Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12][CH2:11][CH2:10][C@@H:9]([C:13](OCC)=[O:14])[CH2:8]1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.O>[OH:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][N:7]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:8]1
Reactant: CCOC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](CO)C1
Reaction time: 0.33 h
Yield: 94.9 %

Procedure:
To a suspension of lithium aluminum hydride (2.9.0 g, 76.3 mmol) in tetrahydrofuran (100 ml) was added a solution of 1-tert-butyl 3-ethyl (R)-piperidine-1,3-dicarboxylate (16.30 g, 63.6 mmol) in tetrahydrofuran (60 ml) over 20 min under ice-cooling, and the mixture was further stirred for 20 min. To the reaction mixture were successively added water (2.9 ml), 4N aqueous sodium hydroxide solution (2.9 ml), water (8.7 ml) and anhydrous sodium sulfate, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered, and the solvent was evaporated under reduced pressure to give tert-butyl (R)-3-hydroxymethylpiperidine-1-carboxylate (13.00 g, yield 95.0%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:7][C:6]=1[N+:17]([O-])=O.[H][H]>[Ni].C(O)C>[F:1][C:2]([F:20])([F:21])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:7][C:6]=1[NH2:17]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reaction time: 5 h

Procedure:
a mixture of 59 g. (0.185 mole) of 2,5-bis-(2,2,2-trifluoroethoxy)nitrobenzene, about 15 g. of Raney nickel and 1200 ml. of ethanol is hydrogenated by shaking on a Parr hydrogenation apparatus with a hydrogen pressure of 40 to 50 p.s.i. for about five hours. The mixture is filtered, and the filtrate is evaporated to a liquid residue. The residue is distilled to provide 2,5-bis(2,2,2-trifluoroethoxy)aniline as a clear, colorless liquid, b.p. 95°-98° C/0.35 mm Hg.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[CH2:8]([O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]1[N:26]=[N:27][N:28]=[C:21]1[C:20]([NH2:29])=[C:19]2[NH:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[CH2:8]([O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]1[N:26]=[N:27][N:28]=[C:21]1[C:20]1[N:29]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:30]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:19]2=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOCC(=O)Cl
Reactant: CC(C)CNc1c(N)c2nnnn2c2ccc(OCc3ccccc3)cc12
Solvent: c1ccncc1
Product: CCOCc1nc2c(c3cc(OCc4ccccc4)ccc3n3nnnc23)n1CC(C)C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
Ethoxyacetyl chloride (2.7 g, 22 mmol) was added dropwise to a solution of 7-(benzyloxy)-N5-(2-methylpropyl)tetraazolo[1,5-α]quinoline-4,5-diamine (7.6 g, 21 mmol) in 200 mL of pyridine. The solution was stirred for 1 hour and additional ethoxyacetyl chloride was added. The solution was refluxed overnight, after which the solvent was removed. The solid material was dissolved in 300 mL of chloroform and stirred with 150 mL of 1% aqueous sodium carbonate. The pH was adjusted to 10 with 10% sodium hydroxide. The organic fraction was washed with 2 portions of 1% sodium carbonate and once with brine solution. The organic fraction was then dried over sodium sulfate and concentrated to give 8.8 g of 8-(benzyloxy)-5-(ethoxymethyl)-6-(2-methylpropyl)-6H-imidazo[4,5-c]tetraazolo[1,5-α]quinoline as a tan solid. A small portion was recrystallized from ethanol to provide an analytical sample, mp 183.5-184.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20](OC)=[O:21])=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:21][CH2:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[CH:12]=[CH:13]2
Reactant: COC(=O)c1ccc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(CO)ccc32)cc1
Reaction time: 0.25 h
Yield: 71.6 %

Procedure:
A solution of methyl 1-(4-methylphenylsulfonyl)indole-5-carboylate (32.2 g) in tetrahydrofuran (250 ml) was added slowly to a slurry of lithium aluminum hydride (5.2 g) in tetrahydrofuran (100 ml) at 0°. The reaction mixture was stirred 15 min at 0°, quenched with saturated sodium sulfate solution and filtered. The filtrate was dried (MgSO4) and evaporated to give 5-hydroxymethyl-1-(4-methylphenylsulfonyl)indole (21.1 g, 72%) as a white solid: NMR (80 MHz, CDCl3): 2.33(s, 3H, ArCH3), 4.74(s, 2H, OCH2), 6.64(d, 1H, H3 -indole).
Reaction SMILES: [OH:1][C:2]1([C:15]([F:18])([F:17])[F:16])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[F:18][C:15]([F:16])([F:17])[C:2]1([OH:1])[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1(C(F)(F)F)CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
To a solution of tert-butyl 4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate (0.07 g, 0.26 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for 30 minutes. Concentration and drying afforded 4-(trifluoromethyl)piperidin-4-ol (0.044 g, 100%). MS (EI) for C6H10F3NO: 269 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2].[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH:21]=[O:22])[CH2:17][CH2:16]1>CN(C)C=O>[CH2:1]([C:3]1[N:4]([CH2:12][CH2:13][CH2:14][CH:15]2[CH2:16][CH2:17][N:18]([CH:21]=[O:22])[CH2:19][CH2:20]2)[CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2]
Reactant: O=CN1CCC(CCCBr)CC1
Reactant: CCc1nc(C)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc(C)cn1CCCC1CCN(C=O)CC1
Reaction time: 4 h
Yield: 51.3 %

Procedure:
2-Ethyl-4-methyl-1H-imidazole (3.3 g, 30 mM) and sodium hydride (50% by weight in mineral oil, 80 mM) in dimethylformamide (20 ml) was heated at 50° C. for 1/2 hour. The solution of 4-(3-bromopropyl)-1-piperidinecarboxaldehyde (7 g, 30 mM) in dimethylformamide (20 ml) was added at 50° C. and stirred at that temperature for 4 hours. After the reaction, solvent was removed in vacuo and water (100 ml) was added and then extracted with ethyl acetate (2×100 ml). The extracts, dried over Na2SO4, was stripped to dryness and purified on silica gel column, eluted with 2% by volume MeOH, 98% by volume CH2Cl2, to give 4-[3-(2-ethyl-4-methyl-1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde as an oil (4.04 g, 51% yield).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:10][O:9][CH2:8][C@H:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:6]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5][O:4][C:3]1=[O:27].[OH:28][C:29]1[C:30]([C:37](O)=[O:38])=[N:31][CH:32]=[CH:33][C:34]=1[O:35][CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C(Cl)Cl>[CH2:12]([O:11][C@@H:7]1[C@@H:6]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5][O:4][C:3](=[O:27])[C@@H:2]([NH:1][C:37](=[O:38])[C:30]2[C:29]([OH:28])=[C:34]([O:35][CH3:36])[CH:33]=[CH:32][N:31]=2)[CH2:10][O:9][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N[C@H]1COC[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)COC1=O
Reactant: COc1ccnc(C(=O)O)c1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccnc(C(=O)N[C@H]2COC[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)COC2=O)c1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.2 %

Procedure:
To a mixture of (3S,7S,8S)-3-amino-7,8-bis(benzyloxy)-1,5-dioxonan-2-one (47 mg, 0.127 mmol), 3-hydroxy-4-methoxypicolinic acid (32.1 mg, 0.190 mmol) and HATU (80 mg, 0.202 mmol) in a vial were added CH2Cl2 (1.5 mL), followed by 4-methylmorpholine (0.083 mL, 0.759 mmol), and the resulting suspension was stirred at room temperature for 12 h. The resulting orange solution was directly purified by flash chromatography (SiO2) to afford the title compound as a white foam (32 mg, 48%): 1H NMR (400 MHz, CDCl3) δ11.90 (d, J=0.6 Hz, 1H), 8.61 (d, J=8.2 Hz, 1H), 8.49 (d, J=5.2 Hz, 1H), 7.43-7.24 (m, 11H), 6.86 (d, J=5.2 Hz, 1H), 5.03 (ddd, J=8.2, 6.8, 6.0 Hz, 1H), 4.80-4.62 (m, 5H), 4.21-4.07 (m, 2H), 3.93 (s, 3H), 3.85 (s, 1H), 3.79-3.65 (m, 2H), 3.55-3.47 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 170.83, 168.92, 155.37, 148.76, 140.66, 137.97, 137.94, 130.17, 128.48, 128.43, 127.91, 127.89, 127.87, 127.81, 109.61, 81.52, 79.29, 73.80, 73.44, 73.24, 72.97, 63.91, 56.10, 52.25; ESIMS m/z 524.1 ([M+H]+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][NH:24][CH2:25][C@H:26]([OH:29])[CH2:27][OH:28]>>[OH:29][C@@H:26]([CH2:27][OH:28])[CH2:25][N:24]([CH3:23])[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:19]
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CNC[C@H](O)CO
Product: CN(C[C@@H](O)CO)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (S)-3-(methylamino)propane-1,2-diol (1.2 equiv) to give 181 (14.9 mg, M+1 401.1)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[Br:12][CH2:13][C:14](Br)=[O:15]>CN(C=O)C.O1CCOCC1>[Br:12][CH2:13][C:14]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5])=[O:15]
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: O=C(Br)CBr
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(CBr)Nc1cccc(Cl)c1C(=O)O
Reaction time: 20 h
Yield: 30 %

Procedure:
A solution of 2-amino-6-chlorobenzoic acid (10.0 g, 0.06 mol) in anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) was cooled to 0° C. in 300 mL 3-necked flask fitted with a magnetic stirring bar and constant additional funnel. Bromoacetyl bromide was added dropwise over a 20-25 min period, while maintaining the internal temperature between 0° C. to 1° C. After the addition was completed, the ice-bath was removed and stirring was continued for 20 h. The reaction mixture was cooled in an ice-bath, water (150 mL) was added, and then the yellow crystalline product which formed was filtered and washed sequentially with 5% HBr solution (50 mL) and water (50 mL). After drying in a vacuum oven (20 h, 40°-45° C.), 5.0 g (30%) of the title compound was obtained: mp 133°-135° C. (dec.); 1H NMR (CD3OD) δ7.70 (d, 1H, J=8), 7.43 (t, 1H, J=8.4), 7.35 (d, 1H, J=8), 4.05 (s, 2H); 13C NMR (CD3OD) δ168.19, 167.84, 137.24, 133.31, 132.85, 132.08, 128.78, 128.21, 124.20, 29.21; MS (EI, m/z) 293 (M+)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[C:17]([F:23])[CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:23][C:17]1[CH:16]=[C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])[CH:22]=[CH:21][C:18]=1[CH:19]=[O:20]
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: O=Cc1ccc(Br)cc1F
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc(C=O)c(F)c2)C1=O
Yield: 59.2 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 300 mg, 1.694 mmol) was reacted with 4-bromo-2-fluoro-benzaldehyde (403 mg, 2.118 mmol), 1,4-dioxane (25 mL), copper iodide (32.186 mg, 0.1694 mmol), trans-1,2-diamino cyclohexane (72.16 mg, 0.5082 mmol) and potassium phosphate (1.077 g, 5.082 mmol) to afford the crude product. Purification by column chromatography on silica gel (1.5% MeOH in CHCl3) afforded 300 mg of 2-Fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehyde (59.05% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10](C(C)=C)[C:9]2=[O:20])C=CC=1.[CH3:21][CH:22]([N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[C:25]1=[O:39])[CH3:23].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[O:20]=[C:9]1[N:8]([CH2:4][CH2:3][CH2:2][N:36]2[CH2:37][CH2:38][CH:33]([N:26]3[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[N:24]([CH:22]([CH3:21])[CH3:23])[C:25]3=[O:39])[CH2:34][CH2:35]2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10]1
Reactant: CC(C)n1c(=O)n(C2CCNCC2)c2ccccc21
Reactant: C=C(C)n1c(=O)n(-c2cccc(Cl)c2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CC(C)n1c(=O)n(C2CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)c2ccccc21
Temperature: 25 °C
Yield: 64 %

Procedure:
A mixture of 4.15 parts of 1-(3-chlorophenyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one, 3.9 parts of 1-(1-methylethyl)-3-(4-piperidinyl)-2H-benzimidazol-2-one, 3.2 parts of sodium carbonate, 0.1 parts of potassium iodide and 120 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. The reaction mixture is cooled to room temperature, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is stirred for 30 minutes with a solution of 12 parts of a concentrated hydrochloric acid solution in 40 parts of ethanol. The solvent is evaporated and the residue is suspended in water. The suspension is alkalized with a diluted ammonium hydroxide solution and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 4.2 parts (64%) of 1-{1-[3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-3-(1-methylethyl)-2H-benzimidazol-2-one; mp. 174.3° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:32]=[CH:31][C:11]([N:12]([CH:19]=[C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]([O:23]CC)=O)[CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)(O)[O-]>ClCCl>[N:1]1([CH2:7][C:8]2[CH:32]=[C:31]3[C:11](=[CH:10][CH:9]=2)[N:12]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:19]=[C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]3=[O:23])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C(=CN(c1ccc(CN2CCOCC2)cc1)C1CCOCC1)C(=O)OCC
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCOC(=O)c1cn(C2CCOCC2)c2ccc(CN3CCOCC3)cc2c1=O
Temperature: 100 °C
Yield: 65.3 %

Procedure:
A flask containing diethyl 2-{[4-(4-morpholinylmethyl)(tetrahydro-2H-pyran-4-yl)anilino]methylene}malonate (0.41 g) is treated with polyphosphoric acid (1.5 g). The reaction mixture is heated to 100° C. under a flow of nitrogen gas. After 1 hour the reaction is cooled to room temperature. The reaction mixture is carefully added to a vigorously stirred mixture of dichloromethane and saturated aqueous bicarbonate. The layers are separated and the basic aqueous layer is extracted with three additional portions of dichloromethane. The combined organic layers are washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica eluting with 2% to 6% methanol in dichloromethane to afford 0.24 g of ethyl 6-(4-morpholinylmethyl)-4-oxo-1-tetrahydro-2H-pyran4-yl-1,4-dihydro-3-quinolinecarboxylate as a tan solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[C:6](=[CH:12][C:13]([NH2:17])=[C:14]([OH:16])[CH:15]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[CH2:19](C(CC)(CC)C([O-])([O-])[O-])[CH3:20]>>[CH3:19][C:20]1[O:16][C:14]2[CH:15]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:18])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][C:13]=2[N:17]=1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: CCOC(=O)c1cc(N)c(O)cc1C(=O)OCC
Product: CCOC(=O)c1cc2nc(C)oc2cc1C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of diethyl-4-amino-5-hydroxyphthalate (4.00 g, 15.8 mmol) and triethylorthoacetate (29.0 mL, 158 mmol) is stirred for 2 hours at reflux temperature, cooled to room temperature and diluted with hexanes. Silica gel chromatography (gradient elution:hexanes to (2:1) hexanes:ethyl acetate) followed by recrystallization from 1% ethyl acetate:-hexanes affords the title product as an off-white crystalline solid, 3.54 g (80.8%), identified by NMR, IR and mass spectral analyses.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([C:18](=O)[CH3:19])[CH:12]=[CH:11]2>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([C:18]([CH3:19])=[CH2:1])[CH:12]=[CH:11]2
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)c1ccc2cc(Br)ccc2n1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)c1ccc2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a stirred suspension of (methyl)triphenylphosphonium bromide (2000 mg, 5.60 mmol) in dry THF (15 ml) was added a solution of potassium tert-butoxide (628 mg, 5.60 mmol) in dry THF (10 ml) with ice cooling. The mixture was then allowed to warm to room temperature. After 2 hours at room temperature, to this was added a solution of 1-(6-bromoquinolin-2-yl)ethanone (Step CA1B) (700 mg, 2.80 mmol) in dry THF (15 ml) with ice-cooling then the mixture was allowed to warm to room temperature. After 3 hours at ambient temperature, the mixture was quenched with water and extracted with ethyl acetate (×2). The combined solution was washed with brine, dried over sodium sulfate and concentrated in vacuo to give crude product, which was purified by column chromatography on silica gel (250 g) with hexane-ethyl acetate (10:1) to furnish the title compound (661 mg, 95%) as a tan solid. 1H NMR (270 MHz, CDCl3) δ 2.34 (3H, s), 5.50 (1H, s), 5.93 (1H, s), 7.65-7.78 (2H, m), 7.88-8.03 (3H, m). MS (ESI): m/z 248.11, 250.14 [M+H]+.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=S)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:18]C1C=CC([Te](C2C=CC(OC)=CC=2)=O)=CC=1>CO>[C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc([Te](=O)c2ccc(OC)cc2)cc1
Reactant: S=C(Nc1ccccc1)Nc1ccccc1
Solvent: CO
Product: O=C(Nc1ccccc1)Nc1ccccc1
Yield: 68 %

Procedure:
1,3-Diphenylthiourea (114 mg, 0,5 mmol) was reacted with bis-(p-methoxyphenyl)-telluroxide for 16 h (methanol as solvent), the methanol was evaporated off under vacuum, the residue triturated with benzene and filtered to afford 1,3-diphenylurea as a white solid (72 mg, 68%), m.p. 234° (lit., 238°-239°).
Reaction SMILES: Cl.[C:2]1([C:8]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][CH:38]=[C:37]2[CH2:43][C:44](O)=[O:45]>>[C:26]1([C:8]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:16]3[C@@H:12]([CH2:13][N:14]([C:44](=[O:45])[CH2:43][C:37]4[C:36]5[C:40](=[CH:41][CH:42]=[C:34]([O:33][CH3:32])[CH:35]=5)[NH:39][CH:38]=4)[CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc2[nH]cc(CC(=O)O)c2c1
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Agent: Cl
Product: COc1ccc2[nH]cc(CC(=O)N3C[C@@H]4[C@H](C3)C(c3ccccc3)(c3ccccc3)CC[C@@]4(O)c3ccccc3OC)c2c1
Yield: 61.3 %

Procedure:
By working in accordance with Example 4, starting from 0.8 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol hydrochloride and 0.41 g of (5-methoxy-3-indolyl)acetic acid, 0.66 g of (3aS,4S,7aS)-7,7-diphenyl-2-[(5-methoxy-3-indolyl)acetyl]-4-(2-methoxyphenyl)perhydroisoindol-4-ol is obtained in the form of a beige foam.
Reaction SMILES: OP(O)(O)=O.[C:6]1(=[O:19])[O:16]CC[O:13][C:11](=[O:12])[C:10]2[CH:17]=[CH:18][C:7]1=[CH:8][CH:9]=2>C(O)CO>[C:6]([OH:19])(=[O:16])[C:7]1[CH:18]=[CH:17][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1
Reactant: O=C1OCCOC(=O)c2ccc1cc2
Agent: O=P(O)(O)O
Solvent: OCCO
Product: O=C(O)c1ccc(C(=O)O)cc1

Procedure:
A 1-liter resin kettle was provided with a Jiffy Mixer stirring agitator with an Electro-Craft Motomatic constant speed controller, a heater, a thermocouple, condenser and nitrogen sweep. To this kettle was added 0.2 g of the TiO1.5 catalyst, 115 ml of ethylene glycol, 6.23 μl of concentrated H3PO4, 0.3 wt % passivated TiO2 delusterant and 400 g of a low molecular weight ethylene terephthalate oligomer formed from ethylene glycol and terephthalic acid. The mixture was stirred at 280° C. at 60 rpm and vacuum of less than 1 torr (133 Pa) for 120 minutes at which time the supply voltage to the vessel's agitator control, an indication of the torque applied to the agitator and therefore of the viscosity of the reactants, reached a limiting value of 150 mv, upon which the polymer was poured into cold water to quench the polymerization. The polymer solid was annealed for crystallization at 150° C. for 12 hours and ground to pass through a 2 mm filter screen for color measurement using a Hunter calorimeter. The polymer color numbers were 69.48 L, -0.91a, 3.08b. The polymer inherent viscosity is 0.58 dL/g, the weight average molecular weight is 27,100 and the Z-average molecular weight is 41,500.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:11][CH:12]1[CH2:17][CH:16]2[N:18](C(OC(C)(C)C)=O)[CH:13]1[CH2:14][CH2:15]2.[ClH:26]>O1CCOCC1.CC(O)C>[ClH:26].[CH:13]12[NH:18][CH:16]([CH2:15][CH2:14]1)[CH2:17][CH:12]2[NH:11][C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(Nc1cnc3ccccc3n1)C2
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: c1ccc2nc(NC3CC4CCC3N4)cnc2c1
Temperature: 70 °C

Procedure:
To the title compound from step A (343 mg, 1 mmol) in 1,4-dioxane (10 mL) was added 6N HCl in iPrOH (1 mL). The reaction was heated to 70° C. for 2 h, cooled to rt, concentrated and used without further purification in subsequent steps.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH2:8][OH:9])[CH:7]=1.[Li]CCCC.C([O:19][B:20](OC(C)C)[O:21]C(C)C)(C)C>C1COCC1>[F:10][C:5]1[CH:4]=[CH:3][C:2]([B:20]([OH:21])[OH:19])=[CH:7][C:6]=1[CH2:8][OH:9]
Reactant: OCc1cc(Br)ccc1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OCc1cc(B(O)O)ccc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To solution of (5-bromo-2-fluoro-phenyl)-methanol (1.0 eq) in THF (0.1M) at −78° C. was added dropwise n-BuLi (2.5M in Hex; 2.2 eq). The resulting mixture was stirred at −78° C. for 30 min then tri-isopropoxy borane (2.2 eq) was added. The final mixture was stirred 15 min at −78° C. then allowed to warm slowly to room temperature and stirred an extra hour. The reaction was quenched with HCl (10%) and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in EtOAc, water (few drops) was added then hexane until a precipitate formed. After 12 h of stirring, the desired compound was isolated by filtration as a white solid.