C:34](=[C:35]([F:46])[CH:36]=[C:37]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:38]=3)[C:33]2=[O:47])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])=[CH:21][N:20]=2)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=1)(=O)C.[OH-].[Li+].O>C(O)(C)C.C1COCC1>[C:42]([C:37]1[CH:38]=[C:39]2[C:34](=[C:35]([F:46])[CH:36]=1)[C:33](=[O:47])[N:32]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[N:20]=[CH:21][C:22]([C:25]([CH3:27])([CH3:26])[C:28]#[N:29])=[CH:23][CH:24]=4)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:41]=[CH:40]2)([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C(C)(C)C#N)cn3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C(C)(C)C#N)cn2)c1=O
Yield: 16.8 %

Procedure:
A mixture of 156e (191 mg, 0.30 mmol) and lithium hydroxide.1water (126 mg, 3.0 mmol) in i-propanol/THF (1:1, 8 mL) and water (2 mL) was stirred at 35° C. for 0.5 h. The mixture was evaporated under reduced pressure and diluted with water (10 mL). It was then extracted with dichloromethane (3×20 mL). The combined dichloromethane extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 156 (30 mg, 17%) as a pale yellow solid. MS-ESI: [M+H]+ 594.3. 1H NMR (500 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.77 (d, J=2.0 Hz, 1H), 8.59 (d, J=5.0 Hz, 1H), 8.54 (d, J=2.5 Hz, 1H), 8.34 (d, J=2.5 Hz, 1H), 7.91 (s, 1H), 7.79-7.74 (m, 2H), 7.57-7.53 (m, 2H), 7.40 (d, J=9.0 Hz, 1H), 4.92 (bs, 1H), 4.43 (s, 2H), 3.62 (s, 3H), 1.67 (s, 6H), 1.39 (s, 9H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>[Cu]>[C:1]1([O:7][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccccc1
Reactant: Oc1ccccc1
Agent: [Cu]
Product: c1ccc(Oc2ccccc2)cc1
Yield: 44.7 %

Procedure:
However, the catalyst disclosed in Japanese Patent KOKAI No. 57-11932 is insufficient in the yield of phenol. Actually, the maximum conversion of benzoic acid was 50.5%, and the maximum selectivity to phenol was 88.6%, and therefore, the maximum yield was 44.7%. Besides, when an exothermic reaction is conducted such as the oxidation reaction of benzoic aicd using the catalyst containing a copper compound, hot spots occur in the catalyst layer to progress calcining of the catalyst. As a result, the catalytic activity is degraded sharply. In the manufacturing process disclosed in Japanese Patent KOKOKU No. 59-20384, the yield of phenol is insufficient. That is, the maximum conversion of benzoic acid was 63.7%, and the maximum selectivity to phenol was 82.2%, and therefore, the maximum yield was 52.4%. Moreover, byproducts such as diphenyl oxide are produced abundantly, and therefore, a purification process for the produced phenol is necessary. In the manufacturing process disclosed in Japanese Patent KOKOKU No. 64-934, the maximum conversion of benzoic acid was 75%, and the maximum selectivity to phenol was 89%. Therefore, the maximum yield was 66.8%. Moreover, all of the above conventional processes are inferior in productivity due to low space time yield (the production amount of phenol per unit volume of catalyst per unit time), and therefore, they are disadvantageous in the industrial production of phenol.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:22][C:23](=[O:35])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:35]=[C:23]1[CH2:24][C:25]([C:27]2[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=2)[C:33]#[N:34])=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][C:9]=2[NH:22]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(C#Cc4ccccc4)cc3NC(=O)C2)c1
Yield: 77.8 %

Procedure:
Prepared from {2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-phenylethynyl-phenyl}-carbamic acid tert.-butyl ester (Example K2) (230 mg, 0.48 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (135 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]([CH:13]2[CH2:15][CH2:14]2)[N:7]=1)=[O:5])[CH3:2].Br[C:17]1[CH:18]=[N:19][CH:20]=[N:21][CH:22]=1.O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1C.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:12][C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[CH:10][CH:9]=[C:8]([CH:13]2[CH2:14][CH2:15]2)[N:7]=1)=[O:5])[CH3:2]
Reactant: Brc1cncnc1
Reactant: CCOC(=O)c1nc(C2CC2)ccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Temperature: 140 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
A suspension of 3-amino-6-cyclopropylpyridine-2-carboxylic acid ethyl ester (763 mg, 3.7 mmol), 5-bromopyrimidine (823 mg, 5.2 mmol), water (140 μl, 7.8 mmol) and potassium carbonate (920 mg, 6.7 mmol) in o-xylene (10 ml) was evacuated and vented with argon. Palladium(II) acetate (33 mg, 0.15 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 107 mg, 0.18 μmol) were consecutively added under inert gas atmosphere and the reaction mixture was heated to 140° C. and stirred overnight. After cooling-down to ambient temperature, the reaction mixture was diluted with methylenechloride (15 ml) and filtrated. The filtrate was concentrated in vacuo and the product was purified by silica gel chromatography using a heptane/ethyl acetate gradient to yield the title compound (796 mg, 75.7%) as light yellow solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.[CH3:18][N:19]([CH3:37])[C:20]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:25][CH2:24][C:23]([CH2:27][C:28](O)=[O:29])(O)[CH2:22][CH2:21]1.C1(N=C=NC2CCCCC2)CCCCC1.[OH-].[Na+]>O.CN(C)C=O>[CH3:37][N:19]([CH3:18])[C:20]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:25][CH2:24][C:23](=[CH:27][C:28]([NH:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:29])[CH2:22][CH2:21]1
Reactant: NCCCc1ccccc1
Reactant: CN(C)C1(c2ccccn2)CCC(O)(CC(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C1(c2ccccn2)CCC(=CC(=O)NCCCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 120 h
Yield: 27 %

Procedure:
3-phenylpropylamine (270 mg, 2.0 mmol) and N-methylmorpholine (0.444 ml, 4.0 mmol) were added to a solution of (4-dimethylamino-1-hydroxy-4-pyridin-2-yl-cyclohexyl)acetic acid (556 mg, 2.0 mmol) in abs. dimethylformamide (30 ml) under argon. The solution was cooled to 0° C., dicyclohexylcarbodiimide (825 mg, 4.0 mmol) was added and the mixture was stirred at RT for 5 d. Working up of the mixture was carried out by separating off the urea which had precipitated out and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). Still further urea thereby precipitated out and was separated off. The aqueous phase was diluted with water (300 ml), 5 M sodium hydroxide solution (7 ml, 35 mmol) was added and the mixture was stored at 5° C. for 16 h. The crude product thereby precipitated out as a beige-coloured oily compound (22.8 mg, 30%). After chromatography on silica gel (40 g) with EA/methanol (4:1), the amide was obtained as a beige-coloured oil in a yield of 27% (203 mg).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:19][O:20][C:21]([C:23]1[CH2:24][N:25]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:26][CH2:27][C:28]=1[C:29]1[CH:34]=[CH:33][C:32]([O:35][Si](C(C)(C)C)(C)C)=[CH:31][CH:30]=1)=[O:22].C(Cl)Cl>C1COCC1>[CH3:19][O:20][C:21]([C:23]1[CH2:24][N:25]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:26][CH2:27][C:28]=1[C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)=[O:22]
Reactant: COC(=O)C1=C(c2ccc(O[Si](C)(C)C(C)(C)C)cc2)CCN(C(=O)OC(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)C1=C(c2ccc(O)cc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
TBAF (9.50 g, 30 mmol) was added to a sol. of compound B1 (13.4 g, 30 mmol) in THF (100 mL) at 0° C. The mixture was stirred at 0° C. for 1 h. CH2Cl2 was added, and the mixture was washed with aq. sat. NH4Cl, water, and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the crude title compound (10.0 g, quantitative yield) that was used further without purification. LC-MS: tR=0.92 min; ES+: 334.23.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:48][CH:49]([C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=1)[C:50]1[CH:55]=[CH:54][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:52][CH:51]=1>CC#N>[F:68][C:65]1[CH:64]=[CH:63][C:62]([CH:49]([NH:48][C:8]([C:7]2[C:2]([OH:1])=[N:3][C:4]([N:11]3[CH:15]=[CH:14][CH:13]=[N:12]3)=[N:5][CH:6]=2)=[O:10])[C:50]2[CH:55]=[CH:54][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:52][CH:51]=2)=[CH:67][CH:66]=1
Reactant: CCOP(C)(=O)c1ccc(C(N)c2ccc(F)cc2)cc1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOP(C)(=O)c1ccc(C(NC(=O)c2cnc(-n3cccn3)nc2O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27 %

Procedure:
To a stirred solution of 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 8-b, (275 mg, 1.33 mmol) and Et3N (404 mg, 4 mmol) in MeCN (6 ml) was added HATU (558 mg, 1.47 mmol). The mixture was stirred for 5 min at room temperature and then compound 17-e (450 mg, 1.47 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. Then the mixture was concentrated under vacuum and the residue was taken into ethyl acetate followed by washing with 1N HCl. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel chromatography (CH2Cl2:CH3OH=50/1) to provide the product, 17-f, (180 mg, 27%).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([Cl:10])[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:13]>O>[Cl:1][C:2]1[N:9]=[C:8]([Cl:10])[C:7]([F:11])=[CH:6][C:3]=1[C:4]([NH2:5])=[O:13]
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: O=S(=O)(O)O
Solvent: O
Product: NC(=O)c1cc(F)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 82 %

Procedure:
A 12-L 3-neck round bottom flask equipped with overhead stirrer, refluxing condenser, and N2 inlet/outlet was charged with 2,6-dichloro-5-fluoronicotinonitrile (2.0 kg, 1.0 eq). Concentrated sulfuric acid (4.93 L) was added and the mixture was stirred at RT until most of the brown solids had dissolved. Next, the reaction mixture was stirred at 65° C. for 1 h. The dark-brown solution was cooled to a temperature<10° C. using an ice bath. The reaction mixture was added to a 50-L round bottom flask, which contained de-ionized water (24.7 L) that had been cooled to a temperature<10° C., using a peristaltic pump. The reaction mixture was added to the water quench over a 2.3 h period, which kept the internal temperature of the mixture below 21° C. The resulting slurry was filtered through a Buchner funnel fitted with a Sharkskin filter paper. The 50-L RBF was rinsed with water (3×4 L) and the rinses were used to wash the filter cake. The filter cake was conditioned for 50 min, transferred to a drying tray, and was dried under high vacuum at 40-50° C. for 24 h and then at 20-25° C. for 18 h to give the title compound as a beige solid (896.4 g, 82%). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.94 (s, 1 H), 8.10 (s, 1 H), 8.24 (d, 1 H). [M+H] calc'd for C6H3Cl2FN2O, 209; found, 209.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([F:13])[CH2:9]1)C1C=CC=CC=1.[C:14]([OH:17])(=[O:16])[CH3:15]>CO.[Pd]>[C:14]([OH:17])(=[O:16])[CH3:15].[F:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: FC1CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: FC1CCNC1

Procedure:
0.3 g (1.67 mmoles) of N-benzyl-3-fluoropyrrolidine, dissolved in 20 ml of methanol containing 2.1 ml of acetic acid, were hydrogenated at room temperature in a Parr apparatus at 50 psi in the presence of a catalytic amount of 10% Pd on charcoal, until the theoretical amount of H2 was consumed.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][NH:12][CH:11]([C:15](OCC)=[O:16])[C:10]=3[C:6]=2[CH:5]=[C:4]([S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.[BH4-].[Li+].O>C(O)C>[Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][NH:12][CH:11]([CH2:15][OH:16])[C:10]=3[C:6]=2[CH:5]=[C:4]([S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:3]=1
Reactant: CCOC(=O)C1NCCc2oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc3c21
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CCO
Product: O=S(=O)(c1ccccc1)c1cc(Cl)c2oc3c(c2c1)C(CO)NCC3
Reaction time: 3 h
Yield: 66.2 %

Procedure:
To a stirred solution of the product of step D (51 mg, 0.12 mmol) in ethanol (5 mL) was added lithium borohydride (44 mg, 2.00 mmol) at ambient temperature. After 3 h, water (2 mL) was added and the mixture was extracted with dichloromethane (3×10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 8:2 hexanes/ethyl acetate to ethyl acetate) to afford (6-chloro-8-(phenylsulfonyl)-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridin-1-yl)methanol (30 mg, 64%) as a brown oil: 1H NMR (CDCl3, 400 MHz) δ 8.01-7.94 (m, 3H), 7.82 (d, J=1.6 Hz, 1H), 7.57-7.50 (m, 3H), 4.23 (dd, J=4.0, 2.0 Hz, 1H), 3.95 (dd, J=11.2, 4.0 Hz, 1H), 3.77 (dd, J=10.8, 7.8 Hz, 1H), 3.31-3.17 (m, 2H), 2.84-2.81 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=[O:11])[CH:3]=[CH:2]1.[CH3:12][N+:13]([CH3:15])=[CH2:14].[I-]>C(#N)C>[CH3:12][N:13]([CH2:15][C:3]1[C:4]2[C:9](=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH3:14]
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: CC#N
Product: CN(C)Cc1c[nH]c2c(C=O)cccc12
Yield: 72.7 %

Procedure:
A mixture of 7-indolcarboxaldehyde (0.25 g, 1.7 mmol) and Eschenmoser's salt (0.35 g, 1.9 mmol) in dry acetonitrile (10 ml) was heated under reflux for 2½h. After cooling, solvent was removed under reduced pressure and water was added to the residue. The cooled mixture (ice bath) was made alkaline with 10% sodium hydroxide and then extracted with dichloromethane. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and evaporated to afford 0.25 g (74%) of the entitled product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].[ClH:10]>C(O)C.[Pd]>[ClH:10].[OH:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:1][NH2:2]
Reactant: N#Cc1cccc(O)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1cccc(O)c1
Reaction time: 2.5 h
Yield: 71.8 %

Procedure:
To a solution of 3-cyanophenol (30 g, 0.252 mol) in ethanol (150 mL) at 25° C. under an atmosphere of nitrogen, was added 10% palladium on carbon (3 g) ) followed by concentrated hydrochloric acid solution (23 mL, 0.277 mol). The reaction mixture was hydrogenated at 50 psi in a Parr apparatus for 2.5 h and was then filtered over Celite® and washed well with ethanol (100 mL). The solvents were concentrated under reduced pressure and the resulting solid was placed under vacuum for 1 h. The solid was dissolved in 150 mL of hot ethanol, filtered and crystallized by adding diethyl ether. The solids were collected by filtration, washed well with diethyl ether and dried under vacuum 24 h to give 3-hydroxybenzylamine hydrochloride (28.88 g, 71% yield) as a colorless solid.