Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:29][CH2:30][CH3:31])[C:17](N[C@H](C2C=CC=CC=2)CO)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:32]S(O)(=O)=O.[OH-].[Na+]>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C@H:16]([O:29][CH2:30][CH3:31])[C:17]([OH:18])=[O:32])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@@H](CO)c1ccccc1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Temperature: 80 °C
Reaction time: 15 h

Procedure:
(2S)-3-[4-(benzyloxy)phenyl]-2-ethoxy-N-[(1R)-2-hydroxy-1-phenylethyl ]propanamide (4.3 kg, 10.2 mol) were dissolved in dioxane (30 L) and diluted with deionized water (35 L). To this opaque reaction mixture, H2SO4 (19.2 kg, 192 mol) was added. The reaction temperature was raised to 80° C. and kept at 80° C. for 15 hours. The reaction mixture was extracted twice with TBME (64 L, 70 L) at room temperature. The combined organic phases were extracted twice with 1 M NaOH (2×20 L, 2×20 mol). The aqueous phases were acidified with H2SO4 (24 L, 24 mol), extracted with TBME (40 L) and the organic phases dried with saturated NaCl solution. The solution was concentrated to yield 64 L concentrate which contained 2.9 kg, 100% (GLC 68% area (2S)-3-[4-(benzyloxy) phenyl]-2-ethoxypropanoic acid and 28% area (2S)-2-ethoxy-(4-hydroxyphenyl) propanoic acid).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8](O)=[O:9])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:19])=O>CN(C=O)C>[C:1]([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:7]([C:8]([Cl:19])=[O:9])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(C(=O)O)cc1OC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cl)cc1OC(C)=O

Procedure:
Using the procedure in Example 85, step (a), 400 mg (1.90 mmol) of 3-acetyloxy-4-methoxybenzoic acid (as prepared in the previous step) was treated with 663 μL (7.60 mmol) of oxalyl chloride and 25 μL of anhyd DMF for 2 h to afford, after workup, the title compound as a beige crystalline solid which was used in the following step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[O:18][CH3:19])([O-])=O>CO.O=[Pt]=O>[CH3:19][O:18][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][C:4]=1[NH2:1]
Reactant: COc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: CO
Product: COc1ccc(OCc2ccccc2)cc1N
Yield: 76.4 %

Procedure:
2-Nitro-4-phenylmethoxy-anisole (73 g) and 1.3 g of platinium oxide in 600 ml of methanol were hydrogenated at room temperature. The catalyst was filtered on Celite and the methanol evaporated. The residue was dissolved in methylene chloride and washed with dilute sodium hydroxide then water. Evaporation of the solvent gave 49.35 g (Yield=76%) of 2-methoxy-5-phenylmethoxy-aniline.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>CS(C)=O.C(O)(C)C>[N+:8]([C:7]1[C:2]([NH2:1])=[N:3][C:4]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: C1CCNC1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: CS(C)=O
Product: Nc1nc(N2CCCC2)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 20 h
Yield: 91.7 %

Procedure:
A suspension of 1.735 g (10 mmol) of 2-amino-6-chloro-3-nitropyridine, 1.66 ml (20 mmol) of pyrrolidine and 1.66 ml (10 mmol) of diisopropylethylamine in a mixture of 1 ml of dimethyl sulfoxide and 5 ml of isopropanol is heated at 60° C., with stirring, in a sealed tube, for 20 hours. The mixture is cooled to ambient temperature and then diluted with 10 ml of isopropanol. The solid is collected by filtration and is then washed with 2×5 ml of isopropanol. The solid is taken up with 20 ml of water. The suspension is stirred for 30 minutes. The solid is filtered off and then washed with 2×5 ml of water and 2×5 ml of ether, and dried under vacuum in the presence of phosphorus pentoxide so as to obtain 1.91 g (9.17 mmol) of product in the form of a vivid yellow powder.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH2:8]([OH:13])[C:9]([F:12])([F:11])[F:10].Br[C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1>O>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([O:13][CH2:8][C:9]([F:12])([F:11])[F:10])=[N:16][CH:17]=1
Reactant: OCC(F)(F)F
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccc(Br)cn1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Sodium hydride (18.6 g, 60%, 464 mmol) was introduced into DMF (500 ml) under nitrogen. Trifluoroethanol (32.2 ml, 443 mmol) was added dropwise at 10° C. After 1 hour, 2,5-dibromopyridine (100 g, 422 mmol) was added portionwise, and the mixture was stirred in a water bath for 24 hours at 20° C. It was then stirred with water and extracted with heptane/ethyl acetate 9:1. Distillation of the crude product (105 g) yielded 5-bromo-2-trifluoroethoxypyridine, 82.1 g (purity 93%), colorless fluid, b.p. 97-104° C. at 18 mbar.
Reaction SMILES: [CH3:1][NH:2][O:3][CH3:4].[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[NH4+].[Cl-]>C1COCC1>[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([N:2]([O:3][CH3:4])[CH3:1])=[O:11])=[CH:8][CH:7]=1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of N,O-dimethylhydroxylamine (1.51 mmol; 147 mg) in dry THF (3 mL), under argon, was added at −78° C. nbutyllithium 2.5M (3.02 mmol; 1.21 mL). The mixture was stirred minutes at −78° C., before addition of 4-fluorobenzoyl chloride (1.26 mmol; 150 μL). The reaction was stirred overnight at room temperature, then treated with saturated NH4Cl and extracted with ethyl acetate. Combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo, to give the title compound (66%; 173 mg) as a yellow oil used without further purification.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH:10]=[O:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[C:12]([O:18][CH2:19]Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([C:5]1[N:6]([CH2:19][O:18][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[C:7]([CH:10]=[O:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCCCc1ncc(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1ncc(C=O)n1COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 79.8 %

Procedure:
A suspension of 2-butylimidazol-5-aldehyde (16.9 g, 0.111 mol), chloromethyl pivalate (21.77 g, 0.145 mol), and potassium carbonate (20.07 g, 0.145) in 200 ml of dimethylformamide was stirred at ambient temperature under argon for four days. The solids were removed by filteration and washed with ether. The combined filtrates were partitioned between diethyl ether and water. The ether phase was washed successively with water and brine, dried over magnesium sulfate and concentrated under vaccum to give 23.6 g of 2-n-butyl-1-pivalyloxymethylimidazol-5-carboxaldehyde.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:8]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C@@H:9]([CH3:14])[CH2:10][N:11]=[N+]=[N-])(=O)=O.N#N.CCN(C(C)C)C(C)C>CO.[Pd]>[Si:16]([O:15][C@@H:8]1[C@@H:9]([CH3:14])[CH2:10][NH:11][CH2:6][C@H:7]1[NH:23][C:24](=[O:25])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])([C:19]([CH3:21])([CH3:22])[CH3:20])([CH3:17])[CH3:18]
Reactant: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: N#N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 2 h
Yield: 96 %

Procedure:
A solution of (2R,3R,4S)-5-azido-2-[(tert-butoxycarbonyl)amino]-3-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentyl methanesulfonate (0.59 g, 1.3 mmol) in MeOH (10 mL) was deoxygenated with N2 for 20 min. DIPEA (0.55 mL, 3.2 mmol) was added, followed by 10 wt % Pd on carbon (0.1 g, 0.1 mmol). The mixture was hydrogenated at 1 atm. for 2 h, and then filtered. The filtrate was concentrated to afford the sub-title compound (0.43 g, 98%). LCMS calc. for C17H37N2O3Si (M+H)+: m/z=345.3. found 345.2. 1H NMR (500 MHz, CDCl3) δ 4.35 (bs, 1H), 3.32 (dt, J=13.1, 6.3 Hz, 1H), 3.25 (d, J=12.3 Hz, 1H), 3.04 (t, J=8.8 Hz, 1H), 2.94 (ddd, J=13.1, 4.1, 1.5 Hz, 1H), 2.33 (dd, J=12.6, 10.5 Hz, 1H), 2.24 (dd, J=13.1, 10.9 Hz, 1H), 1.76 (bs, 1H), 1.55 (tdd, J=8.9, 6.7, 4.2 Hz, 1H), 1.41 (s, 9H), 0.92 (d, J=6.6 Hz, 3H), 0.87 (s, 9H), 0.07 (d, J=10.3 Hz, 6H) ppm.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][NH:3][CH2:2]1.[N+:12]([O-])([OH:14])=[O:13].[OH-].[Na+]>OS(O)(=O)=O>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]2[CH2:5][CH2:4][NH:3][CH2:2][CH2:1][C:7]=2[CH:8]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)CCNCC2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Temperature: 0 °C
Reaction time: 0.38 h
Yield: 46 %

Procedure:
A solution of 2,3,4,5-tetrahydro-1H-benzo[d]azepine dissolved in conc. H2SO4 (1.5 mL) was cooled to 0° C. and a mixture of concentrated H2SO4 (0.12 mL) and fuming HNO3 (0.06 mL) (also cooled to 0° C.) was added dropwise. After the addition was complete, the mixture was stirred for 15-30 min. The reaction mixture was poured onto 10 g of crushed ice, followed by the dropwise addition of 20% NaOH solution. The mixture was extracted with EtOAc (3×). The organic layer was washed with H2O, dried (Na2SO4), concentrated and under vacuum to afford 7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a brown liquid (0.12 g, 46% yield). LC-MS (EI) m/z: 193.0 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])(O)=O.[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC#N>[CH2:16]([O:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[CH:9]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=Cc1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C
Yield: 84.7 %

Procedure:
To a solution of 2,4-dihydroxybenzaldehyde (100 g, 0.72 mol) in CH3CN (1.5 L), NaHCO3 (72.0 g, 0.86 mol) and benzyl bromide (145.4 g, 0.85 mol) were added and the reaction mixture was stirred under reflux. The reaction progression was followed by TLC and on completion the reaction mixture was cooled to room temperature and filtered. The organic solvents were evaporated under vacuum. The off white residue was recrystallized from MeOH to obtain 4-benzyloxy-2-hydroxybenzaldehyde (B2a) (140 g, 0.61 mol) in 85% yield: mp 77-79° C. [lit.42 mp 78-80° C.); TLC Rf 0.73 [EtOAc/hexanes (1:2)]; ((CD3)2CO, 600 MHz) δ 11.50 (1H, s), 9.88 (1H, br), 7.67 (1H, d, J=5.4 Hz), 7.50 (2H, d, J=7.2), 7.41 (2H, m), 7.36 (1H, m), 6.71 (1H, m), 6.57 (1H, s), 5.24 (2H, s).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:18]([O:25][C:26](=[O:29])[CH2:27][NH2:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.Cl>C(Cl)Cl.O>[CH2:18]([O:25][C:26](=[O:29])[CH2:27][NH:28][C:3](=[O:4])[CH:2]([Br:1])[CH3:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(Br)C(=O)Cl
Reactant: NCC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(Br)C(=O)NCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
55.9 9 (326.1 mmol) of 2-bromopropionic acid chloride is added in drops to 100 g (296.4 mmol) of glycine benzyl ester-p-toluenesulfonic acid salt and 33.0 g (326.1 mmol) of triethylamine in 400 ml of methylene chloride at 0° C. The temperature is not allowed to exceed 5° C. After the addition is completed, it is stirred for one hour at 0° C., then for 2 hours at room temperature. 500 ml of ice water is added, and the water phase is adjusted to pH 2 with 10% aqueous hydrochloric acid. The organic phase is separated and washed once each with 300 ml of 5% aqueous soda solution and 400 ml of water. The organic phase is dried on magnesium sulfate and evaporated to dryness in a vacuum. The residue is recrystallized from diisopropyl ether.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([Cl:31])[CH:22]=1.[CH3:32][N:33](C=O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[C-]#N.[Zn+2].[C-]#N>[Cl:31][C:23]1[CH:22]=[C:21]([C:32]#[N:33])[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1ccc(Br)cc1Cl
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C-]#N
Product: COC(=O)c1ccc(C#N)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of triphenylphosphine polymer bound (239 mg, 0.72 mmol) and palladium(II) acetate (75 mg, 0.33 mmol) was prepared in DMF (12 mL) under nitrogen atmosphere and stirred at RT for 2 hours. Zinc cyanide (561 mg, 4.77 mmol) and methyl 4-bromo-2-chlorobenzoate (1.19 g, 4.77 mmol) were added and the resulting mixture was heated under microwave irradiation at 140° C. for 50 minutes. The reaction mixture was filtered and the resin was washed with Et2O (3×10 mL). The combined organic layers were washed with water (3×5 mL) and brine (10 mL), dried (MgSO4) and concentrated under vacuum to give the title compound as a white powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.23 (m, 1H), 7.96 (m, 2H), 3.90 (s, 3H). HPLC (Method A) Rt 3.39 min (Purity: 97.6%).
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.CS(C)=O.[I:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>C1COCC1.O>[OH:3][N:2]=[C:20]([C:19]1[CH:22]=[CH:23][C:16]([I:15])=[CH:17][CH:18]=1)[NH2:21]
Reactant: N#Cc1ccc(I)cc1
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=NO)c1ccc(I)cc1
Reaction time: 1 h

Procedure:
17.3 g (249 mmol) of hydroxylamine hydrochloride and then 35 ml (251 mmol) of triethylamine are added to 80 ml of DMSO. A voluminous white precipitate forms, and the reaction mixture is diluted with a small amount of THF. After stirring for 1 hour, the precipitate is filtered off. The filtrate is collected and then transferred to a flask to which there are added 9.55 g (41.7 mmol) of 4-iodobenzonitrile. The reaction mixture is stirred overnight at ambient temperature and is then cooled in an ice bath and 200 mL of water are added. The precipitate is filtered off to yield the expected product.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:15](Cl)(=[O:17])[CH3:16]>C1COCC1>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:15](=[O:17])[CH3:16])[CH2:4][CH2:3]1
Reactant: OC1CCNCC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxypiperidine (5.00 g, 49.4 mmol) in anhydrous THF (30 mL) and triethylamine (10 mL, 75 mmol) was added acetyl chloride (3.52 mL, 49.4 mmol). After the addition, the mixture was stirred for another 2 hours at room temperature. The solid formed was filtered and the mother liquid was concentrated to yield 5.0 g of crude product, which was purified by column chromatography on silica gel (230-400 mesh), using 5% methanol in dichloromethane as eluent, to give 1-(4-hydroxy-piperidin-1-yl)-ethanone. Yield: 2.40 g (34%).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[O:12]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=2)=[CH:15][N:14]=[CH:13]1>ClCCl>[O:12]1[C:16]([C:17]2[CH:18]=[CH:19][C:20]([CH:23]=[O:24])=[CH:21][CH:22]=2)=[CH:15][N:14]=[CH:13]1
Reactant: OCc1ccc(-c2cnco2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc(-c2cnco2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
Pyridinium chlorochromate (517 mg) and Celite (3 g) were suspended in dichloromethane (20 mL), and a solution of [4-(1,3-oxazol-5-yl)phenyl]methanol (280 mg) in dichloromethane (5 mL) was added to the suspension, followed by stirring at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified through flash column chromatography (n-hexane:ethyl acetate=2:1), followed by concentration, to thereby yield the title compound (115 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].C(C1C(C(C)C)=C(C)C=CC=1)(C)C.[OH-].[Na+].[C:27](=[O:29])=[O:28].S(=O)(=O)(O)O>O>[OH:11][C:2]1[C:3]([C:27]([OH:29])=[O:28])=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: O=C=O
Reactant: Oc1ccc2ccccc2c1
Agent: Cc1cccc(C(C)C)c1C(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc2ccccc2cc1O
Temperature: 85 °C

Procedure:
A reactor was charged with 75 kg/hr of β-naphthol, 30 kg/hr of diisopropyltoluene and 30 kg/hr of a 45% aqueous sodium hydroxide solution for performing the formation of an alkali metal salt of β-naphthol and primary dehydration in a nitrogen atmosphere at 180° C. (residence time: 2 hr). The reaction mixture was fed to the second reactor at a rate of 119 kg/hr where it was subjected to reaction for the formation of an alkali metal salt of β-naphthol and secondary dehydration in a nitrogen atmosphere at 230° C. (residence time: 1 hr). A homogeneous liquid mixture (salt mass) in the second reactor was sent to a carboxylation reactor at a rate of 112 kg per hour where it was reacted with carbon dioxide at 260° C. at a CO2 pressure of 5 kg/cm2G (residence time: 2 hr). The reaction mixture was cooled through a heat exchanger and sent to a primary extraction tank where it was mixed with 200 l/hr of water, 306 kg/hr of diisopropyltoluene layer from a secondary extraction tank and 70% sulfuric acid to adjust its pH to 6.0 at a controlled temperature of 90° C. (residence time: 0.5 hr). The mixture was sent to a separation tank where it was separated into the diisopropyltoluene layer and the aqueous layer at 90° C. The upper diisopropyltoluene layer was freed of β-naphthol by a recovery device. The lower aqueous layer was supplied to the secondary extraction tank where it was mixed with 300 kg of diisopropyltoluene per hour at 90° C. (residence time: 0.5 hr). The mixture was then supplied to a separation tank where it was separated into the diisopropyltoluene layer and the aqueous layer at 85° C. The upper diisopropyltoluene layer was returned to the primary extraction tank and the lower aqueous layer was transferred to an acid precipitation tank where it was adjusted to a pH of 2.0 with dilute sulfuric acid at 85° C. The resulting precipitate was filtered under heat at 85° C. to give 27.8 kg/hr of 2-hydroxynaphthalene-3-carboxylic acid (99% purity and β-naphthol content of 0.1%). The yield of 2-hydroxynaphthalene-3-carboxylic acid was 43.8% based on the sodium salt of β-naphthol and 88.5% based on β-naphthol consumed. The β-naphthol recovered was 50.9 kg per hour.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>>[CH3:9][O:8][C:7]1[C:2]([NH:11][NH2:12])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: NN
Reactant: COc1cccnc1Cl
Solvent: O
Product: COc1cccnc1NN
Temperature: 25 °C
Yield: 57 %

Procedure:
A stirred solution of 2-chloro-3-methoxypyridine (4.86 g, 33.8 mmol) in hydrazine hydrate (40 mL) was heated under reflux for 1.5 hours. After cooling to RT, the reaction mixture was evaporated to dryness. The resulting residue was partitioned between 10% MeOH in CHCl3 and 40% w/v aqueous potassium carbonate. The aqueous phase was isolated and extracted twice with 10% MeOH in CHCl3. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (2.7 g, 57%) as a buff solid. 1H NMR (300 MHz, DMSO-d6): δ 7.65 (dd, J=5.1 and 1.3 Hz, 1H), 6.99 (dd, J=7.7 and 1.3 Hz, 1H) overlapped with 6.98 (br s, 1H), 6.56 (dd, J=7.6 and 5.1 Hz, 1H), 4.05 (br s, 2H), 3.76 (s, 3H). LCMS (Method A): RT=0.34 min, [M+H]+=140.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH:7]([CH3:9])[C:6]2[CH:10]=[C:11](Br)[CH:12]=[CH:13][C:5]=2[CH2:4][CH2:3]1.CN1CC(C)C2C=C(I)C=CC=2CC1.CN1CC(CC)C2C=C(C(F)(F)F)C=CC=2CC1.CN1CC(CC)C2C=C([Cl:61])C=CC=2CC1.CN1CC(CC)C2C=C(Br)C=CC=2CC1.CN1CC(CC)C2C=C(I)C=CC=2CC1.CN1CC(C)C2C=C(Cl)C(Cl)=CC=2CC1.CN1CC(CC)C2C=C(Cl)C(Cl)=CC=2CC1.CN1CC(C)C2C=C(Cl)C(F)=CC=2CC1.CN1CC(CC)C2C=C(Cl)C(F)=CC=2CC1>>[CH3:1][N:2]1[CH2:8][CH:7]([CH3:9])[C:6]2[CH:10]=[C:11]([Cl:61])[CH:12]=[CH:13][C:5]=2[CH2:4][CH2:3]1
Reactant: CC1CN(C)CCc2ccc(Br)cc21
Reactant: CCC1CN(C)CCc2ccc(Cl)cc21
Agent: CC1CN(C)CCc2cc(Cl)c(Cl)cc21
Agent: CC1CN(C)CCc2cc(F)c(Cl)cc21
Agent: CC1CN(C)CCc2ccc(I)cc21
Product: CC1CN(C)CCc2ccc(Cl)cc21

Procedure:
N-methyl-8-Bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-Iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-Trifluoromethyl-1-methyl-2,3,4,5-tetrahydro-1-3-benzazepine; N-methyl-8-Trifluoromethyl-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-Chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-Bromo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-Iodo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-7,8-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-7,8-Dichloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-Chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; and N-methyl-8-Chloro-7-fluoro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; or a pharmaceutically acceptable salt, solvate or hydrate thereof
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]1[CH2:9][C:8](=[O:10])[O:7][C:5](=[O:6])[CH2:4]1.ClCl.[Cl:15][C:16]1[C:22]([O:23][CH2:24][C:25]#[CH:26])=[CH:21][C:19]([NH2:20])=[C:18]([F:27])[CH:17]=1>C(Cl)Cl>[Cl:15][C:16]1[C:22]([O:23][CH2:24][C:25]#[CH:26])=[CH:21][C:19]([NH:20][C:8](=[O:10])[CH2:9][CH:3]([C:2]([F:1])([F:12])[F:11])[CH2:4][C:5]([OH:7])=[O:6])=[C:18]([F:27])[CH:17]=1
Reactant: C#CCOc1cc(N)c(F)cc1Cl
Reactant: O=C1CC(C(F)(F)F)CC(=O)O1
Agent: ClCl
Solvent: ClCCl
Product: C#CCOc1cc(NC(=O)CC(CC(=O)O)C(F)(F)F)c(F)cc1Cl

Procedure:
Into a 1 liter three-necked round-bottomed flask equipped with overhead stirrer, dropping funnel, thermometer and nitrogen (N2) inlet were placed 3-(trifluoromethyl)glutaric anhydride (18.2 g, 0.100 tool) and methylene chloride (CH2 -Cl2) (250 ml). The mixture was stirred to homogeneity and a solution of 4-chloro-2-fluoro-5-propargyloxyaniline (19.9 g, 0.100 mol) in CH2 -Cl2 (50 ml) was added dropwise over 10 minutes to give a clear solution. The mixture was stirred overnight at ambient temperature, during which time a thick white precipitate was formed.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#N.CC(C[AlH]CC(C)C)C.C(O)(=[O:25])C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:25]
Reactant: N#Cc1ccc(C(F)(F)F)nc1Cl
Reactant: CC(=O)O
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: O=Cc1ccc(C(F)(F)F)nc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
2-Chloro-6-(trifluoromethyl)nicotinonitrile (1.0 g, 4.84 mmol) was diluted with toluene (5.0 mL), placed under nitrogen and cooled to −78° C. DIBAL-H (9.68 mL, 9.68 mmol) was added dropwise and the reaction was stirred for 1 hour. The reaction was warmed to 0° C. and acetic acid (2 mL in 8 mL of water) was added dropwise. After stirring for 2 hours, the reaction was extracted twice with ethyl acetate, washed with Rochelle's salt, dried over MgSO4, filtered and concentrated. The material was loaded onto silica gel and eluted with 5% ethyl acetate/hexanes to 30% ethyl acetate/hexanes to yield 2-chloro-6-(trifluoromethyl)nicotinaldehyde (337 mg, 1.61 mmol, 33.2% yield) as a clear oil.