Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[CH:6][N:7]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]=1[CH3:9])[CH3:3].[CH3:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]([S:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)(=[O:41])=[O:40])[C:31]=1[CH2:48][CH:49]=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[CH3:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]([S:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)(=[O:41])=[O:40])[C:31]=1[CH2:48][CH2:49][NH:1][CH:2]([C:4]1[N:5]=[CH:6][N:7]([C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:8]=1[CH3:9])[CH3:3]
Reactant: Cc1c(CC=O)n(S(=O)(=O)c2ccccc2)c2ccccc12
Reactant: Cc1c(C(C)N)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(CCNC(C)c2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C)n(S(=O)(=O)c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
A mixture of 4-(1-aminoethyl)-5-methyl-1-trityl-1H-imidazole (735 mg), 3-methyl-1-(phenylsulfonyl)-2-indoleacetaldehyde (626 mg) and molecular sieves 3A (100 mg) in dry methanol (30 ml) was stirred at ambient temperature for 30 minutes. Acetic acid (0.35 ml) and sodium cyanoborohydride (126 mg) were added and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was treated with cold water, extracted twice with ethyl acetate, which was washed with brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was chromatographed over silica gel (eluted with 3% methanol in chloroform) to give 3-methyl-2-[2-[[1-(5-methyl-1-trityl-1H-imidazol-4-yl)ethyl]amino]ethyl]-1-phenylsulfonylindole (947 mg) as an amorphous powder.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15].[NH3:17]>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH2:17])=[O:15]
Reactant: N
Reactant: COCCCCCCCCCCCC(=O)Cl
Solvent: C1CCOC1
Product: COCCCCCCCCCCCC(N)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the title product from Example 11 (1.1 g, 4.3 mmol) in 70 mL of anhydrous tetrahydrofuran was added 20 mL of freshly distilled liquid ammonia in a Parr shaker which was sealed and shaken at room temperature for 16 hours. After filtering and concentration, the crude residue was dissolved in anhydrous methanol and passed through a basic ion exchange resin and eluted with anhydrous methanol. Concentration afforded the title compound (780 mg) as a white solid, m.p. 83.9°-85.6° C. (DSC). The structure-was supported by NMR, infrared spectroscopy, elemental analysis, and mass spectroscopy.
Reaction SMILES: [CH3:1][O:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][N:11]=[C:10]2O)=[O:6].C(N(CC)CC)C.P(Cl)(Cl)([Cl:27])=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][N:11]=[C:10]2[Cl:27])=[O:6]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCNC(=O)c1ccc2ncnc(O)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COCNC(=O)c1ccc2ncnc(Cl)c2c1
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
4-Hydroxyquinazoline-6-carboxylic acid methoxymethylamide (XIII-1, 2.9 g) was suspended in toluene (57 ml), and 6.8 ml of triethylamine and 3.4 ml of phosphorus oxychloride were added, followed by stirring at 130° C. for 30 minutes. After completion of the reaction, the reaction mixture was cooled to room temperature, and 50 ml of aqueous saturated sodium bicarbonate solution and ethyl acetate were added. Sodium bicarbonate was added until the aqueous layer exhibited a pH 8, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium bicarbonate solution, dried over sodium sulfate. After concentration, the crystalline residue was washed with diethyl ether, and dried to obtain 4-chloroquinazoline-6-carboxylic acid methoxymethylamide (XIV-1, 2.3 g) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@H:14]1[C@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=2[F:26])[C@:17]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[F:36])([C:27]#[N:28])[C@H:16]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:15]1)=[O:13])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([CH:14]1[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=2[F:26])[C:17]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[F:36])([C:27]#[N:28])[CH:16]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:15]1)=[O:13]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NCCCNC(=O)OC(C)(C)C)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)NCCCN)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F

Procedure:
Rac (3-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester (815 mg) was treated with 30% TFA/methylene chloride (10 mL) overnight. Removal of solvent and freeze drying of the residue give a white powder. 800 mg.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[CH3:11])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[C:18]([O:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[C:5]([CH3:11])[CH:6]=1)(=[O:20])[CH3:19]
Reactant: Cc1cc(O)ccc1C(C)C
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.2 %

Procedure:
4-Isopropyl-3-methylphenol (1.00 g) was dissolved in dichloromethane (10 ml) to prepare a solution. Pyridine (724 mg) and acetyl chloride (615 mg) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was dried under the reduced pressure to give 4-isopropyl-3-methylphenyl acetate (1.41 g, yield 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[C@@H:4]([NH:27]C(OCC1C=CC=CC=1)=O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[C:8]([O:20][S:21](=[O:26])(=[O:25])[N:22]([CH3:24])[CH3:23])[CH:7]=1.C([Cl:46])C1C=CC=CC=1>CO.[C].[Pd]>[Cl-:46].[CH3:24][N:22]([CH3:23])[S:21]([O:20][C:8]1[CH:7]=[C:6]([CH2:5][C@H:4]([NH3+:27])[C:3]([O:2][CH3:1])=[O:38])[CH:11]=[CH:10][C:9]=1[OH:12])(=[O:26])=[O:25]
Reactant: ClCc1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OS(=O)(=O)N(C)C)c1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]([NH3+])Cc1ccc(O)c(OS(=O)(=O)N(C)C)c1
Product: [Cl-]
Reaction time: 8 h

Procedure:
(S)-2-Benzyloxycarbonylamino-3-(4-benzyloxy-3-dimethylsulfamoyloxy-phenyl)-propionic acid methyl ester (615 mg) was dissolved in methanol (30 ml) containing benzyl chloride (180 mg) and 5% palladium-carbon (60 mg). The mixture was stirred overnight under an atmosphere of hydrogen gas. The catalyst was removed by filtration and washed with methanol. Evaporation of the filtrate gave a gum which was crystallised by trituration with ether. (S)-2-(3-Dimethylsulfamoyloxy-4-hydroxy-phenyl)-1-methoxycarbonyl-ethyl-ammonium chloride was obtained as an off-white solid, 320 mg; NMR (500 MHz, d6 DMSO) 2.89 (3H, s), 2.97 (1H, dd J 14, 8), 3.01-3.08 (4H, m), 3.67 (3H, s), 4.19 (1H, t J 7), 6.84-6.88 (3H, m), 8.54 (ca 3H, br exch D2O), 9.58 (1H, s, exch D2O); HPLC/MS retention time 2.68 min, m/z 283 (MH+).
Reaction SMILES: CN([S+](N(C)C)N(C)C)C.C[Si-](F)(F)(C)C.[N+:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([O-:19])=[O:18].[O:26]1[CH2:30][CH2:29][CH:28]=[C:27]1[O:31][Si](C)(C)C.BrBr>C(#N)C.C1COCC1>[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([CH:28]2[CH2:29][CH2:30][O:26][C:27]2=[O:31])=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: C[Si](C)(C)OC1=CCCO1
Agent: BrBr
Agent: CN(C)[S+](N(C)C)N(C)C
Agent: C[Si-](C)(C)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C1OCCC1c1ccc([N+](=O)[O-])cc1
Reaction time: 20 h
Yield: 31.9 %

Procedure:
A solution of 2.75 g (10 mmol) of TASF in 3 mL of acetonitrile and 3 mL of THF was added to a solution of 1.02 mL (10 mmol) of nitrobenzene and 1.93 mL (10.50 mmol) of [(oxacyclopent-2-ene-2-yl)oxy]trimethylsilane (OCS) in 12 mL of anhydrous THF at -78° C. over 10 min. The last traces of TASF from the dropping funnel were washed down with additional 5 mL of THF. The mixture was stirred for 20 hrs. at -78° C. Then, 0.460 mL (8.98 mmol) of bromine was added from a dropping funnel. The mixture was stirred at -78° C. for 15 min, and then the cold bath was removed. Stirring was continued for 1 hr. Thirty mL of freshly prepared saturated sodium bisulfite was added, and the product was extracted into four 60 mL portions of ether. Combined ether extracts were washed with saturated potassium hydrogen phosphate and sodium chloride. Concentration and chromatography on silica yielded two products identified as the ortho and para addition products. The ortho-adduct yielded 0.660 g (32%) of product which had a melting point of 112°-117° C. (dec). The para-adduct yielded 0.282 g (14%) of product which had a melting point of 76° to 78° C. Both the o- and p- products were analyzed by ultraviolet absorption, infrared spectroscopy, nuclear magnetic resonance spectroscopy, and mass spectrometry.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH3:18])[C:11]=2[F:19])[N:7]=[C:6]([C:20]([O:22]C)=[O:21])[C:5]=1/[CH:24]=[CH:25]/[Si:26]([O:33]CC)([O:30]CC)[O:27]CC.CO.Cl>O1CCCC1>[NH2:3][C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH3:18])[C:11]=2[F:19])[N:7]=[C:6]([C:20]([OH:22])=[O:21])[C:5]=1/[CH:24]=[CH:25]/[Si:26]([OH:33])([OH:30])[OH:27]
Reactant: CCO[Si](/C=C/c1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OC)(OCC)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(Cl)ccc(-c2nc(N)c(/C=C/[Si](O)(O)O)c(C(=O)O)n2)c1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.5 %

Procedure:
A 2M aqueous solution of sodium hydroxide (150 μL, 0.31 mmol, 1.05 equiv) was added to a stirred solution of (E)-methyl 6-amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-(2-(triethoxysilyl)vinyl)pyrimidine-4-carboxylate (145 mg, 0.29 mmol, 1.0 equiv) in 3:1 methanol:tetrahydrofuran (4.0 mL) at room temperature. The homogeneous yellow solution was stirred at room temperature for 20 h. The reaction mixture was adjusted to pH 4 using concentrated hydrochloric acid and concentrated under vacuum. The residue was slurried in water and vacuum filtered to provide the title compound as a tan powder (95 mg, 81% yield): mp 220-250° C. (decomposition); IR (thin film) 3323 (m), 3195 (m), 2944 (w), 1603 (s), 1534 (s) cm−1; 1H NMR (400 MHz, DMSO-d6) δ 7.56-7.76 (m, 1H), 6.59-7.52 (m, 4H), 3.93 (br s, 3H); ESIMS m/z 402 [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:9][CH2:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=1)[O:1][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27]
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: OCc1cc(O)cc(CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCCOc1cc(CO)cc(CO)c1
Yield: 78 %

Procedure:
To a stirred solution of (5-hydroxy-1,3-phenylene)dimethanol (7.27 g, 47 mmol, 1 eq.) in 200 mL of acetonitrile at room temperature, 2-(4-bromobutyl)isoindoline-1,3-dione (1.2 eq.) and potassium carbonate (K2CO3, 2 eq.) were slowly added. The resultant mixture was then heated at reflux for 8 hours, after which the volatiles were removed, and the residue was partitioned between EtOAc and water. The EtOAc layer was washed with brine and dried over MgSO4. Evaporation of EtOAc gave 2-(4-(3,5-bis(hydroxymethyl)phenoxy)butyl)isoindoline-1,3-dione (13 g, 78% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13].N12CCN(CC1)CC2>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[C:12](=[CH2:13])[C:11]([O:15][CH3:16])=[O:14])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: C=CC(=O)OC
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: C=C(C(=O)OC)C(O)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of 3-chloro-4-fluorobenzaldehyde (10.0 g) and methyl acrylate (8.5 mL) in acetonitrile (63 mL) was added 1,4-diazabicyclo[2.2.2]octane (1.41 g), and the mixture was stirred at room temperature for 5 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (11.5 g).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].CCN(CC)CC.[CH:20]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1>CCOCC.CCOC(C)=O>[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:25]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:26])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: O=C(Cl)C1CCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(NC(=O)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(Methanesulfonyl)aniline hydrochloride (19 mmol) suspended in 25 mL of Et2O was added Et3N (48 mmol) and then a solution cyclopentanecarbonyl chloride (19 mmol) in 25 mL of Et2O was added dropwise during in 10 min. The reaction mixture was stirred for 3 h at RT and then diluted with EtOAc (100 mL) washed with 1N aq HCl, water and aq sat NaHCO3. The organic phase was dried and concentrated in vacuo to give crude cyclopentanecarboxylic acid (4-methanesulfonyl-phenyl)-amide which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18](SC)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[O:25][S:26]([O-:28])=O.[K+].[CH3:30]O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[C:15]2[CH:16]=[CH:17][C:18]([S:26]([CH3:30])(=[O:28])=[O:25])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CO
Reactant: O=S([O-])OO
Reactant: CSc1ccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
To solution of the above sulfide (1.2 g, 3.58 mmol) in MeOH (58 mL) cooled to 0° C. was added OXONE® (4.40 g, 7.15 mmol) and the mixture was stirred at 0° C. for 4 hours to afford 4-(4-methanesulfonyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (802 mg, 61%) after basic work-up and purification.
Reaction SMILES: [C:1]([O:5][O:6][C:7]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12])=[O:8])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH2:24]([OH:28])[CH:25]([OH:27])[CH3:26]>C(OC)(C)(C)C>[C:7]([O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])[C:9]1[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:11]([O:28][CH2:24][CH:25]([OH:27])[CH3:26])=[O:12]
Reactant: CC(C)(C)OOC(=O)c1ccccc1C(=O)Cl
Reactant: CC(O)CO
Solvent: c1ccncc1
Solvent: COC(C)(C)C
Product: CC(O)COC(=O)c1ccccc1C(=O)OOC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.4 %

Procedure:
A 300 mL 3-neck round-bottom flask, equipped with a magnetic stirrer, a thermometer, a cold water condenser and an addition funnel, was charged with 100 mL of methyl t-butyl ether, 16.7 g (0.06 mole) of 91.3% of 2-(t-butylperoxycarbonyl)benzoyl chloride and 5.5 g (0.07 mole) of pyridine. To this vigorously stirred solution at 20° C. was added 22.8 g (0.30 mole) of 1,2-propanediol over a period of 20 minutes. During the addition there was a slight exotherm and a white precipitate formed. The reaction mass was warmed to 25° C. and stirred at 25° C. for 240 minutes. The precipitate was separated by filtration and the white solid was washed with about 25 mL of methyl t-butyl ether. The methyl t-butyl ether washings were combined with the filtrate and the filtrate was washed twice with 50 mL portions of 5% aqueous HCl solution, then twice with 50 mL portions of 3% aqueous NaHCO3 solution. The methyl t-butyl ether solution was then dried over 10% by weight of anhydrous MgSO4 and, after separation of the spent desiccant by filtration, the solvent was removed in vacuo leaving 17.4 g (98.3% of theory, uncorrected) of a straw-color liquid. An infrared spectrum of the product showed a strong OH band at ca. 3500 cm-1 and two carbonyl bands at ca. 1720 cm-1 and 1770 cm-1. The product had a peroxyester Act[O] content of 5.02%. Based on a theoretical Act[O] of 5.40% for the desired title product, the assay was 93.0% and the corrected yield was 91.4%.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=[CH:17][C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]3[CH2:26][OH:27])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:30]I.O>O1CCCC1>[C:1]1([C:7]2[C:15]([CH:16]=[CH:17][C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]3[CH2:26][O:27][CH3:30])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(C=Cc1c(-c2ccccc2)nn2ccccc12)N1CCCCC1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC1CCCCN1C(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-hydroxymethylpiperidine (trans isomer) (0.30 g) was added to a stirred solution of tetrahydrofuran (2 ml) and sodium hydride (62.8%, 0.04 g) with ice-cooling. After 30 minutes, a solution of methyl iodide (0.14 g) in tetrahydrofuran (2 ml) was added to that stirred solution at 0° C. The reaction mixture was stirred for 4 hours at room temperature, then poured into water (20 ml), extracted with chloroform (20 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (20 g) with chloroform as an eluent. The fractions containing the objective compound were combined and evaporated in vacuo to give 1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-methoxymethylpiperidine (trans isomer) (0.30 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH2:20][NH:19][CH2:18][CH2:17]2.C(N(CC)CC)C>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH2:20][N:19]([C:7]([C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:8])[CH2:18][CH2:17]2
Reactant: COc1ccc2c(c1)CCNC2
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCc3cc(OC)ccc3C2)cc1
Reaction time: 18 h
Yield: 69.5 %

Procedure:
4-Methoxy-benzoyl chloride (2.35 g) was added dropwise to a solution of 6-methoxy-1,2,3,4-tetrahydro-isoquinoline (0.75 g) and triethylamine (1.54 mL) in dichloromethane (40 mL) at 0° C. After 18 h at room temperature, the reaction was washed with 1N NaOH (2×50 mL), then water (2×50 mL). The organic extract was dried over sodium sulfate, filtered through celite and concentrated. The (6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-(4-methoxy-phenyl)-methanone (0.95 g) product was obtained after purification by chromatography on silica gel (eluant: methylene chloride).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[ClH:7].Cl.[Cl:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[N:23]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:22]3[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=3[N:20]=2)[CH2:14][CH2:13]1.[I-].[K+]>CN(C)C=O>[ClH:9].[ClH:7].[ClH:9].[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]2[C:22]3[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=3[N:20]=[C:19]2[NH:18][CH:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH2:17][CH2:16]2)=[CH:26][CH:27]=1
Reactant: C1COCCN1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCCl)CC3)nc3ccccc32)cc1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2c(NC3CCN(CCN4CCOCC4)CC3)nc3ccccc32)cc1
Temperature: 70 °C
Yield: 18.3 %

Procedure:
A mixture of 3.6 parts of morpholine, 4.8 parts of N-[1-(2-chloroethyl)-4-piperidinyl]-1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine dihydrochloride, 0.1 parts of potassium iodide and 135 parts of N,N-dimethylformamide is stirred and heated overnight at 70° C. The reaction mixture is poured onto water and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is converted into the hydrochloride salt in methanol. The salt is filtered off and dried, yielding 1 part (18.3%) of 1-(4-fluorophenylmethyl)-N-{1-[2-(4-morpholinyl)ethyl]-4-piperidinyl}-1H-benzimidazol-2-amine trihydrochloride; mp.+300° C.
Reaction SMILES: [OH:1]S(O)(=O)=O.[C:6]([C@:8]([NH:19][C@H:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21]([NH2:23])=[O:22])([CH3:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)#[N:7]>C(Cl)Cl>[C:21]([C@H:20]([NH:19][C@@:8]([CH3:18])([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[C:6]([NH2:7])=[O:1])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:22])[NH2:23]
Reactant: COc1ccc(C[C@@](C)(C#N)N[C@@H](C(N)=O)c2ccccc2)cc1
Reactant: O=S(=O)(O)O
Solvent: ClCCl
Product: COc1ccc(C[C@](C)(N[C@@H](C(N)=O)c2ccccc2)C(N)=O)cc1
Temperature: 15 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
Into a 10 L reactor equipped with anchor stirrer was charged CH2Cl2 (1.64 L). The solvent was cooled to 15° C., then 95% H2SO4 (492 mL) and 2-[1-(S)-cyano-2-(4-methoxyphenyl)-1-methylethylamino]-2-(R)-phenylacetamide 2 (410 g, 1.27 mol) were added alternately in 9 portions over approximately 45 min (specifically: 164 mL of H2SO4 then 82 g of 2; subsequently, at approximately 5 min intervals, 8×[41 mL of H2SO4 then immediately 41 g of 2]). On addition of each portion, the suspension of 2 in the dense oily phase slowly dissolved (1-2 min) to provide a biphasic mixture. The resulting biphasic mixture (a red-brown dense oil with a pale yellow supernatant CH2Cl2 layer) was stirred for 0.5 h at 25° C. Ice-cold water (4.1 L) was added over 30 min, very slowly initially (200 mL dropwise over 15 min) due to a violent exotherm, and the biphasic mixture was stirred for 0.5 h. The phases were separated and the organic phase discarded. The combined aqueous phases were washed with CH2Cl2 (450 mL), and residual CH2Cl2 was stripped from the aqueous phase by distillation under vacuum at 55° C. (20-30 mBar). The aqueous solution was then cooled to 20° C. and was basified with 32% aq NH3 (1150 mL) to pH 8-9 at such a rate that the temperature was kept below 28° C. (approximately 120 min). The suspension was stirred for 30 min to ascertain a stable pH. The white solid which formed was separated by filtration, washed with H2O (2×2050 mL), and was thoroughly drained of water (but was not dried) to provide 2-[(R)-(carbamoylphenylmethy)-amino]-3-(4-methoxyphenyl)-2-(S)-methylpropionamide 3 (1087 g (391 g theoretical, the sample contains 64% w/w of H2O), yield 90%, 97% HPLC purity, 96% de) as a wet white solid. HPLC (Luna C18, H2O/MeCN 95:5 to 0:100 30 min, 254 nm, sample 2 mg/mL in MeOH). tR(3)=15.3 min, 96% de. (2 degrades under these conditions: 3 peaks are detected at 17.7, 18.9 and 19.9 min). HPLC (R,R/S,S)-diastereoisomer of 3, tR=15.0 min. de determination: HPLC comparing integration of peaks at tR=15.3 min (97.3 area % 3) and tR=15.0 min (1.6 area % (R,R)-diastereoisomer of 3 (reference (R,R/S,S) prepared from nearly rac-phenylglycinamide).