Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Cl[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: Oc1cccc(Br)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
To 60% sodium hydride (9.8 g, 245 mmol) in 250 mL dimethylformamide at 5° C. under nitrogen is added portionwise 3-bromophenol (42.6 g, 246 mmol). After thirty minutes a solution of 2-(chloromethyl)quinoline (43.6 g, 246 mmol) in 250 mL dimethylformamide is rapidly added. The reaction is allowed to warm to room temperature. After overnight stirring, the reaction is freed of solvent and then partitioned between 1N sodium hydroxide and methylene chloride. The organic layer is separated, dried over magnesium sulfate and evaporated to 67.9 g of a yellow solid. Recrystallization from acetonitrile affords 42.8 g (55%) of brown crystals, m.p. 79°-81° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[BH4-].[Na+]>O.CO>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:1][CH2:2][C:3]([OH:5])=[O:4])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: NCC(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CNCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.9 %

Procedure:
To a solution of glycine (8.11 g, 108 mmol) in water (40 ml) were added an aqueous solution of sodium hydroxide (108 mmol, 15 ml) and a solution of 4-bromobenzaldehyde (20 g, 108 mmol) in methanol (240 ml). After 30 minutes stirring at room temperature sodium borohydride (4.09 g, 108 mmol) was added portionwise to this suspension. After 18 h stirring at room temperature the reaction mixture was concentrated under reduced pressure and the resulting aqueous phase was washed with diethyl ether. The aqueous phase was neutralized by the addition of an aqueous solution of 2M hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and diethyl ether. Drying the white solid afforded 2-(4-bromobenzylamino)acetic acid (14.2 g). The product was used in the following step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[CH:15]=[C:16]([C:18](=O)[CH2:19]Br)[O:17][C:13]=2[CH:12]=[C:11]([O:22][CH3:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C@H:25]([C:27]1[S:31][C:30]([NH2:32])=[N:29][N:28]=1)[CH3:26].CC(O)C>C(Cl)Cl.C(#N)C>[CH2:1]([O:8][C:9]1[C:14]2[CH:15]=[C:16]([C:18]3[N:32]=[C:30]4[N:29]([CH:19]=3)[N:28]=[C:27]([C@@H:25]([F:24])[CH3:26])[S:31]4)[O:17][C:13]=2[CH:12]=[C:11]([O:22][CH3:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OCc2ccccc2)c2cc(C(=O)CBr)oc2c1
Reactant: C[C@H](F)c1nnc(N)s1
Solvent: CC#N
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(OCc2ccccc2)c2cc(-c3cn4nc([C@H](C)F)sc4n3)oc2c1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
In a 20 mL vial, 1-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-bromoethanone (Example 1E, 407 mg, 1.085 mmol) and (S)-5-(1-fluoroethyl)-1,3,4-thiadiazol-2-amine (Example 40A, 202 mg, 1.373 mmol) were suspended in 2-propanol (10 ml, 130 mmol) and heated at 80° C. for 18 h. After 5 min. the solution became homogeneous. A precipitate was present after overnight stirring. The cooled mixtures were transferred into 20 mL microwaves vials and then heated 30 min at 150° C. The mixtures were combined, diluted in CH2Cl2 (200 mL) and washed once with sat. NaHCO3, once with brine, dried over anh. Na2SO4 and concentrated. The residue was purified on ISCO using a REDISEP® Gold 40 g column (CH2Cl2/EtOAc). The crude product was adsorbed on SiO2. Fractions were collected and the orange solid obtained was tritured twice in ACN to give the title material a light yellow solid. LC (Method B): 2.403 min. MS (ESI) calcd. for C22H19FN3O3S [M+H]+ m/z: 424.1126. found: 424.1146. 1H NMR (400 MHz, DMSO-d6) d ppm 8.61 (s, 1H) 7.51 (d, J=7.4 Hz, 2H) 7.42 (t, J=7.6 Hz, 2H) 7.35 (t, J=7.0 Hz, 1H) 7.08 (s, 1H) 6.83-6.85 (m, 1H) 6.54 (d, J=1.2 Hz, 1H) 6.16 (dq, J=47.1, 6.4 Hz, 1H) 5.26 (s, 2H) 3.80 (s, 3H) 1.79 (dd, J=24.5, 6.8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:16][CH2:15][CH2:14][C:13]3[C:12](=[NH:17])[NH:11][C:10](=N)[C:9]2=3)=[CH:4][CH:3]=1.Cl.[CH2:20]([C:22]1[CH:34]=[CH:33][C:25]([NH:26][C:27]2[S:28][CH2:29][C:30](=[NH:32])[N:31]=2)=[CH:24][CH:23]=1)[CH3:21].Cl.N=C1NC(=N)CS1>>[NH:17]=[C:12]1[C:13]2[CH2:14][CH2:15][CH2:16][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:9]=2[C:10](=[C:29]2[S:28][C:27]([NH:26][C:25]3[CH:24]=[CH:23][C:22]([CH2:20][CH3:21])=[CH:34][CH:33]=3)=[N:31][C:30]2=[NH:32])[NH:11]1
Reactant: CCc1ccc(NC2=NC(=N)CS2)cc1
Reactant: N=C1NC(=N)C2=C1CCCC2c1ccc(Cl)cc1
Agent: Cl
Agent: N=C1CSC(=N)N1
Product: CCc1ccc(NC2=NC(=N)C(=C3NC(=N)C4=C3C(c3ccc(Cl)cc3)CCC4)S2)cc1

Procedure:
Proceeding in a manner similar to that described above in Example 10, part A but substituting equivalent amounts of 4-(p-chlorophenyl)-4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2-(p-ethylanilino)-4-imino-2-thiazoline hydrochloride for 4,5,6,7-tetrahydro-1,3-diiminosioindoline and 2,4-diiminothiazolidine hydrochloride, there is obtained as the product 1-imino-4-(p-chlorophenyl)-4,5,6,7-tetrahydro-3-[2-(p-ethylanilino)-4-imino-2-thiazolin-5-ylidene]isoindoline.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([C:15]3[C:16]([NH:32][C:33]4[CH:34]=[N:35][C:36]([O:39][CH3:40])=[N:37][CH:38]=4)=[N:17][CH:18]=[C:19]([CH2:21][N:22]4[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]4)[CH:20]=3)[N:12]=[C:11]([CH3:41])[N:10]=2)=CC=1.FC(F)(F)C(O)=O>FC(F)(F)S(O)(=O)=O>[CH3:40][O:39][C:36]1[N:35]=[CH:34][C:33]([NH:32][C:16]2[C:15]([C:13]3[N:12]=[C:11]([CH3:41])[N:10]=[C:9]([NH2:8])[N:14]=3)=[CH:20][C:19]([CH2:21][N:22]3[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:26][CH2:27]3)=[CH:18][N:17]=2)=[CH:38][N:37]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3cnc(OC)nc3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc(CN3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 80 °C
Yield: 32.4 %

Procedure:
A mixture of N,N-bis(4-methoxybenzyl)-4-(2-(2-methoxypyrimidin-5-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (301 mg, 0.414 mmol) in trifluoroacetic acid (638 nL, 8.28 mmol) was treated with a couple of drops of trifluoromethanesulfonic acid and the mixture was heated at 80° C. overnight. After cooling, the mixture was concentrated and the residue was dissolved in 5% (2 M NH3 in MeOH)/DCM (5 mL) and the crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (pure DCM→3% MeOH in DCM). The isolated yellow solid was dissolved in DMSO and was subjected to a reversed phase preparative HPLC purification (10% MeCN in H2O to 100% MeCN w/0.1% (v/v) TFA). The product fraction was basified with saturated NaHCO3(aq), extracted with dichloromethane (3×20 mL) and the combined organic layers were dried over Na2SO4, filtered, and concentrated to give 4-(2-(2-methoxypyrimidin-5-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (65 mg, 0.134 mmol, 32.3% yield) as a bright yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 11.78 (s, 1H); 9.03 (s, 2H); 8.73 (d, J=1.56 Hz, 1H); 8.23 (d, J=1.76 Hz, 1H); 7.91 (br. s., 1H); 7.75 (br. s., 1H); 3.91 (s, 3H); 3.50 (s, 2H); 3.11 (br. s., 4H); 2.86 (s, 3H); 2.46-2.49 (m, 4H); 2.44 (s, 3H). m/z (ESI, +ve ion) 486.8 (M+H)+.
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=2)=[CH:10][CH:9]=[C:8]([CH3:20])[N:7]=1)=[O:5])C.[NH2:21][C:22]1[N:23]=[C:24]([CH3:27])[S:25][CH:26]=1>>[CH3:27][C:24]1[S:25][CH:26]=[C:22]([NH:21][C:4]([C:6]2[C:11]([NH:12][C:13]3[CH:14]=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=3)=[CH:10][CH:9]=[C:8]([CH3:20])[N:7]=2)=[O:5])[N:23]=1
Reactant: Cc1nc(N)cs1
Reactant: CCOC(=O)c1nc(C)ccc1Nc1cncc(C)c1
Product: Cc1cncc(Nc2ccc(C)nc2C(=O)Nc2csc(C)n2)c1

Procedure:
The title compound, was prepared from 6-Methyl-3-(5-methyl-pyridin-3-ylamino)-pyridine-2-carboxylic acid ethyl ester and 4-Amino-2-methylthiazole in accordance with the general method of Example 78, step 2 to yield the final compound as a light-yellow solid, MS (ISP): m/e=340.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[CH:9]=[C:8]([C:16](OC2CCCC(=O)C=2)=[O:17])[C:7]1=[O:26].C(N(CC)CC)C.C[C:39]([CH3:43])([OH:42])[C:40]#N.[C:44](O)(=O)[CH2:45][C:46](CC(O)=O)(C(O)=O)[OH:47]>ClCCl>[OH:47][C:46]1[CH2:45][CH2:44][CH2:43][C:39](=[O:42])[C:40]=1[C:16]([C:8]1[C:7](=[O:26])[N:6]([CH2:5][C:4]2[CH:27]=[CH:28][CH:29]=[CH:30][C:3]=2[O:2][CH3:1])[C:15]2[C:10]([CH:9]=1)=[CH:11][CH:12]=[CH:13][N:14]=2)=[O:17]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: COc1ccccc1Cn1c(=O)c(C(=O)OC2=CC(=O)CCC2)cc2cccnc21
Reactant: CC(C)(O)C#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1Cn1c(=O)c(C(=O)C2=C(O)CCCC2=O)cc2cccnc21
Temperature: 25 °C
Yield: 33 %

Procedure:
4.82 g (11.9 mmol) of 3-oxo-1-cyclohexenyl 1-(2-methoxybenzyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate was dissolved in dichloromethane (100 mL), and 2.01 mL (14.3 mmol) of triethylamine and 1.11 g (13.1 mmol) of acetone cyanohydrin were added to the above solution. The mixture was stirred for one whole day and night at room temperature. The reaction mixture was poured into an aqueous solution of citric acid, and the mixture was extracted with dichloromethane. The organic phase was washed with water, dried, and concentrated. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:3 to 1:1), and thus 1.59 g (yield: 33%) of the title compound was obtained as yellow crystals.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:5][C:6]=1[C:7](=[O:21])/[C:8](=[N:13]/[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[C:9]([O:11][CH3:12])=[O:10].[H-].[Na+]>C1COCC1>[N:23]1([CH2:22][C:4]2[S:3][C:2]3[N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7](=[O:21])[C:6]=3[CH:5]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: COC(=O)/C(=N\Nc1ccccc1)C(=O)c1cc(CN2CCOCC2)sc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1nn(-c2ccccc2)c2sc(CN3CCOCC3)cc2c1=O
Reaction time: 8 h
Yield: 15.6 %

Procedure:
To a solution of methyl (2Z)-3-(2-chloro-5-(4-morpholinylmethyl)-3-thienyl)-3-oxo-2-(phenylhydrazono)propanoate (Preparation 65, 2.67 g) in dry THF (150 mL) is added NaH (0.43 g; 60% dispersion in mineral oil) portionwise at ambient temperature. The reaction is continued overnight and the solvent is removed in vacuo. Water (50 mL) is added to residue and the aqueous layer is extracted with EtOAc (3×50 mL). The organic layer is separated, dried over MgSO4, filtered, and concentrated in vacuo. The resulting precipitate is filtered to afford 0.38 g (16%) of the title compound as a brown solid. Physical characteristics: m.p. 167-169° C.; 1H NMR (400 MHz, CDCl3)δ 7.67, 7.57, 7.43, 3.98, 3.68, 2.50; IR (diffuse reflectance) 2816, 1731, 1615, 1515, 1353, 1279, 1200, 1172, 1133, 1121, 1106, 1026, 867, 809, 749 cm−1; MS (ESI+) 386; HRMS (FAB) m/z 386.1180 (C19H19N3O4S+H). Anal. Found: C, 59.14; H, 5.02; N, 10.48.
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].CC(C)=O.O.[C:15]([OH:24])(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]>CC(C)=O.O>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].[C:15]([O-:24])(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O-:22])=[O:21]
Reactant: O=C(O)CCCCC(=O)O
Agent: CN(C)C(=N)NC(=N)N
Solvent: O
Solvent: CC(C)=O
Product: O=C([O-])CCCCC(=O)[O-]
Temperature: 25 °C
Yield: 139.1 %

Procedure:
9.75 g (2.5 molar equivalents) of the metformin free-base was stirred in a mixed solution of 112.5 ml of acetone and 5 ml of water at 40° C., and then a solution of 4.41 g (1 molar equivalent) of adipic acid in acetone-water was added dropwise thereto and stirred at room temperature. The produced crystal was filtered and dried in hot air, thus obtaining 11.47 g (yield: 93.9%) of metformin adipate.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[C:4]([CH2:13][NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:3]=1.[C:19]([NH:26][C@H:27]([C:29]([OH:31])=O)[CH3:28])([O:21][C:22]([CH3:25])([CH3:24])C)=[O:20].[CH3:32]CN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:32][CH2:25][CH:22]([O:21][C:19]([NH:26][C@@H:27]([CH3:28])[C:29]([N:14]([CH2:13][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]2[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=1)[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:31])=[O:20])[CH3:24]
Reactant: CC(C)CNCc1cc(Cl)c2c(c1)OCCCO2
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(C)OC(=O)N[C@@H](C)C(=O)N(Cc1cc(Cl)c2c(c1)OCCCO2)CC(C)C
Reaction time: 8 h

Procedure:
A mixture of N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-2-methylpropan-1-amine (100 mg), Boc-L-alanine (70 mg), EDAC (100 mg), and DMAP (60 mg) in DCM (8 ml) was stirred overnight. The reaction mixture was partitioned between EtOAc and water (8 ml each×3). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purificatied by flash chromatography on silica (33% EtOAc in hexane), which yielded (+)-(2S)-2-(Methylpropan-2-yl)oxycarbonylamino-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide as a resin: MS (m+1)=441.1. The chiral integrity of this compound was not examined.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[S:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:7][C:6]1[C:2]([O:1][CH3:13])=[C:3]([C:9]([O:11][CH3:12])=[O:10])[S:4][C:5]=1[CH3:8]
Reactant: COC(=O)c1sc(C)c(C)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)c1sc(C)c(C)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-hydroxy-4,5-dimethylthiophene-2-carboxylate (Preparation 1) (29.7 g, 160 mmol) in anhydrous acetone (500 ml) was added anhydrous potassium carbonate (24.5 g, 178 mmol) and the mixture stirred for 1 hour at room temperature. Dimethyl sulphate (22.4 g, 178 mmol) was added and the mixture stirred under reflux for 2.5 hours. The solvent was evaporated under reduced pressure and the residue partitioned between water and ethyl acetate. The organic phase was washed with brine, dried with sodium sulphate and evaporated to give crude product which was used in the following preparation.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:5](=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])[CH:11]=[CH:12][CH:13]=1)C(OC)=O.[N+:23]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O)([O-:25])=[O:24].C([BH3-])#N.[Na+].Cl>C1(C)C=CC=CC=1.CCOCC>[CH3:1][O:2][C:3](=[O:22])[C:13]1[C:4](=[CH:5][C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([N+:23]([O-:25])=[O:24])[CH:27]=2)=[CH:11][CH:12]=1)[C:3]([O:2][CH3:1])=[O:22]
Reactant: COC(=O)c1cccc(Oc2ccccc2N)c1C(=O)OC
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)c1ccc(Oc2ccccc2NCc2cccc([N+](=O)[O-])c2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3-(2-aminophenoxy)phthalic acid dimethyl ester (200 mg, 0.54 mmol) and 3-nitrobenzaldehyde (90 mg, 0.60 mmol) in toluen (20 ml) was refluxed for 30 hours with a Dean-Stark trap. The reaction mixture is cooled to room temperature and evaporated to dryness in vacuo. The residue was dissolved in methanol (5ml), sodium cyanoborohydride (100 mg, 1.58 mmol) was added, and pH adjusted to 4.5 by means of hydrogen chloride in ether. The mixture was stirred at room temperature for 20 hours, evaporated in dryness in vacuo, and partioned between methylene chloride (5 ml) and water (5 ml). The organic phase was isolated, dried over magnesium sulphate, and evaporated to dryness in vacuo. The crude compound was purified on silica gel (eluent: methylene chloride:ethyl acetate (95:5)) to give 4-[2-(3-nitrobenzylamino)phenoxy]phthalic acid dimethyl ester as a yellow oil (yield: 130 mg (55%). 1H—NMR (CDCl3) in ppm: δ 8.05-8.18 (2H,m); 7.84 (1H,d); 7.63 (1H,d); 7.50 (1H,t); 7.20 (1H,d); 6.9-7.1 (3H,m); 6.73 (1H,d.t.); 6.6 (1H,d.d.); 4.56 (1H,broad, s): 4.48 (2H,broad s); 3.9 (3H,s); 3.87 (3H,s). LC-MS: m/e 459 (M+Na), 437 (MH+).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1.[O:10]=O.CC1C=C(C)C=C(C)C=1CC1C=C(C)C=C(C)C=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(=O)C>[CH3:9][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[OH:10]
Reactant: Cc1cc(C)cc(C)c1
Reactant: O=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1cc(C)cc(Cc2c(C)cc(C)cc2C)c1
Solvent: CC(=O)O
Product: Cc1cc(C)c(O)c(C)c1

Procedure:
In a flask, 30 mmol of mesitylene, 4.5 mg (0.02 mmol) of palladium(II) acetate, 323 mg (about 0.14 mmol) of H4PMo11V1O40-nH2O, and 10 ml of acetic acid were placed and were stirred at a constant temperature of 90° C. in an atmosphere of oxygen gas at 1 atm (0.1 MPa) for 15 hours. The resulting reaction mixture was analyzed by gas chromatography to find that 8.5 mmol of 1,3,5-trimethyl-2-(3′,5′-dimethylbenzyl)benzene, and 1 mmol of 2,4,6-trimethylphenol were produced.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Cl:19])C(=O)C1>C(#N)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[C:9]([Cl:19])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CC(C)(C)c1ccc(O)c(Cl)c1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
1.50 g (10 mmol) of 4-tert.-butyl phenol were dissolved in 40 ml acetonitrile. 1.34 g (10 mmol) of NCS were added and the reaction mixture was stirred at rt over night. The reaction mixture was heated for 1.5 h to reflux. Then additional 134 mg (1 mmol) of NCS were added and the reaction mixture was heated to reflux for 2 h. The solvent was evaporated and the residue was stirred with diethyl ether for 15 min. The solid was filtered off and the filtrate was evaporated. The residue was purified by column chromatography (100 silica gel, DCM) to yield 1.49 g (81%) of 4-tert.-butyl-2-chloro-phenol as a colorless viscous oil. 1H NMR (DMSO-d6, 300 MHz): δ 9.85 (s, 1H), 7.26 (s, 1H), 7.14 (d, 2H), 6.88 (d, 2H), 1.22 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][S:7][C:8]2[C:9](=[O:17])[CH2:10][C:11]([CH3:16])([CH3:15])[CH2:12][C:13]=2[OH:14])=[CH:4][CH:3]=1.[OH:20]O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][S:7]([C:8]2[C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10][C:9]=2[OH:17])=[O:20])=[CH:18][CH:19]=1
Reactant: OO
Reactant: CC1(C)CC(=O)C(SCc2ccc(F)cc2)=C(O)C1
Solvent: CC(=O)O
Product: CC1(C)CC(=O)C(S(=O)Cc2ccc(F)cc2)=C(O)C1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 2-(p-fluorobenzylthio)-3-hydroxy-5,5-dimethyl-2-cyclohexen-1-one (12.4 g., 0.0443 mole) 30 percent hydrogen peroxide (5.0 g., 0.044 mole) and 100 ml. of glacial acetic acid was allowed to stand at room temperature for 24 hours. The solution was poured into ice water and the precipitated pink crystals were filtered and dried (12.3 g., m.p. 122°-125°C.).
Reaction SMILES: [OH:1][CH:2](CN1CCC(COC2C=CC=CC=2)CC1)COC1C=CC(C)=C([N+]([O-])=O)C=1[N+]([O-])=O.C(N)CC.[OH:37][CH:38]([CH2:55][N:56]1[CH2:61][CH2:60][CH:59]([CH2:62][O:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH2:58][CH2:57]1)[CH2:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[C:43]([N+:48]([O-])=O)[C:42]=1[NH:51][CH2:52][CH2:53][CH3:54]>[Pt]=O>[OH:37][CH:38]([CH2:55][N:56]1[CH2:61][CH2:60][CH:59]([CH2:62][O:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH2:58][CH2:57]1)[CH2:39][O:40][C:41]1[C:42]2[N:51]([CH2:52][CH2:53][CH3:54])[C:2](=[O:1])[NH:48][C:43]=2[C:44]([CH3:47])=[CH:45][CH:46]=1
Reactant: Cc1ccc(OCC(O)CN2CCC(COc3ccccc3)CC2)c([N+](=O)[O-])c1[N+](=O)[O-]
Reactant: CCCNc1c(OCC(O)CN2CCC(COc3ccccc3)CC2)ccc(C)c1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCCN
Product: CCCn1c(=O)[nH]c2c(C)ccc(OCC(O)CN3CCC(COc4ccccc4)CC3)c21

Procedure:
15.0 g. 1-[2-hydroxy-3-(4-phenoxymethylpiperidino)-propoxy]-4-methyl-2,3-dinitrobenzene (see preparation of the starting material for Example (4a) are heated under reflux in 12 ml. n-propylamine for 3.5 hours. After cooling, there are isolated 8.8 g. (59% of theory) crystalline 1-[2-hydroxy-3-(4-phenoxymethylpiperidino)-propoxy]-4-methyl-2-propylamino-3-nitrobenzene; m.p. 91°-93° C. This compound is hydrogenated in the presence of platinum oxide to give the desired 3-amino-1-[2-hydroxy-3-(4-phenoxymethylpiperidino)-propoxy]-4-methyl-2-propylaminobenzene.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([C@@H:9]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][NH:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:32][C:33]1([C:36]([N:38]2[CH2:43][CH2:42][CH:41]([C:44](O)=[O:45])[CH2:40][CH2:39]2)=[O:37])[CH2:35][CH2:34]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:22])[N:7]([C@@H:9]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:44]([CH:41]2[CH2:40][CH2:39][N:38]([C:36]([C:33]3([CH3:32])[CH2:35][CH2:34]3)=[O:37])[CH2:43][CH2:42]2)=[O:45])[CH2:10]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C(=O)N2CCC(C(=O)O)CC2)CC1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)OC(C)(C)C)[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 75.2 %

Procedure:
To a solution of rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (2.78 g, 7.56 mmol) in DMF (28 mL) were added at 0° C. N,N-diisopropyl ethyl amine (8.26 mL, 48.2 mmol), 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid (2.78 g, 8.04 mmol), 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.67 g, 9.65 mmol). The resulting solution was stirred for 6 h at ambient temperature. After diluting with EtOAc (50 mL) the solution was washed twice with water (50 mL) and brine (50 mL). The aqueous layers were extracted with EtOAc (50 mL) and dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate:methanol=80:20:0 to 0:90:10) afforded the title compound (3.06 g, 75%) as a light brown foam. MS m/e: 538.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N[CH2:6][CH2:7][CH2:8][CH2:9][OH:10]>>[OH:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:1][C:2]([NH2:4])=[O:3]
Reactant: NCCCCO
Reactant: NC(N)=O
Product: NC(=O)NCCCCO

Procedure:
A mixture of 6.0 g (0.1 mole) of urea and 9.8 g (0.11 mole) of 4-amino-1-butanol was heated at 130°-135° C. for 4 hours to form monohydroxybutylurea. Without isolation the reaction mixture was cooled to 70° C. and then 31.0 g (0.21 mole) of chloral was slowly added while the temperature was maintained below 80° C. using external cooling. The reaction mixture was vigorously stirred and heated at 80°-85° C. for 1 hour. On cooling 43 g of a viscous syrupy product was isolated.