Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+].[CH:12](=O)[CH3:13]>C1(C)C=CC=CC=1.[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[CH:1]1([CH:7]([CH:6]2[C:12]3[C:13](=[CH:9][CH:1]=[CH:2][CH:3]=3)[CH:4]=[CH:5]2)[CH3:8])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C1=Cc2ccccc2C1
Reactant: CC=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C1C=Cc2ccccc21)C1C=Cc2ccccc21
Reaction time: 0.5 h
Yield: 82 %

Procedure:
100.0 g (0.86 mol) of indene are dissolved in 400 ml of toluene and a solution of 86.2 g (2.2 mol) of sodium hydroxide and 19.6 g (86 mmol) of triethylbenzylammonium chloride in 86.2 ml of water (50% strength NaOH solution) is then added. The addition of 18.9 g (0.43 mol) of acetaldehyde is carried out dropwise over a period of 30 minutes. After a reaction time of 5 hours, the aqueous phase is separated off, extracted twice with 100 ml each time of diethyl ether and the combined organic phases are dried over MgSO4. The solvent is removed under reduced pressure and the crude product is purified by recrystallization from toluene/hexane. This gives 91.5 g of 1,1-bisindenylethane in 82% yield in the form of a yellow powder.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([C:2]2[CH:3]=[N:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(O)c1ncc(Br)cn1
Product: O=C(O)c1ncc(-c2ccccc2)cn1

Procedure:
Conducting the operations similar to those of Production Example 14 using 5-bromopyrimidine-2-carboxylic acid and phenylboronic acid, the title compound was obtained as white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[OH:55][CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>CN(C=O)C>[OH:55][CH:56]1[CH2:61][CH2:60][N:59]([C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:23][CH:22]=2)=[O:21])[CH2:58][CH2:57]1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: OC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCC(O)CC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (114 mg, 0.35 mmol), N,N-diisopropyl ethyl amine (275 μL, 1.6 mmol) and 4-hydroxypiperidine (1 M solution in MeOH, 354 μL, 0.35 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (93 mg, 73%) which was obtained as a white solid. MS: m/e=394.2 [M+H]+.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:22])[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([OH:21])[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1.[BH4-].[Na+]>CO>[OH:1][NH:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([OH:21])[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1
Reactant: O=C(C=CCCCCC(O)c1ccc2ccccc2c1)NO
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(CCCCCCC(O)c1ccc2ccccc2c1)NO
Reaction time: 0.25 h
Yield: 46 %

Procedure:
To a solution of 187 (20 mg, 0.067 mmol) in methanol (670 μL) was added solid sodium borohydride (2.5 mg, 0.067 mmol). The mixture was stirred for 15 minutes and the solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was dried (MgSO4) and concentrated. Purification by flash silica gel chromatography (6% methanol in dichloromethane) afforded the title compound 188 in 46% yield (9.1 mg). 1H NMR: (300 MHz, CD3OD) δ: 7.84-7.76 (m, 4H), 7.50-7.40 (m, 3H), 4.75 (t, J=6.6 Hz, 1H), 2.05 (t, J=7.4 Hz, 2H), 1.86-1.76 (m, 2H), 1.62-1.55 (m, 2H), 1.43-1.23 (m, 6H). HRMS: (calc.) 283.1572 (M−H2O), (found) 283.1581.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:19])[C:16]([OH:18])=O)=[CH:11][C:10]=1[CH2:20][CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[NH2:31][C@H:32]1[CH2:41][CH2:40][C:39]2[C:34](=[CH:35][C:36]([OH:42])=[CH:37][CH:38]=2)[CH2:33]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:19])[C:16]([NH:31][C@H:32]2[CH2:41][CH2:40][C:39]3[C:34](=[CH:35][C:36]([OH:42])=[CH:37][CH:38]=3)[CH2:33]2)=[O:18])=[CH:11][C:10]=1[CH2:20][CH2:21][O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(O)c1ccc(OCc2ccccc2)c(CCOCc2ccccc2)c1
Reactant: N[C@H]1CCc2ccc(O)cc2C1
Agent: Br
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CCc2ccc(O)cc2C1)C(O)c1ccc(OCc2ccccc2)c(CCOCc2ccccc2)c1
Temperature: 25 °C

Procedure:
2-[4-Benzyloxy-3-(2-benzyloxyethyl)phenyl]-2-hydroxyacetic acid (1.73 g), 1.18 g of (S)-2-amino-7-hydroxytetralin hydrobromide and 1.95 g of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate were dissolved in 11 ml of N,N-dimethylformamide, 1.23 ml of triethylamine was added to the solution with stirring at room temperature and the mixture was subjected to 3 hours of reaction. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The extract was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was partially purified by silica gel medium pressure liquid column chromatography (eluent: hexane/ethyl acetate=1/1) to give 2-[4-benzyloxy-3-(2-benzyloxyethyl)phenyl]-2-hydroxy-N-((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2yl)acetamide (diastereomer mixture). The mixture was separated by silica gel medium pressure liquid column chromatography (eluent: diethyl ether) to give 1.08 g of amorphous (-)-(2R)-2-[4-benzyloxy-3-(2-benzyloxyethyl)phenyl]-2-hydroxy-N-((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (low polarity isomer) and 0.94 g of amorphous (-)-(2S)-2-[4benzyloxy-3-(2-benzyloxyethyl)phenyl]-2-hydroxy-N-((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (high polarity isomer).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[C:18]4[S:22][C:21](SC)=[N:20][C:19]4=[O:25])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:28]([F:31])([F:30])[F:29])[CH:4]=1.[NH:32]1[CH2:35][CH2:34][C@H:33]1[C:36]([OH:38])=[O:37]>>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[C:18]4[S:22][C:21]([N:32]5[CH2:35][CH2:34][C@H:33]5[C:36]([OH:38])=[O:37])=[N:20][C:19]4=[O:25])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:28]([F:29])([F:30])[F:31])[CH:4]=1
Reactant: O=C(O)[C@@H]1CCN1
Reactant: COc1ccc(Cn2ncc3cc(C=C4SC(SC)=NC4=O)ccc32)c(C(F)(F)F)c1
Product: COc1ccc(Cn2ncc3cc(C=C4SC(N5CC[C@H]5C(=O)O)=NC4=O)ccc32)c(C(F)(F)F)c1

Procedure:
1-{5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-2-(S)-carboxylic acid was prepared from 5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and azetidine-2-(S)-carboxylic acid following General Procedure C.
Reaction SMILES: [CH3:1][CH:2]([S:4]([NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])(=[O:6])=[O:5])[CH3:3].[O:14]([C:21]1[CH:26]=[CH:25][C:24]([Mg]Br)=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>C1COCC1.O>[OH:13][C:9]1([C:24]2[CH:25]=[CH:26][C:21]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:22][CH:23]=2)[CH2:10][CH2:11][CH2:12][CH:8]1[NH:7][S:4]([CH:2]([CH3:1])[CH3:3])(=[O:6])=[O:5]
Reactant: CC(C)S(=O)(=O)NC1CCCC1=O
Reactant: Br[Mg]c1ccc(Oc2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)S(=O)(=O)NC1CCCC1(O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C

Procedure:
Into a flame dried 250 mL 3 neck flask that was fitted with a thermometer and condenser, and while stirring at room temperature under a nitrogen atmosphere, 2-{[(methylethyl)sulfonyl]amino}cyclopentan-1-one (1.00 g, 4.9 mmol) in THF (40 mL) was added dropwise to 15 mL of 0.5 M 4-phenoxyphenylmagnesium bromide. The addition of 2-{[(methylethyl)sulfonyl]amino}cyclopentan-1-one was continued dropwise, keeping the temperature above 35° C. After the addition of 2-{[(methylethyl)sulfonyl]amino}cyclopentan-1-one was complete, the reaction was stirred overnight at room temperature. Enough saturated ammonium chloride in water was then added to precipitate salts and the organic layer was decanted off. The remaining salts were washed two times with ether and the combined organic layers were concentrated under reduced vacuum. The resulting semi-solid was taken into ethyl acetate, washed once with water, dried over potassium carbonate, filtered, and concentrated under reduced vacuum to yield 2.14 g of as a dark oil. This material was purified via silica gel chromatography employing the Water's Prep. 2000 while eluting with a solvent of hexane/ethyl acetate 7:3 to provide the title compound (540 mg) as a white solid. Ion spray M.S. 374.1 (M*−1). Calculated for C20H25NO4S: Theory: C, 63.98; H, 6.71; N, 3.73. Found: C, 63.70; H, 6.77; N, 3.55.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].C(N(C(C)C)CC)(C)C>O1CCOCC1.C(OCC)(=O)C>[C:1]1([CH:7]2[CH2:8][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:11][N:12]2[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(c2ccccc2)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(c2ccccc2)C1
Yield: 58.9 %

Procedure:
A solution of tert-butyl 3-phenylpiperazine-1-carboxylate (0.95 g, 3.6 mmol), benzyl chloroformate (0.85 g, 5.0 mmol) and diisopropylethylamine (1.0 g, 7.7 mmol) in dioxane (20 mL) was heated to 95° C. for 3 hours. After cooling, the reaction mixture was diluted with ethyl acetate (100 mL), and washed with saturated aqueous sodium bicarbonate (50 mL) and brine (25 mL). After drying over anhydrous sodium sulfate, filtration and concentration, the residue was purified by silica gel column chromatography (ethyl acetate/hexanes, 1:8) to give 1-benzyl 4-tert-butyl 2-phenylpiperazine-1,4-dicarboxylate (0.84 g, 59% yield).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:13]2[CH:35]=[CH:34][C:16]([CH2:17][NH:18][C@@H:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:20]([O:22]C3CCCC3)=[O:21])=[CH:15][CH:14]=2)[S:7][C:8]=1[NH:9][C:10](=[O:12])[NH2:11])(=[O:3])[NH2:2].[Li+].[OH-]>O1CCCC1>[C:1]([C:4]1[CH:5]=[C:6]([C:13]2[CH:35]=[CH:34][C:16]([CH2:17][NH:18][C@@H:19]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=2)[S:7][C:8]=1[NH:9][C:10](=[O:12])[NH2:11])(=[O:3])[NH2:2]
Reactant: NC(=O)Nc1sc(-c2ccc(CN[C@H](C(=O)OC3CCCC3)c3ccccc3)cc2)cc1C(N)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)Nc1sc(-c2ccc(CN[C@H](C(=O)O)c3ccccc3)cc2)cc1C(N)=O
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of cyclopentyl (2S)-({-4-[4-carbamoyl-5-(carbamoylamino)-2-thienyl]benzyl}amino)(phenyl)acetate (Example 1) (50 mg, 102 μmol) in tetrahydrofuran (1 ml) was added 1.0M aq LiOH (0.508 ml, 508 μmol). The reaction was stirred at an oil bath temperature of 40° C. After 4 hours LCMS indicated 90% completion. The heating was removed and the reaction left to stir at room temperature overnight. The solvent was removed in vacuo and to the residue was added water (2 ml). 5 drops of acetic acid was added to the solution and a solid precipitated. The solid was collected by filtration and washed sequentially with water, ethanol and diethyl ether before drying under reduced pressure (26 mg, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH:12]=[C:13]2[C:18](=[O:19])OC(C)(C)OC2=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:6]=1[C:18]([OH:19])=[CH:13][CH:12]=[N:11]2
Reactant: COc1cc(NC=C2C(=O)OC(C)(C)OC2=O)cc(OC)c1
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cc(OC)c2c(O)ccnc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-((3,5-dimethoxyphenylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (9.23 g, 30.0 mmol) in diphenyl ether was heated at 200° C. for 20 min. It was cooled down to RT. Hexane was added and the mixture was stirred at RT for 30 mins. The solvent was removed to furnish 5,7-dimethoxyquinolin-4-ol as a light brown solid, which was used for next step without further purification. MS: m/z=[M+H]+. 206.2 Calc'd for C11H11NO3: 205.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[N:9]/[S@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[C:4]([F:16])[CH:3]=1.[CH3:17][Mg]Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:9][S@:10]([C:12]([CH3:13])([CH3:15])[CH3:14])=[O:11])[CH3:17])=[C:4]([F:16])[CH:3]=1
Reactant: CC(C)(C)[S@](=O)/N=C/c1ccc(Br)cc1F
Reactant: C[Mg]Cl
Solvent: ClCCl
Product: C[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(Br)cc1F
Temperature: -48 °C
Reaction time: 6 h
Yield: 82.1 %

Procedure:
To a solution of (S)-2-methyl-propane-2-sulfinic acid 1-(4-bromo-2-fluoro-phenyl)-meth-(E)-ylideneamide (4.5 g, 14.7 mmol) in DCM (80 ml) was added methylmagnesium chloride (7.35 ml, 22.0 mmol, 3M solution in ether) dropwise at −48° C. After 1 h additional methylmagnesium chloride (2.45 ml, 7.35 mmol, 3M solution in ether) was added dropwise and the reaction mixture was stirred at −48° C. for 6 h. The reaction was then quenched by addition of sat. NH4Cl solution and the mixture was extracted three times with DCM. The combined organic layers were dried with Na2SO4 and evaporated. The remaining white solid was purified by chromatography (silica gel; heptane/EtOAc 2:1-1:1) to obtain the title compound as white solid (3.89 g, 82%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[NH:5][NH:6][C:7](=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].FC(F)(F)[C:28]([OH:30])=[O:29]>>[CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[NH:5][NH:6][C:7](=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:28]([O:30][C:8]([CH3:13])([CH3:9])[CH3:7])=[O:29])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)CC[C@H](NNC(=O)c1ccc(N)cc1[N+](=O)[O-])C(=O)OC
Product: COC(=O)CC[C@H](NNC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-])C(=O)OC

Procedure:
The synthesis was achieved in analogy to example 3. From 17 g of dimethyl-N-(4-(tert.-butoxycarbonylamino)-2-nitrobenzamido)-L-glutamate 19.5 g of N-(4-amino-2-nitrobenzamido)-L-glutamic acid-dimethylester×trifluoroacetic acid salt were obtained which were used directly in example 4(c).
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].C(=O)([O-])[O-].[K+].[K+].[C:28](#[N:30])[CH3:29]>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][C:4]2[CH:11]=[CH:12][C:29]([C:28]#[N:30])=[CH:6][CH:5]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: CC#N
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: N#Cc1ccc(CCN2CCC(C(C(N)=O)(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C

Procedure:
A mixture contaiing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.6 g--g see Preparation 13), anhydrous potassium carbonate (0.5 g) and acetonitrile (20 ml) was heated under reflux for 1.5 hours. On cooling to room temperature, water (60 ml) was added and the mixture extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless foam, yield, 0.25 g.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:19]=[C:20]([O:22]CC3C=CC=CC=3)[CH:21]=2)[C:10]([NH:12][C:13]2[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=2)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:19]=[C:20]([OH:22])[CH:21]=2)[C:10]([NH:12][C:13]2[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=2)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OC3CCCC3)c2)n1
Agent: [Pd]
Solvent: CCO
Product: Cn1ccc(NC(=O)c2cc(O)cc(OC3CCCC3)c2)n1
Reaction time: 86 h

Procedure:
3-(Cyclopentyloxy)-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide (1.87 g, 4.78 mmol) was dissolved in ethanol (40 mL) and 10% palladium on charcoal (102 mg) catalyst added under argon. The reaction was stirred under an atmosphere of hydrogen for 86 hours, then filtered through Celite® and concentrated in vacuo to a light brown solid (1.31 g). 1H NMR (d6-DMSO): 1.54 (m, 2H), 1.76 (m, 4H), 1.96 (m, 2H), 2.75 (s, 1H), 3.83 (s, 3H), 4.91 (m, 1H), 6.49 (m, 1H), 6.61 (m, 1H), 6.98 (m, 1H), 7.06 (m, 1H), 7.65 (s, 1H), 9.73 (br s, 1H); m/z 302 (M+H)+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12]C)=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[Li+].[OH-].Cl>CO.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2cc[nH]c2c1
Temperature: 0 °C
Yield: 83.3 %

Procedure:
To a solution of methyl indole-6-carboxylate (3.0 g) in MeOH (34 mL), a 3M aqueous solution of LiOH (17 mL, 3.0 equiv.) was added. The reaction mixture was heated at reflux for 1 Hr, then cooled at 0° C., diluted with water (50 mL) and acidified with HCl 12M (5 mL). The mixture was extracted with AcOEt (3*30 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4 and concentrated to give the product as a yellow solid (2.3 g, 85%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[O-]S(C(F)(F)[F:19])(=O)=O.F[N+]1C(C)=CC(C)=CC=1C>CO>[F:19][C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: Cc1cc(C)[n+](F)c(C)c1
Solvent: CO
Product: COC(=O)c1ccc2c(F)c[nH]c2c1

Procedure:
A solution of methyl 1H-indole-6-carboxylate 20a (11.4 mmol, 2.0 g) and N-fluoro-2,4,6-trimethylpyridinium triflate (14.8 mmol, 4.3 g) in MeOH (100 mL) was heated at reflux for 18 h. The reaction mixture was concentrated and purified by flash column chromatography (silica gel, 15-20% EtOAc/hexanes) to give compound 20b as an off-white solid.
Reaction SMILES: CC(=C[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C(O)=O.OOS([O-])=O.[K+].[C:19]([O-:22])(O)=[O:20].[Na+].[O-]S([O-])=O.[Na+].[Na+]>CN(C=O)C.O=[Os](=O)(=O)=O.CCOC(C)=O>[C:19]([OH:22])(=[O:20])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=Cc1ccccc1)C(=O)O
Reactant: O=C([O-])O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])OO
Agent: O=S([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccccc1
Reaction time: 0.08 h
Yield: 82 %

Procedure:
The α-Methyl cinnamic acid (100 mg) was dissolved in DMF (5 mL), and OsO4 (0.076 mL, 2.5% in tBuOH) was added and stirred for 5 min. A solid mixture of OXONE (1.52 g) and NaHCO3 (0.206 g) was added in one portion and the reaction had a final volume (7 mL). The reaction was stirred at room temperature for 3 hours or until the solution becomes colorless. This usually marks the completion of the reaction which was verified by TLC or GC. Na2SO3 (600 mg) was added, to reduce the remaining Os(VIII), and stirred for an additional hour or until solution became dark brown/black. EtOAc was added to extract the products and 1N HCl was used to dissolve the salts. The organic extract was washed with 1N HCl (30 mL×3) and brine (30 mL), dried over Na2SO4, and the solvent was removed under reduced pressure to obtain the crude product. Benzoic acid was obtained in 82% yield, 90% yield by GC, without the need for further purification.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH:20]=[CH:19][C:18]3[N:17]([CH3:21])[CH2:16][CH:15]4[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]4)[C:9]=3[C:8]=2[CH:22]=1.[BrH:23]>>[BrH:23].[CH3:21][N:17]1[CH2:16][C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C@@H:9]2[C@@H:18]1[CH2:19][CH2:20][C:7]1[CH:6]=[CH:5][C:4]([OH:3])=[CH:22][C:8]=12
Reactant: COc1ccc2ccc3c(c2c1)C1CCCCC1CN3C
Agent: Br
Agent: Cl
Product: CN1Cc2ccccc2[C@H]2c3cc(O)ccc3CC[C@@H]21

Procedure:
(See FIG. 2) A suspension of 0.456 g. (1.44 mmol) of 11-methoxy-6- methyl-hexahydrobenzo[a]phenanthridine hydrochloride in 10 ml 48% HBr was heated for 2.5 hours at reflux under N2 in an oil bath. The heat was removed, and the reaction mixture was placed in the refrigerator overnight. The white precipitate was collected by suction filtration, and after washing the crystals on the filter with cold ethanol and ether, the product weighed 403 mg (80.6%), mp 251°-254° C. The filtrate was concentrated and the residue was crystallized from ethanol to provide additional product, giving essentially a quantitative total yield of the phenol, mp 254° C. CIMS (NH3): M+1 266; 1H-NMR (CDCl3, free base); δ 7.38 (d, 1, ArH, J=7.5 Hz), 7.22 (m, 3, ArH), 7.04 (d, 1, ArH, J=8.2 Hz), 6.69 (s, 1, ArH); 6.64 (d, 1, ArH, J=8.2 Hz,) 3.98 (d, 1, Ar2CH), 3.84 (d, 1, ArCH2N, J=14.5 Hz), 3.50 (d, 1, ArCH2N, J=14.5 Hz), 2.87 (m, 2, CH2 and CHN) 2.38 (s, 3, NCH3), 2.09 (m, 2, CH), 1.86 (m, 1, CH2CN).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.[CH3:12][O:13][NH:14][CH3:15].C(N(CC)CC)C.O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:14]([O:13][CH3:12])[CH3:15])=[O:5]
Reactant: CNOC
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccccc1Cl
Reaction time: 8 h

Procedure:
50 ml of 2-chlorobenzoyl chloride are added slowly to a mixture of 37.33 g of N-methoxymethanamine hydrochloride and 104 ml of triethylamine in 500 ml of DCM and the mixture is left to stir overnight at AT. Water is added to the reaction mixture, the mixture is extracted with DCM, the organic phase is washed with a buffer solution pH=2 and dried over Na2SO4, and the solvent is evaporated off under vacuum. 78.57 g of the expected compound are obtained.