Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[CH2:3].CN(P(N(C)C)(N(C)C)=O)C>CCOC(C)=O>[CH2:3]=[C:2]([CH2:3][CH2:2][C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])[C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: C=CC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=C(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 140 °C

Procedure:
Benzyl acrylate (500 g, 3 mol) was heated to 100° C. under an atmosphere of nitrogen. The heating was stopped and HMPT (10 g, 61 mmol) was added dropwise while maintaining an internal temperature of 135-145° C. Once addition was complete the mixture was cooled to room temperature and a slurry of silica with 5:1 Hex/EtOAc was added. The slurry was then transferred to a column containing a plug of dry silica. The column was then washed with 1:1 Hex/EtOAc and the solvent was collected and evaporated. The clear yellow liquid was distilled under high vacuum (200 μHg) to give an initial fraction of 8 g distilling at 45° C. and then the desired product at 180-185° C. (212 g, 42%) as a clear and colorless liquid. 1H NMR (CDCl3) 7.3 ppm (3, 10H); 6.2 ppm (s, 1H); 5.5 ppm (s, 1H); 5.2 ppm (s, 2H); 5.1 ppm (s,2H); 2.6 ppm (m, 4H).
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].Cl[C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[O:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[N:10]1[CH2:11][CH2:12][N:8]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:9]1=[O:13]
Reactant: Clc1nc2ccccc2o1
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2nc3ccccc3o2)C1=O
Yield: 16.1 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.84650 mmol) was reacted with 2-chloro-benzooxazole (96 mL, 0.84650 mmol), 1,4-dioxane (50 mL), copper iodide (16 mg, 0.084650 mmol), trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and potassium carbonate (468 mg, 3.3860 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in DCM) afforded 40 mg of the product (16% yield).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:23]=[C:22]([CH3:24])[S:21][C:12]=2[N:13]=[C:14]([C:16]2[O:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[O:20]1[C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[CH:23]=[C:22]([CH3:24])[S:21][C:12]=3[N:13]=2)=[CH:17][CH:18]=[N:19]1
Reactant: Cc1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCc1ccccc1
Product: Cc1cc2c(NCc3ccccc3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(isoxazol-5-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-benzylamino-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25]CC2C=CC=CC=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][CH:15]=2)[CH:7]=1.Br>C(O)(=O)C.C(OCC)C.O.C(=O)([O-])[O-].[K+].[K+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][CH:15]=2)[CH:7]=1
Reactant: CCOC(=O)c1cccc(-c2ccccc2-c2cc(Cl)ccc2OCc2ccccc2)n1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cccc(-c2ccccc2-c2cc(Cl)ccc2O)n1
Reaction time: 16 h
Yield: 82.3 %

Procedure:
Ethyl 6-{5′-chloro-2′-[(phenylmethyl)oxy]-2-biphenylyl}-2-pyridinecarboxylate (1.22 g, 2.75 mmol) was dissolved in acetic acid (5 ml) and 48% hydrogen bromide in acetic acid (5 ml), left at room temperature for 0.5 hours then diluted with diethyl ether/water and basified with potassium carbonate. The organic phase was separated, dried (magnesium sulphate), evaporated and chromatographed on silica eluting with ethyl acetate/iso-hexane (1:3). The product was dissolved in ethanol (20 ml), 60% sodium hydride (2 mg) added and the solution left at room temperature for 16 hours. The resulting solution was acidified with acetic acid, diluted with water/ether and the organic phase washed with saturated sodium bicarbonate solution, dried (magnesium sulphate), evaporated and chromatographed on silica to give 801 mg of colourless gum. LC/MS t=3.33, [MH+] 354.3, 356.3
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][O:29][C@H:30]1[CH2:34][CH2:33][C@H:32]([CH2:35][C:36](OC)=[O:37])[CH2:31]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:36](=[O:37])[CH2:35][C@H:32]5[CH2:33][CH2:34][C@H:30]([O:29][CH3:28])[CH2:31]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: COC(=O)C[C@H]1CC[C@H](OC)C1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CO[C@H]1CC[C@H](CC(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4CCO5)CC3)CC2)C1

Procedure:
The title compound, white solid (80 mg, 85%), MS (ISP) m/z=471.6 [(M+H)+], mp 241° C., was prepared in accordance with the general method of example 2 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and methyl 2-((1S,3S)-3-methoxy-cyclopentyl)-acetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:19]([CH:20]3[CH2:23][NH:22][CH2:21]3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([CH:20]3[CH2:21][NH:22][CH2:23]3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2nccnc2C2CNC2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2nccnc2C2CNC2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.9 %

Procedure:
To a solution of 4-(3-azetidin-3-yl-pyrazin-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (50) (540 mg, 1.7 mmol) in MeOH was added Pd/C (10%, 0.5 g) under nitrogen. The reaction was stirred under hydrogen (30 psi) at RT for 6 h. Filtered to remove Pd/C and concentrated to dryness to give 4-(3-azetidin-3-yl-pyrazin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (51) (502 mg, 1.58 mmol yield 92.9%).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[C:11]([CH2:14][CH2:15][C:16]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[NH:18][CH:17]=1)([OH:13])=[O:12]>ClCCl.O>[C:11]([CH2:14][CH2:15][C:16]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[NH:18][C:17]=1[CH:3]=[O:4])([OH:13])=[O:12]
Reactant: CN(C)C=O
Reactant: O=C(O)CCc1c[nH]c2c1CCCC2
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Temperature: -4 °C
Yield: 31 %

Procedure:
Dimethylformamide (11.7 g) and 240 mL of dichloromethane in a 1 L, 3-neck round bottom flask equipped with magnetic stirring, a reflux condenser, and a dropping funnel, was cooled to −4° C. in an ice-salt bath maintained at −10° C. Phosphorus oxychloride (24.5 g) was rapidly added via the dropping funnel. The temperature increased to −3° C., and then, with further stirring, decreased to −7° C. Crude 3-(2-carboxyethyl)-4,5,6,7-tetrahydroindole dissolved in 160 mL of dichloromethane was added via the dropping funnel over 15 min keeping the temperature below 1° C. The mixture was refluxed for 10 min, cooled to 5° C., and diluted with 300 mL of water. The aqueous layer was evaporated and was saved, and the organic layer was extracted with another 30 mL of water. The aqueous layers were combined, were washed with 30 mL of dichloromethane and were cooled to 5° C. The aqueous layer was adjusted to pH 10 with about 48 mL of 10 N sodium hydroxide, accompanied by a temperature increase to 15° C. The mixture was then cooled to 10° C. and adjusted to pH 2-3 with about 48 ml of 10 N hydrochloric acid. The oil which formed solidified, and was collected by vacuum filtration, was washed three times with 20 mL of water each time, and was dried under high vacuum to give 5.5 g (31% yield) of 3-(2-carboxyethyl)-2-formyl-4,5,6,7-tetrahydroindole as a brown solid.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH:11]1([O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[NH2:19])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>ClC(Cl)C>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:19][C:18]([CH3:21])([C:17]([O:16][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:22])[CH3:20]
Reactant: O=Cc1cccc(CBr)c1
Reactant: CC(C)(N)C(=O)OC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CC(C)(NCc1cccc(CBr)c1)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.2 %

Procedure:
To a solution of 3-(bromomethyl)-benzaldehyde (0.503 g, 2.52 mmol) in dichloroethane (20 mL) was added α,α-dimethylglycine cyclopentyl ester (0.893 g, 5.2 mmol) and sodium triacetoxyborohydride (1.47 g, 6.9 mmol). The mixture was stirred at room temperature for 3 hours, then poured into ethyl acetate (200 mL) and washed with saturated ammonium chloride solution (3 times 50 mL). The organic fraction was dried (MgSO4), concentrated and purified by flash column chromatography (SiO2, 7:3 heptane:ethyl acetate) to yield the desired product (0.350 g, 39% yield). LC/MS: m/z 354/356 [M+H]+
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C@@H:25]1[C@@H:65]([CH2:66][O:67]C(=O)C)[O:64][C@@H:28]([O:29][N:30]2[CH:34]=[C:33]([CH2:35][O:36][C@H:37]3[CH2:61][CH2:60][C@@:59]4([CH3:62])[CH:39]([CH2:40][CH2:41][C@@H:42]5[C@@H:58]4[CH2:57][CH2:56][C@@:55]4([CH3:63])[C@H:43]5[CH2:44][CH2:45][C@@H:46]4[C@H:47]([CH3:54])[CH2:48][CH2:49][CH2:50][CH:51]([CH3:53])[CH3:52])[CH2:38]3)[N:32]=[N:31]2)[C@H:27]([O:71]C(=O)C)[C@H:26]1[O:75]C(=O)C)(=O)C.C[O-].[Na+].CO>CO.C(Cl)(Cl)Cl.CO>[C@@H:6]1([O:24][C@@H:25]2[C@@H:65]([CH2:66][OH:67])[O:64][C@@H:28]([O:29][N:30]3[CH:34]=[C:33]([CH2:35][O:36][C@H:37]4[CH2:61][CH2:60][C@@:59]5([CH3:62])[CH:39]([CH2:40][CH2:41][C@@H:42]6[C@@H:58]5[CH2:57][CH2:56][C@@:55]5([CH3:63])[C@H:43]6[CH2:44][CH2:45][C@@H:46]5[C@H:47]([CH3:54])[CH2:48][CH2:49][CH2:50][CH:51]([CH3:53])[CH3:52])[CH2:38]4)[N:32]=[N:31]3)[C@H:27]([OH:71])[C@H:26]2[OH:75])[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](On3cc(CO[C@H]4CC[C@@]5(C)C(CC[C@H]6[C@@H]7CC[C@H]([C@H](C)CCCC(C)C)[C@@]7(C)CC[C@@H]65)C4)nn3)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@@H](OCc5cn(O[C@@H]6O[C@H](CO)[C@@H](O[C@@H]7O[C@H](CO)[C@H](O)[C@H](O)[C@H]7O)[C@H](O)[C@H]6O)nn5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dry N-glycoside 91 (100 mg, 0.092 mmol) was dissolved in anhydrous CH3OH and a solution of NaOMe/CH3OH (11M, 30 μL) was added dropwise to the mixture at 0° C. under argon. The solution was allowed to stir at RT overnight. After monitoring by TLC, additional anhydrous CH3OH (2 mL) and NaOMe/CH3OH (11M, 50 μL) was added and the reaction mixture found to be pH 11. Upon completion, the reaction was neutralised to pH 6 by the addition of Dowex H+ ion-exchange resin, and the resulting suspension dissolved in CHCl3/CH3OH (1:1) at 40° C. The solution was filtered, concentrated and dried over P2O5 to yield the crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:20][S:21]([C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[Cl:31])(=[O:23])=[O:22].Cl[C:33]1C=CC(Cl)=C[C:34]=1S(Cl)(=O)=O>>[CH2:33]([O:14][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[C:3]([NH:20][S:21]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=3[Cl:31])(=[O:22])=[O:23])[CH:4]=2)=[CH:17][CH:16]=1)[CH3:34]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: O=C(O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3cc(Cl)ccc3Cl)c2)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3cc(Cl)ccc3Cl)c2)cc1

Procedure:
4-[4-Chloro-3-(2,5-dichloro-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=497.0 (M−H), was prepared in analogy to example 21, steps A to D. Step C was performed using 2,5-dichloro-benzenesulfonyl chloride and yielded 4-[4-chloro-3-(2,5-dichloro-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[SH:18][C:19]1[N:23]=[CH:22][NH:21][N:20]=1.CN(C)C=O>O>[NH2:1][C:2]1[CH:7]=[C:6]([S:18][C:19]2[N:23]=[CH:22][NH:21][N:20]=2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Sc1nc[nH]n1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Sc2nc[nH]n2)ccc1[N+](=O)[O-]

Procedure:
A mixture of 3.5 g. 2-amino-4-chloro-1-nitrobenzene, 5.5 g. of potassium carbonate, 4.0 g. of 3-mercapto-1,2,4-triazole in 30 ml. dimethylformamide is heated under nitrogen for 4 hours at 130°-140° C. The mixture is cooled, diluted with water and the pH adjusted to about 6. The crude product is filtered off and recrystallized from methanol, yielding 2-amino-1-nitro-4-(1,2,4-triazol-3-ylthio)benzene.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=[O:2].[H][H]>[Ni].C1(C)C=CC=CC=1>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Ni]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CO)cc1
Yield: 90 %

Procedure:
A mixture of methyl 4-formylbenzoate (500 g, 3.05 mole), Raney nickel (25 g) and toluene (1000 mL) is heated in an autoclave between 60 and 75° C. under a hydrogen atmosphere at between 41 and 44 bars absolute for 3.5 hours. The hydrogen pressure then is released and the catalyst removed from the reaction mixture by filtration at 40° to 60° C. The toluene is removed by distillation and the product, methyl 4-(hydroxymethyl)benzoate obtained in a 90% yield, is used in the next step without further purification.
Reaction SMILES: C[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:14][NH2:15]>CN(C=O)C>[CH3:14][NH:15][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[CH:2][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: CN
Reactant: Cc1c(C#N)ccc(F)c1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CNc1ccc(C#N)cc1[N+](=O)[O-]

Procedure:
4-Methylamino-3-nitro-benzonitrile (1.69 mg) was prepared by following General Procedure A starting from methyl 4-fluoro-3-nitrobenzonitrile (1.66 g) and methylamine (2 M in THF, 10.0 mL) in DMF. The crude product was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([C:14](=O)[NH2:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:9][CH2:10][C@@H:11]([CH2:14][NH2:15])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(N)=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CN)CC1
Temperature: 25 °C

Procedure:
To a solution of cis-(4-carbamoyl-cyclohexyl)-carbamic acid tert-butyl ester obtained in step B of example 2332 (9.68 g, 40 mmol) in THF (100 mL) was added a solution of 1 M BH3 in THF (80 mL, 80 mmol) over 30 min. The mixture was stirred at reflux for 2 hr. After cooling the reaction mixture to ambient temperature, 1 M aqueous sodium hydroxide was carefully added. The solvents were removed under reduced pressure and the aqueous layer was extracted with CH2Cl2 (twice). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give cis-(4-aminomethyl-cyclohexyl)-carbamic acid tert-butyl ester as colorless oil (5.16 g, 57%).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].[Na].[H][H]>O.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)C1CCC=CO1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na]
Solvent: O
Product: O=C(O)C1CCCCO1

Procedure:
3,4-Dihydro-2H-pyran-2-carboxylic acid, sodium salt (5.0g) in water (30ml) was treated with 10% Palladium on carbon catalyst (0.2g) and the mixture hydrogenated until there was no further uptake of hydrogen. The mixture was filtered through Kieselguhr, the filtrate passed through a column of 'Amberlite IR120(H+), evaporated in vacuo and the residue dissolved in dichloromethane, dried and evaporated to give the title compound as colourless oil. (3.3g, 76%); (Found: M+, 130.0631. C6H10O3 requires M, 130.0630; vmax (CH2Cl) 3500-2750 (v.br), 1772, 1725cm-1 ; δH (CDCl3), 1.5-1.7 (4H, m), 1.8-2.1 (2H, m), 3.50-3.59 (1H, m), 3.99-4.14 (2H, m) and 7.28 (1H, br.s).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+].[CH2:12]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1)[CH3:13].O>CO>[CH2:12]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[OH:19])=[CH:16][CH:15]=1)[CH3:13]
Reactant: CCc1ccc(C=O)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1ccc(C(O)c2c[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 16.3 %

Procedure:
To a solution of indole (6.00 g) in methanol (60 ml) were added sodium hydroxide (2.25 g) and 4-ethylbenzaldehyde (7.56 g), and the mixture was stirred at room temperature for 3 days under argon atmosphere. Added thereto was water, and methanol was evaporated under reduced pressure. The residue was extracted with diethyl ether, and the extract was washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-70:30) to give 4-ethylphenyl-(1H-indol-3-yl)methanol (2.10 g) as a colorless solid. APCI-Mass m/Z 234 (M+H—H2O). (2) The above 4-ethylphenyl-(1H-indol-3-yl)methanol was treated in a manner similar to Reference Example 1-(2) to give the desired 3-(4-ethylphenylmethyl)-1H-indole as colorless crystals. APCI-Mass m/Z 236 (M+H).
Reaction SMILES: [CH2:1]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])P(=O)(OCC)OCC.[Li]CCCC.[CH3:23][C:24]1[C:25]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[C:26]([O:36][C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)[C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([O:34][CH3:35])=[CH:29][CH:28]=2.CCOC(C)=O>C1COCC1.O>[CH2:15]([O:14][P:10]([CH:1]=[CH:41][C:40]1[CH:39]=[CH:38][C:37]([O:36][C:26]2[C:27]3[C:32](=[CH:31][C:30]([O:34][CH3:35])=[CH:29][CH:28]=3)[CH:33]=[C:24]([CH3:23])[C:25]=2[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:44][CH:43]=1)(=[O:17])[O:11][CH2:12][CH3:13])[CH3:16]
Reactant: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccccc3)c(C)cc2c1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOP(=O)(C=Cc1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)cc1)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a stirring solution of tetraethyl methylenediphosphonate (0.11 mL, 0.537 mmol) in hexanes (1 mL) was slowly added 1.6 M nBuLi (0.051 mL, 0.537 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h under nitrogen. The reaction mixture was cooled to 0° C. then a solution of 4-[(6-methoxy-3-methyl-2-phenyl-1-naphthyl)oxy]benzaldehyde (8) (0.198 g, 0.537 mmol) in THF (1 mL) was added dropwise. After addition, reaction mixture was stirred at above temperature for 10 min then heated at 80° C. for 3 h. Reaction mixture was cooled to room temperature then diluted with water followed by EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water followed by brine, dried over MgSO4, filtered and concentrated to give oil. The crude oil was chromatographed with 9% EtOAc in hexanes followed by straight MeOH to give 0.151 g (56%) of the title compound (197) as oil. 1H NMR (400 MHz, d-CDCl3): δ 1.33 (t, J=7.1 Hz, 6H), 2.25 (s, 3H), 3.93 (s, 3H), 4.07-4.11 (m, 4H), 6.01 (t, J=17.6 Hz, 1H), 6.59 (d, J=8.8 Hz, 2H), 7.03 (dd, J1=2.4, J2=9.2 Hz, 1H), 7.12-7.14 (m, 3H), 7.22-7.28 (m, 5H), 7.30-7.36 (m, 1H), 7.40 (s, 1H), 7.69 (d, J=9.1 Hz, 1H).
Reaction SMILES: O.[C:2]1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:13]([O:15][C:16]([C:18]1[CH:19]=[CH:20][C:21]([O:36]COC)=[C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][N:25]2[C:29](OC(C)(C)C)=[O:30])[CH:23]=1)=[O:17])[CH3:14].C(=O)(O)[O-].[Na+].C(OC(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.C(OCC)(=O)C.CO.C(N(CC)CC)C.N1C=CC=CC=1>[C:29]([N:25]1[CH2:26][CH2:27][CH2:28][CH:24]1[C:22]1[CH:23]=[C:18]([CH:19]=[CH:20][C:21]=1[OH:36])[C:16]([O:15][CH2:13][CH3:14])=[O:17])(=[O:30])[CH3:2]
Reactant: CCOC(=O)c1ccc(OCOC)c(C2CCCN2C(=O)OC(C)(C)C)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1ccc(O)c(C2CCCN2C(C)=O)c1
Reaction time: 1 h

Procedure:
13 g of p-toluenesulfonic acid monohydrate was added to a solution of 26 g of t-butyl 2-(5-ethoxycarbonyl-2-methoxymethoxy-phenyl)-pyrrolidine-1-carboxylate in a mixture of 250 ml of ethanol and 50 ml of water, and the reaction liquid was heated under reflux for 2 days. After cooled, the reaction liquid was diluted with water, neutralized with aqueous sodium bicarbonate, extracted with a mixed solvent of chloroform/methanol (10/1), and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure to obtain a crude product. 13 ml of acetic anhydride was added to a pyridine (200 ml) solution of the resulting crude product, and stirred. After 1 hour, 6 ml of acetic anhydride was added to it. Further after 1 hour, 150 ml of pyridine was added to it, and further after 40 minutes, 5 ml of triethylamine was added thereto. Further after 30 minutes, 3 ml of acetic anhydride was added to it, and the reaction liquid was stirred for 30 minutes. The reaction liquid was diluted with ethyl acetate, and washed with aqueous saturated sodium bicarbonate, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure to obtain a crude product. 10 g of potassium carbonate was added to a methanol (200 ml) solution of the resulting crude product, and the reaction liquid was stirred for 4 hours at room temperature. The reaction liquid was distilled under reduced pressure, and the resulting residue was diluted with aqueous saturated ammonium chloride solution, and extracted with ethyl acetate. This was dried with anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure, and the resulting solid was taken out through filtration with ethyl acetate to obtain the entitled compound as a white solid.