Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:22]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:10]([NH:13][C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:42].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH2:1]([O:8][C@H:9]([C@@H:22]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:10]([NH:13][C@@H:14]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:15])[C:11]([OH:42])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: C[C@@H](N[C@H](CO)[C@H](OCc1ccccc1)[C@H](COCc1ccccc1)OCc1ccccc1)c1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: C[C@@H](N[C@H](C(=O)O)[C@H](OCc1ccccc1)[C@H](COCc1ccccc1)OCc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of (2R,3S,4S)-3,4,5-tris(benzyloxy)-2-(((R)-1-phenylethyl)amino)pentan-1-ol (110 mg, 0.209 mmol) in acetone (2 mL, 0.1 M) was added Jones reagent (0.21 mL, 0.522 mmol, 2.5 M solution in H2O) at 0° C. The reaction mixture was stirred for 4 hrs at 0° C., quenched with isopropyl alcohol and filtered through a pad of celite and washed with CH2Cl2. The reaction mixture was partitioned between CH2Cl2 and water. The aqueous layer was extracted with CH2Cl2 and the combined organic layer was washed with brine, dried over MgSO4, filtered through a pad of celite, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate/hexane (1/2) to CH2Cl2/MeOH (20/1) to afford the title product. Yield: 59 mg (0.11 mmol, 52%); white solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][O:12][CH2:13][CH3:14])=[C:6]([CH2:15][CH3:16])[CH:5]=1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.FC(F)(F)S(O[C:32]1[CH:33]=[C:34]([C:42]([O:44][CH3:45])=[O:43])[C:35](=[CH:40][CH:41]=1)[C:36]([O:38][CH3:39])=[O:37])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C1COCC1.CN(C=O)C.P[C-]1C=CC=C1.[C-]1(P)C=CC=C1.[Fe+2].Cl[Pd]Cl>[CH2:13]([O:12][CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH2:3][C:41]2[CH:40]=[C:35]([C:36]([O:38][CH3:39])=[O:37])[C:34](=[CH:33][CH:32]=2)[C:42]([O:44][CH3:45])=[O:43])=[CH:5][C:6]=1[CH2:15][CH3:16])[CH3:14]
Reactant: C=CCc1ccc(OCOCC)c(CC)c1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1C(=O)OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOCOc1ccc(CCCc2ccc(C(=O)OC)c(C(=O)OC)c2)cc1CC
Temperature: 0 °C
Reaction time: 12 h

Procedure:
5 g (22.7 mmol) of 4-allyl-1-ethoxymethoxy-2-ethylbenzene are dissolved in 100 ml of anhydrous THF, and the medium is cooled to 0° C. 6.6 g (27 mmol) of 9-BBN are added, and the medium is brought to room temperature and then stirred for 12 hours. A solution of 7.8 g (22.6 mmol) of dimethyl 4-trifluoromethanesulphonyloxyphthalate in 100 ml of DMF is added, as well as 6.2 g (44.8 mmol) of potassium carbonate. The reaction medium is degassed with a nitrogen stream, and then 930 mg (1.1 mmol) of dichloropalladium diphosphinoferrocene are added. The medium is heated at 50° C. for 3 hours, and then poured into an ammonium chloride solution and extracted with ethyl acetate. The residue obtained after drying and concentration is purified by chromatography on a silica column (eluent heptane, and then heptane 85/ethyl acetate 15). A yellow oil is obtained (m=6.9 g, y=73%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O.[CH3:20][CH:21]([CH3:37])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=1)=[O:23]>>[CH3:20][CH:21]([CH3:37])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:36][CH2:35][N:34]([CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[C:7]([O:6][C:5]4[CH:15]=[CH:16][CH:17]=[C:3]([C:2]([F:19])([F:18])[F:1])[CH:4]=4)[CH:8]=3)[CH2:33][CH2:32]2)[CH:26]=1)=[O:23]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1cccc(Oc2cccc(C(F)(F)F)c2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc(Oc4cccc(C(F)(F)F)c4)c3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 3-[3-(trifluoromethyl)phenoxy]benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 497.2 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[C:30]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:29][S:28][CH:27]=1.[CH3:39][O:40][C:41]([C:43]1[CH:44]=[CH:45][C:46]([C:49](O)=[O:50])=[N:47][CH:48]=1)=[O:42].CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C.O>[C:35]([O:34][C:32]([NH:31][C:30]1[C:26]([NH:25][C:49]([C:46]2[CH:45]=[CH:44][C:43]([C:41]([O:40][CH3:39])=[O:42])=[CH:48][N:47]=2)=[O:50])=[CH:27][S:28][CH:29]=1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Reactant: CC(C)(C)OC(=O)Nc1cscc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc(C(=O)Nc2cscc2NC(=O)OC(C)(C)C)nc1
Yield: 67 %

Procedure:
HATU (1.3 g, 3.5 mmol) was added to a solution of 3-amino-4-t-butoxycarbonylaminothiophene (Reference Compound No. 1-1, 0.68 g, 3.2 mmol), 5-methoxycarbonylpyridine-2-carboxylic acid (0.64 g, 3.5 mmol), and N-methylmorpholine (0.70 mL, 6.4 mmol) in DMF (20 mL), and then the reaction mixture was stirred at room temperature overnight. Water (0.30 L) and ethyl acetate (0.40 L) were added thereto, and the insoluble materials were filtered off to give 0.50 g of the title reference compound as a pale yellow solid. The filtrate was partitioned and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and then the obtained solid was collected by filtration with ethylacetate (30 mL) to give 0.30 g of the title reference compound as a pale brown solid. (Yield 67%)
Reaction SMILES: [Cl:1][C:2](=[CH:5][CH3:6])[CH:3]=O.[C:7]1([S:13]([C:16]#[N:17])(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(C)C=CC=CC=1.B(OCCCC)(OCCCC)OCCCC>C(O)CCC>[C:7]1([S:13]([C:16]2[CH:6]=[CH:5][C:2]([Cl:1])=[CH:3][N:17]=2)(=[O:14])=[O:15])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC=C(Cl)C=O
Reactant: N#CS(=O)(=O)c1ccccc1
Agent: CCCCOB(OCCCC)OCCCC
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: O=S(=O)(c1ccccc1)c1ccc(Cl)cn1
Temperature: 121 °C
Yield: 69.9 %

Procedure:
First, 11.2 g (107 mmol) of 2-chloro-2-butenal and 8.35 g (50.0 mmol) of benzenesulfonyl cyanide were introduced to the same reaction vessel as in Example 1. Toluene (15 ml) as the solvent and butanol (1.5 ml) were added, and 1.30 g (5.65 mmol) of tributyl borate was added. Then the mixture was heated under reflux for 7 hours while agitating at an internal temperature of 121° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml toluene that had been cooled to 5° C. or lower. Then the crystals were dried for 2 hours in vacuo to give 8.87 g of 2-benzenesulfonyl-5-chloropyridine with the following properties as colorless crystals (purity of 98%, yield of 69% based on benzenesulfonyl cyanide).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][C@@H:22]1[C@@H:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[CH2:26][CH2:25][N:24]([C:35]2[C:44]([F:45])=[CH:43][C:38]([C:39]([O:41]C)=[O:40])=[CH:37][C:36]=2[F:46])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[CH2:26][CH2:25][N:24]([C:35]2[C:44]([F:45])=[CH:43][C:38]([C:39]([OH:41])=[O:40])=[CH:37][C:36]=2[F:46])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(F)c(N2CC[C@H](c3ccccc3F)[C@@H](CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C2)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(c2c(F)cc(C(=O)O)cc2F)CCC1c1ccccc1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 98.7 %

Procedure:
143 mg of methyl 4-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(2-fluorophenyl)piperidin-1-yl]-3,5-difluorobenzoate was dissolved in 4.0 mL of THF-2.0 mL of methanol and added with 2.0 mL of a 1 M aqueous sodium hydroxide solution at room temperature. After stirring at room temperature for 3 days, it was neutralized by addition of 2.1 mL of 1 M hydrochloric acid. The reaction mixture was concentrated under reduced pressure, and then extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol-chloroform) to obtain 138 mg of 4-[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(2-fluorophenyl)piperidin-1-yl]-3,5-difluorobenzoic acid. ESI+: 619
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[CH:31][C:30]=2[O:42][CH3:43])[C:25]([Cl:44])=[CH:24][N:23]=1>>[Cl:44][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[CH:31][C:30]=2[O:42][CH3:43])=[N:27][C:22]([NH:1][C:2]2[C:18]([O:19][CH3:20])=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:23][CH:24]=1
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCN(C)CC4)cc3OC)n1)CCN(CC(=O)N(C)C)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide and (2,5-Dichloro-pyrimidin-4-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white foam (0.031 g, 37%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.26-8.22 (m, 1H), 8.11 (s, 1H), 8.02-8.00 (m, 1H), 7.53 (s, 1H), 7.42 (s, 1H), 6.63 (s, 1H), 6.57-6.55 (m, 1H), 6.54-6.50 (m, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.27 (s, 2H), 3.23-3.18 (m, 4H), 3.15 (s, 3H), 2.98 (s, 3H), 2.91-2.82 (m, 4H), 2.72-2.65 (m, 4H), 2.64-2.58 (m, 4H), 2.37 (s, 3H). MS: 609 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([OH:20])=O)[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18](=[O:20])[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[O:8][N:9]=2
Reactant: O=C(O)Cc1cc(Cl)cc2c(-c3ccccc3)onc12
Reactant: C1CNCCN1
Product: O=C(Cc1cc(Cl)cc2c(-c3ccccc3)onc12)N1CCNCC1

Procedure:
The title compound is prepared by reacting the acid chloride of 5-chloro-3-phenyl-2,1-benzisoxazole-7-acetic acid with piperazine in an aprotic solvent and washing the reaction mixture with sodium bicarbonate solution.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([F:13])[CH:3]=1.[N+:14]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19])([O-:16])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[F:13][C:4]1[CH:3]=[C:2]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[N+:14]([O-:16])=[O:15])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(Br)cc1F
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1F
Yield: 77.1 %

Procedure:
1.0 g ethyl 4-bromo-2-fluorobenzoate, 0.56 g 2-nitroaniline, 1.85 g cesium carbonate, 37 mg tris(dibenzylideneacetone)-dipalladium (0), 38 mg 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (racemic mixture) and 15 mL toluene were stirred at 100° C. for 24 hours under nitrogen atmosphere. Water was added thereto, then the reaction mixture was extracted with ether, and the organic layer was dried over sodium sulfate. After the solvent was evaporated, the residue was purified by NH silica gel chromatography (ethyl acetate/hexane). By recrystallization from ethyl acetate/hexane, 0.95 g of the title compound was obtained as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].Br[CH:18]([CH2:24]Br)[C:19]([O:21][CH2:22]C)=[O:20]>CC(C)=O.CO>[C:5]([C:4]1[CH:7]=[CH:8][C:9]2[O:10][CH:18]([C:19]([O:21][CH3:22])=[O:20])[CH2:24][NH:1][C:2]=2[CH:3]=1)#[N:6]
Reactant: CCOC(=O)C(Br)CBr
Reactant: N#Cc1ccc(O)c(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CO
Product: COC(=O)C1CNc2cc(C#N)ccc2O1
Temperature: 25 °C
Yield: 50.7 %

Procedure:
3-Amino-4-hydroxy-benzonitrile (180 mg, 1.34 mmol) was dissolved in acetone (1.4 mL). To the solution was added K2CO3 (555 mg, 4.02 mmol) and ethyl 2, 3-dibromopropanoate (380 mg, 1.46 mmol). The mixture was heated to reflux for 16 h. After cooling to room temperature the reaction mixture was filtered and concentrated in vacuo to give an oil. The oil was dissolved in methanol and was purified by silica gel chromatography (0-10% dichloromethane/hexanes) to afford methyl 6-cyano-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate (148 mg, 0.68 mmol). The methyl ester was isolated as methanol was used for loading the compound on silica resulting in transesterification. 1H NMR (400.0 MHz, DMSO-d6) δ 6.98 (dd, J=2.0, 8.2 Hz, 1H), 6.93-6.90 (m, 2H), 6.34 (s, 1H), 5.13 (t, J=3.3 Hz, 1H), 3.66 (s, 3H), 3.50-3.41 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH:15]=O)=[N:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[CH3:18]>>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][NH:27][C:24]2[CH:23]=[CH:22][C:21]([C:20]([O:19][CH2:17][CH3:18])=[O:28])=[CH:26][CH:25]=2)=[N:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=Cc1nccnc1OCc1ccccc1
Product: CCOC(=O)c1ccc(NCc2nccnc2OCc2ccccc2)cc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
2-Benzyloxypyrazine-3-aldehyde (455 mg) was mixed with ethyl-4-aminobenzoate (321 mg) and stirred at 120° C. for 1 hour. The solid was then azeotroped with toluene (20 mL) to remove the last traces of water. The residue was dissolved in ethanol (10 mL) under argon, and sodium borohydride (81 mg) added with stirring at ambient temperature. The mixture was then heated to reflux for one hour, and allowed to cool to ambient temperature over 16 hours. Water (70 mL) was added, and the mixture acidified to pH 3 with acetic acid and then extracted with ethyl acetate (4×10 mL), washed with water (50 mL), brine (50 mL) and dried over magnesium sulphate. The residue was purified by MPLC (3% ethyl acetate in dichloromethane, silica) to give ethyl 4-[2-benzyloxypyrazin-3-ylmethylamino]benzoate yield, 460 mg, mp 111.7° C.
Reaction SMILES: BrC[CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].[CH:18]([N:21]([CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:22](=[O:24])[CH3:23])([CH3:20])[CH3:19]>CN(C=O)C>[CH:8]([C:7]1[CH:6]=[CH:5][C:4]([CH2:3][N:28]2[CH2:29][CH2:30][CH:25]([N:21]([CH:18]([CH3:20])[CH3:19])[C:22](=[O:24])[CH3:23])[CH2:26][CH2:27]2)=[CH:11][CH:10]=1)=[O:9]
Reactant: CC(=O)N(C(C)C)C1CCNCC1
Reactant: O=Cc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N(C(C)C)C1CCN(Cc2ccc(C=O)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.6 %

Procedure:
To a mixture of 4-(bromoethyl)benzaldehyde (0.840 g, 4.2 mmol) and K2CO3 (1.75 g, 12.6 mmol) in DMF (15 mL) was added N-isopropyl-N-(piperidin-4-yl)acetamide (0.92 g, 4.2 mmol) and the reaction was stirred at room temperature 5 hours, then concentrated in vacuo. The resulting mixture was diluted with H2O and extracted with EtOAc. The organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 1% to 10% MeOH/CH2Cl2, afforded N-(1-(4-formylbenzyl)piperidin-4-yl)-N-isopropylacetamide (0.770 g, 61%).
Reaction SMILES: [CH2:1]([N:3]([C:27](=O)[C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([O:20]C(=O)C(C)(C)C)[CH:14]=[CH:13][C:12]=2[CH2:11]1)[CH3:2].Cl[CH2:37][C:38]([N:40]([CH2:42][CH2:43][O:44][CH3:45])[CH3:41])=O>>[CH2:1]([N:3]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][CH2:37][CH2:38][N:40]([CH2:42][CH2:43][O:44][CH3:45])[CH3:41])=[CH:32][CH:33]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:10]1[CH2:19][CH2:18][C:13]2[CH:14]=[C:15]([OH:20])[CH:16]=[CH:17][C:12]=2[CH2:11]1)[CH3:2]
Reactant: COCCN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1ccccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)CCOC)cc1)c1ccccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 42.9 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]phenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (18 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.0 mg) was obtained.
Reaction SMILES: [OH-].[K+].[C:3]([O:7][OH:8])([CH3:6])([CH3:5])[CH3:4].[C:9]([N:13]=[N:14][C:15]1(Cl)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:12])([CH3:11])[CH3:10].[OH-].[Na+].[Cl-].[K+]>O>[C:9]([N:13]=[N:14][C:15]1([O:8][O:7][C:3]([CH3:6])([CH3:5])[CH3:4])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)N=NC1(Cl)CCCCC1
Reactant: CC(C)(C)OO
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)N=NC1(OOC(C)(C)C)CCCCC1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a solution of 42 grams (0.64 moles) of 85% potassium hydroxide in 100 ml. of water, cooled to 15° C in a 2 liter jacketed reactor was added 81 grams (0.81 moles) of 90% t-butylhydroperoxide slowly and with rapid stirring. The temperature was held at 20°-25° C by the rate of addition and by circulating 15° C water through the reactor jacket. After the addition was complete, the reaction was stirred for 30 minutes at 20° C and then 118 grams (0.58 moles) of 1-t-butylazo-1-chlorocyclohexane was added dropwise over a 30 minute period holding the temperature at 20°-22° C. After the addition was complete the reaction was stirred for 15 minutes at 20° C. It was then cooled to 0°-5° C and stirred for 90 minutes. A 0.2 mole (16 grams) portion of 50% NaOH was then added and the reaction stirred for 15 minutes. Ice water was then added until the potassium chloride dissolved. The mixture was extracted with 200ml. of pentane, the pentane extract washed with ice cold water saturated NaHCO3 solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure at 10° C to leave 130 grams (88% yield) of crude 1-t-butylazo-1-(t-butylperoxy)-cyclohexane. The product was stored in a dry ice chest.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38])[C:6]([O:8][CH2:9][C:10]([N:19](C(OC(OC(=O)CNC(=O)C)C)=O)[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:11][CH3:12])=[O:7].[OH2:41]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38])[C:6]([O:8][CH2:9][C:10]([NH:19][CH2:20][C:9]([O:8][CH2:6][C:5]1[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[CH:3][CH:4]=1)=[O:41])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:11][CH3:12])=[O:7]
Reactant: O
Reactant: CCC(COC(=O)c1cc(OC)c(OC)c(OC)c1)(c1ccccc1)N(C)C(=O)OC(C)OC(=O)CNC(C)=O
Product: CCC(COC(=O)c1cc(OC)c(OC)c(OC)c1)(NCC(=O)OCc1ccc(OC)cc1)c1ccccc1

Procedure:
20 ml water is added to the mixture. The product is extracted with ethyl acetate (3 times 50 mL) then the organic phase is washed successively with water and a saturated solution of sodium chloride (10 mL). The organic phases are dried over Na2SO4, filtered then concentrated to dryness in order to produce a brown oil. The oil is purified by flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate: 3/7) in order to produce 200 mg of the expected product (S) 2-{[1-(2-acetylamino-acetoxy)-ethoxycarbonyl]-methyl-amino}-2-phenyl-n-butyl 3,4,5-trimethoxy-benzoate in the form of a brown solid (yield=7%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].S(Cl)([Cl:16])(=O)=O>C(Cl)(Cl)(Cl)Cl>[Cl:16][C:3]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1=[O:1]
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C1(Cl)CCCCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
First, ethyl 1-chloro-2-oxocyclohexanecarboxylate was prepared from ethyl 2-oxocyclohexanecarboxylate referring to the process described in Organic Synthesis volume 4, page 162. 17 g (0.1 mol) of ethyl 2-oxocyclohexanecarboxylate was dissolved in 50 ml of carbon tetrachloride, and to the solution was added dropwise 14.8 g (0.11 mol) of sulfuryl chloride dissolved in 15 ml of carbon tetrachloride at 0° C. After stirring at room temperature for 2 hours, the reaction solution was poured into 100 ml of ice water, the mixture was extracted three times with 50 ml each of carbon tetrachloride, and the extract was washed twice with 75 ml each of saturated aqueous sodium bicarbonate and once with 75 ml of saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled away to obtain 18 g (yield: 88%) of ethyl 1-chloro-2-oxocyclohexanecarboxylate. 1.22 ml (2 mmol) of dimethyl sulfide borane was dissolved in 40 ml of tetrahydrofuran, and 2.5 g (12 mmol) of ethyl 1-chloro-2-oxocyclohexanecarboxylate was added dropwise at -5° C. to 0° C. After stirring at 0° C. for 1 hour, the solvent was distilled away under reduced pressure and the reaction solution was poured into 50 ml of ice water. The mixture was extracted three times with 50 ml each of ethyl acetate, and the resulting organic layer was washed once with 75 ml of saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled away to obtain 2.2 g of a stereoisomer mixture of ethyl 1-chloro-2-hydroxy-1-cyclohexanecarboxylate.