Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]#[C:16][C:17]2[CH:18]=[C:19]([CH:24]=[C:25]([N+:27]([O-])=O)[CH:26]=2)[C:20]([O:22][CH3:23])=[O:21])[CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:27][C:25]1[CH:24]=[C:19]([CH:18]=[C:17]([CH2:16][CH2:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:10]=2)[CH:26]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1cc(C#Cc2cccc(NC(=O)OC(C)(C)C)c2)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)cc(CCc2cccc(NC(=O)OC(C)(C)C)c2)c1
Reaction time: 72 h
Yield: 98.3 %

Procedure:
To a solution of methyl 3-({3-[(tert-butoxycarbonyl)amino]phenyl}ethynyl)-5-nitrobenzoate (1.85 g, 4.67 mmol) in methanol (50 mL) was added 10% palladium on carbon (1.85 g, 1.58 mmol), and the mixture was hydrogenated under 55 psi of H2 for 72 hours with shaking. The solution was filtered through a pad of celite, and filtrate was concentrated. The residue was purified by flash column chromatography to give the desired product as a yellow oil (1.70 g, 98%). LCMS for C21H27N2O4 (M+H)+: m/z=371.1.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9]O.[Ge]=O.[O-2].[Ba+2]>[O-2].[Fe+2].[O-2].[Cr+3].[O-2].[O-2].[Cr+3].O>[C:6]1([OH:7])[C:5]([CH3:9])=[CH:4][CH:3]=[CH:2][C:1]=1[CH3:8]
Reactant: Cc1ccccc1O
Reactant: CO
Agent: [Cr+3]
Agent: [Fe+2]
Agent: O=[Ge]
Solvent: O
Product: Cc1cccc(C)c1O

Procedure:
o-cresol, methanol and water in a ratio of 1:2.5:2.5 were reacted in the same way as described in Example 1. The catalyst considered iron oxide, germanium oxide, chromium oxide and barium oxide in a ratio of 100:2:10:1. After working up, 2,6-xylenol was obtained with a selectivity of 99.2%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2.O.C(=O)([O-])[O-:18].[K+].[K+]>COCCOC>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([OH:18])[CH2:10][CH:9]=[CH:8]2
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Cc1ccc2ncccc2c1
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1ccc2c(c1)C=CCN2O
Reaction time: 2 h

Procedure:
m-Perchlorobenzoic acid (6.85 g, 39.8 mmol) was added to a solution of commercially available quinolin-6-yl-acetic acid methyl ester (5.00 g, 24.8 mmol) in 1,2-dimethoxyethane at room temperature and stirred for 2 hours. Water was added and the solution was basified to pH 9-10 with saturated potassium carbonate and the product was extracted with ethyl acetate to give quantitative yield of (1-hydroxy-quinolin-6-yl)-acetic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, 1H, J=8.4 Hz), 7.93 (d, 1H, J=8.4 Hz), 7.65 (m, 1H), 7.60 (m, 1H), 7.32 (d, 1H, J=8.8 Hz), 7.19 (s, 1H), 3.74 (s, 2H), 3.65 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>[Pd].O.C(O)C>[CH2:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([F:16])[CH:18]=3)=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH3:15]
Reactant: CCc1ccc(-c2ccc(Br)cc2)cc1
Reactant: OB(O)c1cccc(F)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1ccc(-c2ccc(-c3cccc(F)c3)cc2)cc1
Yield: 145.4 %

Procedure:
A mixture of 5.6 g (21.4 mmol) of 4-bromo-4′-ethylbiphenyl, 3.6 g (25.7 mmol) of 3-fluorophenyl dihydroxyborane, 4.4 g (32.2 mmol) of potassium carbonate, 0.3 g of 5%-Pd/C and 60 mL of a mixed solvent of toluene, ethanol and water (ratio: 1/1/1) was refluxed for 6 hours to obtain a reaction solution. After removing the catalyst by filtration, 50 mL of toluene was added to the reaction solution, which was then washed with water. The reaction solution having been washed with water was dried over anhydrous magnesium sulfate, and the solvent was distilled off from the reaction solution under reduced pressure to obtain 8.6 g of a residue. The residue was purified by silica gel column chromatography (eluent: heptane/toluene=4/1) to obtain 5.1 g of crude crystals of the compound (E-8). The crude crystals were dissolved in a mixed solvent of ethanol and ethyl acetate (ratio: 10/1) and recrystallized therefrom to obtain 4.5 g of purified crystals of the compound (E-8).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:11]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:10][C:7]([CH:8]=O)=[C:6]([O:17][CH3:18])[CH:5]=1)[CH3:2].[C:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>>[CH2:1]([O:3][C:4]1[C:11]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:10][C:7](/[CH:8]=[CH:20]/[C:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)=[O:21])=[C:6]([O:17][CH3:18])[CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: CCOc1cc(OC)c(C=O)cc1-c1cccs1
Product: CCOc1cc(OC)c(/C=C/C(=O)c2ccc(C(=O)O)cc2)cc1-c1cccs1
Yield: 76 %

Procedure:
The title compound was prepared by condensing 4-ethoxy-2-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-53A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 210–212° C., 76% yield. 1H-NMR (300 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.23 (d, 2H, J=9.0 Hz), 8.06–8.11 (m, 3H), 7.92 (d, 1H, J=16.2 Hz), 7.71 (d, 1H, J=3.9 Hz), 7.52 (d, 1H, J=5.1 Hz), 7.13 (dd, 1H, J=5.1, 3.9 Hz), 6.82 (s, 1H), 4.33 (q, 2H, J=6.1 Hz), 3.99 (s, 3H), 1.48 (t, 3H, J=6.1 Hz). MS (ESI) m/z=409 ([M+H]+, 100%). Anal. Calcd. for C23H20O5S.½H2O: C, 66.17; H, 5.07; S, 7.68. Found: C, 65.88; H, 5.24; S, 7.36.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23][C@H:24]2[O:41][C@H:40]([CH2:42][O:43]C(=O)C)[C@@H:35]([O:36]C(=O)C)[C@H:30]([O:31]C(=O)C)[C@H:25]2[O:26]C(=O)C)[C@@H:16]([CH2:47][O:48]C(=O)C)[O:15][C@H:6]1[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([SH:14])[CH:9]=1)(=O)C.[Na]>CO>[C@H:24]1([O:23][C@@H:17]2[C@@H:16]([CH2:47][OH:48])[O:15][C@@H:6]([S:7][C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([SH:14])[CH:9]=3)[C@H:5]([OH:4])[C@H:18]2[OH:19])[O:41][C@H:40]([CH2:42][OH:43])[C@@H:35]([OH:36])[C@H:30]([OH:31])[C@H:25]1[OH:26]
Reactant: CC(=O)OC[C@H]1O[C@@H](Sc2cccc(S)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1O[C@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Na]
Solvent: CO
Product: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](Sc3cccc(S)c3)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 3 h
Yield: 86.3 %

Procedure:
To a solution of 5.1 g of 3-mercaptophenyl 2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-1-thio-β-D-glucopyranoside in 50 ml of methanol was added 0.15 g of sodium spheres. The reaction was stirred 3 hours, concentrated in vacuo and warmed with 50 ml of methanol:water (1:1). This reaction was filtered, the filtrate stirred with Dowex® 50WX8 resin and refiltered. This filtrate was concentrated in vacuo, giving 2.7 g of the desired intermediate as a yellow solid, [α]D26 =+81°±1° (0.818%, methanol).
Reaction SMILES: [OH:1][N:2]=C(C1C=CC2NC=NC=2C=1)N.[C:14]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[NH:21][C:20]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:19]2)#[N:15]>>[NH2:15][C:14](=[N:2][OH:1])[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[NH:21][C:20]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:19]2
Reactant: CCOC(=O)c1cc2cc(C#N)c(OC)cc2[nH]1
Reactant: NC(=NO)c1ccc2[nH]cnc2c1
Product: CCOC(=O)c1cc2cc(C(N)=NO)c(OC)cc2[nH]1

Procedure:
The title compound was prepared following procedure described for Intermediate 1, step 2, but starting from ethyl 5-cyano-6-methoxy-1H-indole-2-carboxylate obtained in step 1 (120 mg; 0.49 mmol) as a beige solid (135 mg, 99%). 1H NMR (DMSO-d5) δ 9.25 (s, 1H), 7.60 (s, 1H), 7.11 (s, 1H), 6.90 (s, 1H), 5.53 (bs, 2H), 4.31 (q, J=7 Hz, 2H), 3.80 (s, 3H), 1.32 (t, J=7 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16](B(O)O)=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.I[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO.COCCOC.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:26]=4[O:27][CH3:28])=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccnc2c1cnn2-c1ccc(F)cc1
Reactant: COc1ccncc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: COc1ccncc1-c1ccnc2c1cnn2-c1ccc(F)cc1
Temperature: 105 °C
Yield: 31.4 %

Procedure:
Example 6 was prepared according to the general procedure of Example 1, except that the reaction mixture was heated at 105° C. for 2.25 h and using the following materials: Intermediate 5A (38.0 mg, 0.148 mmol), 3-iodo-4-methoxypyridine (86.2 mg, 0.367 mmol), sodium carbonate (56.1 mg, 0.529 mmol), degassed EtOH:DME:H2O (1.2:2.5:1.0 ratio) (1.5 mL) and tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.015 mmol). Example 6 was isolated as an off white solid (14.9 mg, 31.1%). Purification was done by preparative HPLC (Condition A) using a Phenomenex Luna Axia 30×100 mm S10 column from 10% Solvent B to 95% Solvent B over 12 min, ret. T=8.6 min. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.75 (1 H, d, J=4.88 Hz), 8.64 (1 H, d, J=5.80 Hz), 8.59 (1 H, s), 8.27-8.36 (3 H, m), 7.42-7.51 (3 H, m), 7.35 (1 H, d, J=6.10 Hz), 3.93 (3 H, s). LC/MS (Condition B): ret. T=2.84 min, (M+H)+ 321.05. Analytical HPLC: (Condition A): >99%, ret. T=22.96 min, (Condition B): >99%, ret. T=23.17 min, (Condition C): >99%, ret. T=9.33 min, (Condition D): >99%, ret. T=9.91 min.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[N:16][CH:17]=3)=[C:9]([C:24]3[CH:29]=[CH:28][C:27]([O:30]C)=[CH:26][CH:25]=3)[S:8][C:7]=2[CH:32]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[N:16][CH:17]=3)=[C:9]([C:24]3[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=3)[S:8][C:7]=2[CH:32]=1
Reactant: COC(=O)/C=C/c1ccc(Oc2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cn1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc(Oc2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (E)-methyl 3-(5-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)acrylate (0.096 g, 0.215 mmol) in DCM (2.145 mL) at room temperature was added BBr3 (1.0 M in heptane, 0.858 mL, 0.86 mmol) and the reaction was stirred at room temperature for 30 min. Upon completion the reaction was quenched with MeOH (2.0 mL) and stirred for 10 min at room temperature then concentrated in vacuo onto silica gel then purified by column chromatography (SiO2, 0-20% MeOH/DCM) to afford (E)-methyl 3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)acrylate. LC/MS (m/z, MH+): 420.3.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH2:10]1[CH2:23][O:22][C:12]2([CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][C:14]([CH3:21])([CH3:20])[CH2:13]2)[O:11]1>C1(C)C(C)=CC=CC=1>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:15]2[C:16]([CH3:19])([CH3:18])[CH2:17][C:12]3([O:11][CH2:10][CH2:23][O:22]3)[CH2:13][C:14]2([CH3:21])[CH3:20])[N:7]=1
Reactant: CC1(C)CC2(CC(C)(C)N1)OCCO2
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: Cc1ccccc1C
Product: CC1(C)CC2(CC(C)(C)N1c1nc(Cl)nc(Cl)n1)OCCO2

Procedure:
A solution of 55.3 g (0.3 mol) of cyanuric chloride in 300 ml of xylene is added dropwise with stirring and cooling to 0°-5° to a solution of 119.6 g (0.6 mol) of 4,4-ethylenedioxy-2,2,6,6-tetramethylpiperidine in 100 ml of xylene. The mixture is subsequently heated to reflux and kept at boiling point for 26 hours. After addition of 150 ml of xylene, the mixture is allowed to cool and the precipitate is filtered off. The filtrate is evaporated in vacuo. The residue is recrystallized from 300 ml of acetonitrile. The product obtained is a brownish powder which melts at 169°-172°.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][CH2:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1.[CH:17](OCC)(OCC)OCC.C(O)C.[BH4-].[Na+]>C(OCC)(=O)C>[CH3:17][NH:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][CH2:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: Nc1ccc2c(c1)C(=O)c1cccn1CC2
Reactant: CCOC(OCC)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNc1ccc2c(c1)C(=O)c1cccn1CC2
Reaction time: 2 h

Procedure:
A solution of 9-amino-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one in triethyl orthoformate (2.14 g.; 10 mmoles in 80 ml) is refluxed for 5 hours. The volatiles are removed under vacuum and the residue dissolved in 100 ml. of absolute ethanol is stirred in an ice bath as sodium borohydride (0.88 g.; 0.024 moles) is added over a period of 10 minutes. The mixture is stirred for a period of 2 hours. After concentration of the ethanol, the residue is dissolved in ethyl acetate, washed with water, dried over Na2SO4 and concentrated to dryness to yield 9-methylamino-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one.
Reaction SMILES: [CH3:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:11][Si](C=[N+]=[N-])(C)C>CO.CCOCC>[CH3:1][C:2]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC1(C(=O)O)CCCCC1
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C1(C)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Treat a solution of 1-methylcyclohexane carboxylic acid (7.11 g, 50.0 mmol) in MeOH (10 mL) and Et2O (40 mL) dropwise with trimethylsilyldiazomethane (2.0 M/hexanes; 26 mL, 52 mmol). Stir the reaction mixture at room temperature overnight, then concentrate under reduced pressure to yield the title compound as a clear, pale yellow oil (7.811 g, 50 mmol; 100%). MS(ES): m/z=156 [M+H].
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:11])[CH:8]=2)[C:3]1=[O:12].[S:13]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[S:22])=[CH:19][CH:18]=1)(=[O:16])(=[O:15])[NH2:14]>>[Cl:11][C:7]1[CH:6]=[CH:5][C:4]2[C:3]3([OH:12])[N:23]=[C:21]([C:20]4[CH:19]=[CH:18][C:17]([S:13]([NH2:14])(=[O:15])=[O:16])=[CH:25][CH:24]=4)[S:22][CH:2]3[CH2:10][C:9]=2[CH:8]=1
Reactant: NC(=S)c1ccc(S(N)(=O)=O)cc1
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Product: NS(=O)(=O)c1ccc(C2=NC3(O)c4ccc(Cl)cc4CC3S2)cc1

Procedure:
4-(6-Chloro-3a-hydroxy-8,8a-dihydro-3aH-indeno[1,2-d]thiazol-2-yl)benzenesulfonamide is prepared in a similar manner by reacting 2-bromo-5-chloroindan-1-one with 4-sulfamoylthiobenzamide. The compound has a melting point of 160° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][N:11](C(=O)C)[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[CH:8]([OH:20])[CH2:7][C:6]=2[CH:21]=1>CO.O=[Mn]=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][NH:11][C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[C:8](=[O:20])[CH2:7][C:6]=2[CH:21]=1
Reactant: CC(=O)N1Cc2ccc(Br)cc2CC(O)c2ccccc21
Agent: O=[Mn]=O
Solvent: CO
Product: O=C1Cc2cc(Br)ccc2CNc2ccccc21
Reaction time: 36 h
Yield: 49 %

Procedure:
To a solution of 1-(9-Bromo-1 2-hydroxy-11,12-dihydro-6H-dibenzo[b,f]azocin-5-yl)-ethanone (prepared similar to Example 1E using the appropriate starting materials) (50 mg, 0.17 mmol) in MeOH (5 mL) was added MnO2 (72 mg, 0.83 mmol). The mixture was stirred under argon for 36 hours, filtered, and the filtrate was concentrated. The resulting residue was dissolved in THF (5 mL), MnO2 (144 mg, 1.66 mmol) was added, and the resulting mixture was stirred at room temperature overnight. The suspension was filtered, concentrated and purified by flash chromatography (SiO2, 15% EtOAc/hexanes) to afford Example 213A (25 mg, 49%) as an off-white solid.
Reaction SMILES: [CH:1]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14](F)[C:11]=1[C:12]#[N:13]>>[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:8][CH:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c(N)cccc1F
Reactant: OC1CCCCCC1
Product: N#Cc1c(N)cccc1OC1CCCCCC1

Procedure:
Prepared as in Example 22b from cycloheptanol and 2-amino-6-fluorobenzonitrile as yellow oil (11%). 1H NR (400 MHz, DMSO-d6) δ 1.42-1.71 (m, 10H), 1.88-1.93 (m, 2H), 4.56 (m, 1H), 5.95 (s, 2H), 6.20 (d, J=8.0 Hz, 1H), 6.30 (d, J=8.0 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H). MS 231 (MH+).
Reaction SMILES: [OH-].[Na+].[CH3:3][NH:4][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)[CH2:22][C:23]([O:25]CC)=[O:24])=[CH:16][CH:15]=2)[CH:8]=[CH:7][CH:6]=1>CO>[CH3:3][NH:4][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH:21]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:33]=3)[CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:19]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)CC(Cc1ccc(OCCc2cccc(NC)n2)cc1)c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNc1cccc(CCOc2ccc(CC(CC(=O)O)c3ccc(C(F)(F)F)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.8 %

Procedure:
1.0 N NaOH (8.2 mL, 0.823 mmole) was added dropwise to a cooled (15° C.) solution of ethyl (±)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-1 ethoxy]phenyl]-3-[4-(trifluoromethyl)phenyl)butanoate (200 mg, 0.41 mmole) in MeOH (3 mL), and the mixture was stirred at RT for 24 hr. The resulting solution was concentrated in vacuum and the residue was dissolved in H2O (5 mL). The pH was adjusted to 5 with 1.0 N HCl, and the precipitate was collected, washed with small amount of water, and dried in vacuum at 60° C. The title compound (120 mg, 64%) was obtained as a white, foamy solid: MS (ES) me 459 (M+H)+. Anal. Calcd for C25H25FN2O3.0.85H2O: C, 63.38; H, 5.68; N, 5.91. Found: C, 63.23; H, 5.41; N, 5.73.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[C:23]([CH2:22][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)([O:25][CH2:26][CH3:27])=[O:24]
Reactant: O=C1CCC(c2ccc(O)cc2)=NN1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C2=NNC(=O)CC2)cc1
Temperature: 100 °C
Yield: 69.3 %

Procedure:
A mixture of 2.00 g (10.5 mmol) of the phenol prepared above, 1.60 g (11.6 mmol) of anhydrous K2CO3, 1.304 ml (11.8 mmol) of ethyl bromoacetate, and 40 ml of DMF is heated at 100° C. for 2 hrs under N2. The DMF is removed under vacuum and the residue taken up in 150 ml of EtOAc and 75 ml of water. The organic phase is washed with 50 ml of 5% aqueous NaOH, twice with saturated NaCl, dried (MgSO4), filtered, and the solvent removed to leave 2.186 g of a slightly yellow solid. This is recrystallized from hexane-EtOAc to give 2.01 g of 6-(4-carboethoxymethoxyphenyl)-4,5-dihydro-3(2H)-pyridazinone as a white, crystalline solid, m.p. 127°-129° C. Yield 69%.
Reaction SMILES: [BH4-].[Na+].CCO.[CH3:6][CH:7]([O:21][C:22]([O:24][C:25]1[C:32]([CH3:33])=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][C:26]=1[CH3:34])=[O:23])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19]>C(Cl)Cl>[CH3:6][CH:7]([O:21][C:22]([O:24][C:25]1[C:26]([CH3:34])=[CH:27][C:28]([CH2:29][OH:30])=[CH:31][C:32]=1[CH3:33])=[O:23])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19]
Reactant: COc1cc(C(C)OC(=O)Oc2c(C)cc(C=O)cc2C)c([N+](=O)[O-])cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1cc(C(C)OC(=O)Oc2c(C)cc(CO)cc2C)c([N+](=O)[O-])cc1OC
Yield: 74 %

Procedure:
Sodium borohydride (9 ing, 0.25 inmol) followed by EtOH (0.5 mL) was added to 7k (100 mg, 0.25 mmol) in CH2Cl2 (2 mL) at r.t. and then refluxed for 30 minutes. Aqueous workup (CH2Cl2, MgSO4) followed by concentration in vacuo yielded 8k (75 mg, 75%) as a light yellow solid: 1H NMR (270 MHz, CDCl3) d 1.68 (d, J=6.4 Hz, 3H), 2.03 (s, 6H), 3.86 (s, 3H), 3.91 (s, 3H), 4.45 (s, 2H), 6.39 (q, J=6.4 Hz, 1H), 6.92 (s, 2H), 7.06 (s, 1H), 7.52 (s, 1H); 13C NMR (68 MHz, CDCl3) d 16.0, 21.9, 56.3, 56.4, 64.4, 73.0, 107.4, 107.6, 127.2, 129.9, 132.3, 138.7, 139.8, 147.4, 148.1, 151.7, 153.7.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.C1(C)C=CC(S(O[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)(=O)=O)=CC=1>>[F:37][C:33]1[CH:32]=[C:31]([CH2:30][CH2:29][N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]34[CH2:18][CH:13]5[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]5)[CH2:10]3)[CH2:16]4)=[O:8])[CH2:2]2)[CH:36]=[CH:35][CH:34]=1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(S(=O)(=O)OCCc2cccc(F)c2)cc1
Product: O=C(N[C@H]1CCN(CCc2cccc(F)c2)C1)C12CC3CC(CC(C3)C1)C2
Yield: 29.6 %

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide (0.5 g) and 2-(3-fluorophenyl)ethyl p-toluenesulfonate (0.59 g) were reacted under the same conditions as in Example 6 to give (S)-N-(1-(2-(3-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide (0.22 g), melting point 87-89° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])=[CH:12][C:11]=1[Cl:23])(=O)C.[OH-].[Na+].O.Cl>CO>[Cl:22][C:20]([Cl:21])=[CH:19][CH2:18][O:17][C:13]1[CH:12]=[C:11]([Cl:23])[C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:4])=[C:15]([Cl:16])[CH:14]=1
Reactant: CC(=O)OCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
Twenty seven grams (0.067 mole) of 4-[4-(3,3-dichloroprop-2-enyloxy)-2,6-dichlorophenoxy]butyl acetate was stirred and a solution of 5.4 grams (0.134 mole) of sodium hydroxide in 300 mL of methanol was added portion-wise. Upon completion of addition the reaction mixture was stirred at ambient temperature during a two hour period. After this time the reaction mixture was stirred with 400 mL of water and was neutralized with concentrated hydrochloric acid. The neutral mixture was extracted with four 150 mL portions of diethyl ether, and the combined extracted were washed with one 150 mL portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a residue, yielding 22.5 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([NH:10][CH3:11])[C:7]([F:12])=[CH:6][C:3]=1[C:4]#N.[H-].C([Al+]CC(C)C)C(C)C.C[OH:24].Cl>C(OCC)C>[F:1][C:2]1[CH:9]=[C:8]([NH:10][CH3:11])[C:7]([F:12])=[CH:6][C:3]=1[CH:4]=[O:24]
Reactant: CO
Reactant: CNc1cc(F)c(C#N)cc1F
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOCC
Product: CNc1cc(F)c(C=O)cc1F
Reaction time: 16 h

Procedure:
To a solution of 2,5-difluoro-4-methylaminobenzonitrile (0.509 g, 3.03 mmol) in dry diethyl ether (40 ml) stirred at room temperature under nitrogen, was added dropwise by syringe diisobutylaluminium hydride (5.5 ml, 1.0 M in toluene, 5.5 mmol) and stirring continued for 16 h. The solution was chilled in an ice-bath and methanol (2.8 ml) was added dropwise and the mixture stirred for 1 h before 1.0 M HCl (17 ml) was added and stirring continued for a further 1 h. The reaction mixture was then partitioned between ether (50 ml) and water (50 ml) and the aqueous layer re-extracted with ether (50 ml). The combined ether extract was washed with 5% sodium bicarbonate solution (34 ml), then brine, dried (MgSO4) and evaporated to give a mixture of the desired aldehyde and unhydrolysed imine (0.511 g). The material was filtered through a plug of silica gel using 100% dichloromethane to give pure 2,5-difluoro-4-methylaminobenzaldehyde (x).