Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(C(C)C)CC)(C)C.Br[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1)=[O:31]>CC(=O)CC>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]([N:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][CH2:33]2)=[O:31])[CH2:12][CH2:11]1
Reactant: O=C(CCCCBr)N1CCc2ccccc21
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC(C)=O
Product: O=C(CCCCN1CCN(c2cccc(Cl)c2Cl)CC1)N1CCc2ccccc21
Temperature: 45 °C

Procedure:
A mixture of 1-(2,3-dichlorophenyl)piperazine hydrochloride (8.0 g) and diisopropylethylamine (15 mL) in butanone (50 mL) was heated to 45° C. followed by the addition of 5-bromo-1-(2,3-dihydro-1H-indol-1-yl)pentan-1-one (5.4 g). The resulting mixture was boiled under reflux for 40 h and filtered hot. The remaining organic phase was left to crystallise, and a white crystalline material was collected by filtration and washed with acetone (3.8 g). Mp 121–123° C. 1H NMR (DMSO-d6): 1.50–1.70 (m, 4H); 2.30–2.65 (m, 8H); 3.00 (s, 4H); 3.15 (t, 2H); 4.10 (t, 2H); 6.95 (t, 1H); 7.10–7–15 (m, 2H); 7.20 (d, 1H); 7.25–7.35 (m, 2H); 8.10 (d, 1H). MS m/z: 432 (MH+), 315, 202.
Reaction SMILES: Br[C:2]1[C:7]2[O:8][CH:9]([CH3:11])[CH2:10][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1.[CH3:26][Si:27]([C:30]#[CH:31])([CH3:29])[CH3:28]>C(N(CC)CC)C.CN(C=O)C.[Cu]I>[F:25][C:4]1[CH:3]=[C:2]([C:31]#[C:30][Si:27]([CH3:29])([CH3:28])[CH3:26])[C:7]2[O:8][CH:9]([CH3:11])[CH2:10][C:6]=2[C:5]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[N:14]([CH3:23])[C:13]1=[O:24]
Reactant: C#C[Si](C)(C)C
Reactant: CC1Cc2c(c(Br)cc(F)c2-n2c(=O)cc(C(F)(F)F)n(C)c2=O)O1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1Cc2c(c(C#C[Si](C)(C)C)cc(F)c2-n2c(=O)cc(C(F)(F)F)n(C)c2=O)O1
Yield: 33.4 %

Procedure:
3-(7-Bromo-5-fluoro-2-methyl-2,3-dihydrobenzo[b]furan-4-yl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (1.15 g), trimethylsilylacetylene (0.53 g), a palladium chloride-ditriphenylphosphine complex (95 mg) and copper(I) iodide (27 mg) was suspended in triethylamine (11 ml) and DMF (3 ml), and the mixture was stirred at 50° C. for 12 hours. After the reaction, triethylamine was distilled off under reduced pressure. Ethyl acetate was added thereto, and the insolubles were filtered. Then, ethyl acetate was distilled off, and the resulting residue was purified by chromatography on silica gel (ethyl acetate:n-hexane=1:3 v/v) to obtain the objective 3-{5-fluoro-2-methyl-7-[2-(trimethylsilyl)-1-ethynyl]-2,3-dihydrobenzo[b]furan-4-yl}-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (0.40 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][CH:28]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([N:18]3[CH2:21][CH:20]([N:22]([CH3:24])[CH3:23])[CH2:19]3)=[CH:11][C:10]=2[O:25][CH3:26])=[N:6][CH:7]=1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[Cl:1][C:2]1[C:3]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][CH:28]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([O:25][CH3:26])=[CH:11][C:12]([N:18]3[CH2:21][CH:20]([N:22]([CH3:24])[CH3:23])[CH2:19]3)=[C:13]([NH2:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Yield: 99.5 %

Procedure:
A mixture of 5-chloro-N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(1H-indol-3-yl)pyrimidin-2-amine (Intermediate 119, 347 mg, 0.70 mmol), iron (235 mg, 4.22 mmol) and NH4Cl (26.3 mg, 0.49 mmol) in ethanol (9 mL) and water (3 mL) was heated at reflux for 1 h. The mixture was then purified by ion exchange chromatography, using an SCX column and eluting with 7M methanolic ammonia. Appropriate fractions were combined and concentrated in vacuo onto silica. Further purification by FCC, eluting with 0-5% 7M methanolic ammonia in CH2Cl2 gave the title compound (323 mg, 99%) as a tan solid; 1H NMR: 2.12 (6H, s), 3.06 (1H, p), 3.48 (2H, t), 3.68 (3H, s), 3.92-4.02 (4H, m), 6.28 (1H, s), 6.91 (1H, s), 7.04 (1H, dd), 7.12-7.19 (1H, m), 7.44 (1H, d), 8.14 (1H, s), 8.28 (1H, s), 8.30 (1H, d), 8.46 (1H, s), 11.77 (1H, s); m/z: ES+ MH+ 464.21.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][C:11]([F:37])([F:36])[C@:12]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[C:17]([NH:22][C:23]([C:25]3[C:30]([Cl:31])=[CH:29][C:28]([C:32]([F:35])([F:34])[F:33])=[CH:27][N:26]=3)=[O:24])[N:16]=2)([CH3:14])[N:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:7][C:8]1[O:9][CH2:10][C:11]([F:37])([F:36])[C@:12]([C:15]2[N:16]=[C:17]([NH:22][C:23]([C:25]3[C:30]([Cl:31])=[CH:29][C:28]([C:32]([F:35])([F:33])[F:34])=[CH:27][N:26]=3)=[O:24])[CH:18]=[CH:19][C:20]=2[F:21])([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2nc(NC(=O)c3ncc(C(F)(F)F)cc3Cl)ccc2F)C(F)(F)CO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@]1(c2nc(NC(=O)c3ncc(C(F)(F)F)cc3Cl)ccc2F)N=C(N)OCC1(F)F
Reaction time: 1 h

Procedure:
To a solution of ((R)-4-{6-[(3-chloro-5-trifluoromethyl-pyridine-2-carbonyl)-amino]-3-fluoro-pyridin-2-yl}-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl)-carbamic acid tert-butyl ester (180 mg, 0.317 mmol) in DCM (1.5 ml) was added TFA (0.5 ml) and the mixture was stirred at it for 1 h. The reaction mixture was poured on 10% aq. Na2CO3, more DCM was added and the layers were separated. The aq. phase was extracted with DCM (3×), the combined DCM phases were dried with K2CO3 and evaporated to provide the title compound as colorless solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][CH3:25])[CH2:12][CH2:11]2)=[N:2]1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>ClC(Cl)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]([CH3:25])[C:33](=[O:35])[CH3:34])[CH2:12][CH2:11]2)=[N:2]1
Reactant: CC(=O)Cl
Reactant: CNc1ccccc1CCN1CCN(c2nsc3ccccc23)CC1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(=O)N(C)c1ccccc1CCN1CCN(c2nsc3ccccc23)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
{2-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-methyl-amine was diluted to 0.20 M with anhydrous dichloroethane, then delivered to an 8 mL vial via pipette (0.20 mmol). To the amine solution was added base (0.4 M triethylamine in dichloroethane, 0.40 mmol). Acetyl chloride was diluted to 0.20 M with dichloroethane, and added at rt (0.2 mmol). The reaction was shaken overnight at 50° C., then evaluated by MS. Polyamine scavenging resin was added (0.5 mmol). The solution was shaken overnight at rt, then filtered into an 8 mL vial. The reaction was concentrated using an HT-12 GeneVac, then purified by HPLC (30×100 mm ODS-A C(18) 5u column). N-{2-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-N-methyl-acetamide was isolated in 100% purity @ 254 nm, LCMS (APCI): 479 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:38])([CH3:37])[O:6][C@@H:7]1[C@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:9][C@H:8]1[N:29]1[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]1=[O:31])([CH3:4])[CH3:3].[Cl:39][C:40]1[CH:54]=[CH:53][C:43]([C:44]([C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=2)=[O:45])=[CH:42][CH:41]=1>>[Cl:39][C:40]1[CH:41]=[CH:42][C:43]([C:44]([OH:45])([C:35]2[C:33](=[O:34])[NH:32][C:30](=[O:31])[N:29]([CH:36]=2)[C@@H:8]2[O:9][C@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[C@@H:11]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[C@H:7]2[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:38])[CH3:37])[C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=2)=[CH:53][CH:54]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C(O)(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
5-(1,1-Bis(4-chlorophenyl)hydroxymethyl)-2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine was prepared from 2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine according to the method of Example 1 step (i) (using 4,4'-dichlorobenzophenone instead of benzophenone) to afford the product as a colourless foam.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccccn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccccn1)C1CCNCC1
Yield: 99.3 %

Procedure:
To a solution of compound 4-(pyridine-2-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester (260 mg, 0.90 mmol) in dichloromethane (10 mL) was then added TFA (0.69 mL, 8.95 mmol) the reaction was then stirred at 25° C. for 3 hours and the solvent was removed under vacuum and the crude material was co-evaporated 3 times with dichloromethane to remove most of the remaining TFA, affording crude the title compound as an orange oil (170 mg, 100%). The crude material was used directly in the next step without subsequent purification. LRMS m/z ES+=190.8 (M+H), retention time 0.60.
Reaction SMILES: Cl.O1CCCCC1[N:8]1[C:12]([C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][CH:26]=2)[C:23]2[N:19]([CH:20]=[C:21]([C:27]4[N:31]([CH:32]([CH3:34])[CH3:33])[N:30]=[CH:29][N:28]=4)[N:22]=2)[CH2:18][CH2:17][O:16]3)=[CH:11][CH:10]=[N:9]1>C(OCC)(=O)C>[CH3:34][CH:32]([N:31]1[C:27]([C:21]2[N:22]=[C:23]3[N:19]([CH:20]=2)[CH2:18][CH2:17][O:16][C:15]2[C:24]3=[CH:25][CH:26]=[C:13]([C:12]3[NH:8][N:9]=[CH:10][CH:11]=3)[CH:14]=2)=[N:28][CH:29]=[N:30]1)[CH3:33]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3ccnn3C3CCCCO3)cc1OCC2
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3ccn[nH]3)cc1OCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
To a solution of 3N HCl in ethyl acetate at −20° C. (100 mL) was added dropwise a solution of 12-[1-(oxan-2-yl)-1H-pyrazol-5-yl]-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (2.20 g, 6.09 mmol) in ethyl acetate (20.0 mL). After being stirred at this temperature for 1 h, the reaction mixture was warmed to room temperature and stirred for 3 hr. After removal of the solvent, the residue was treated with water and basified to pH around 10. The aqueous layer was then extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and concentrated to afford 4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-12-(1H-pyrazol-5-yl)-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (1.4 g, 78% yield) as pale yellow solid. LCMS (ESI) m/z: 362.0 [M+H+].
Reaction SMILES: [CH:1]([C@H:14]1[CH2:20][C@@H:19]2[C@@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1OCCOCCOCCOC1>CCCCC>[CH:1]([C@@H:14]1[O:15][CH2:16][C@H:17]([OH:18])[CH2:19][CH2:20]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(c2ccccc2)[C@H]2C[C@H]3O[C@H]3CO2)cc1
Agent: C1COCCOCCOCCO1
Agent: [Al+3]
Agent: [H-]
Solvent: CCCCC
Product: O[C@@H]1CC[C@H](C(c2ccccc2)c2ccccc2)OC1
Yield: 74.5 %

Procedure:
Treatment of (1S, 4R, 6R)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]heptane 28d (0.06 g, 0.23 mmol) with a suspension of LiAlH4 (0.06 g, 1.58 mmol) in pentane along with 12-crown-4 ether (0.31 g, 1.74 mmol) for 15 h at room temperature afforded (3R, 6R)-6-benzhydryl-tetrahydropyran-3-ol 38 0.046 g (77%, [α]D=(+)74.9, c=1, MeOH).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([NH:21][C:22](=[O:41])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]4[CH2:33][CH2:32][CH2:31][N:30]4C(OC(C)(C)C)=O)[CH:24]=3)=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:42].O1CCOCC1>C(Cl)Cl>[ClH:42].[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([NH:21][C:22](=[O:41])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]4[CH2:33][CH2:32][CH2:31][NH:30]4)[CH:24]=3)=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cccc(C(=O)Nc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(Nc1ccc2c(c1)CN(C(=O)OCc1ccccc1)CC2)c1cccc(C2CCCN2)c1

Procedure:
To a solution of 7-[3-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-benzoylamino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (900 mg, 1.62 mmol) in methylene chloride (50 mL) add 4M HCl in dioxane (8.1 mL, (32.4 mmol)) and stir the reaction at room temperature for 24 h. Remove the solvents in vacuo at 40° C., dissolve the residue in EtOAc, and concentrate again concentrate to dryness. Dry the residue in vacuo then triturate in EtOAc and hexane to afford 2.63 g of 7-(3-pyrrolidin-2-yl-benzoylamino)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester HCl as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:11]=3[C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.[CH:22](Br)([CH3:24])[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+].N>CN1CCCC1=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][C:11]=3[C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: CC(C)Br
Reactant: COC(=O)c1c(-c2ccc(F)cc2)oc2ccc(O)cc12
Agent: N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OC(C)C)cc12
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A mixture of methyl 2-(4-fluorophenyl)-5-hydroxy-1-benzofuran-3-carboxylate (18.86 g, 65.9 mmol), isopropyl bromide (24.74 mL, 264 mmol) and cesium carbonate (42.9 g, 132 mmol) in dry N-Methyl-2-pyrrolidone (191 mL) was stirred at 60° C. under nitrogen for 20 hours. The resultant thick suspension was allowed to cool to room temperature and then 7% aqueous ammonia solution (200 mL) was added with rapid stirring. This mixture was extracted with heptane (700 mL) and then the aqueous phase was separated off. Ethyl acetate (˜100 mL) was added to the organic phase and the resultant mixture was shaken and then dried over Na2SO4 and evaporated to give a brown oil which crystallized on standing overnight. This material was recrystallized from hot methanol and the solid was collected by filtration, washed with methanol and finally dried under vacuum to give methyl 2-(4-fluorophenyl)-5-[(1-methylethyl)oxy]-1-benzofuran-3-carboxylate. LCMS (m/z, ES+)=329 (M+1). The mother liquors from the first recrystallization were crystallized a second time to give an additional batch of methyl 2-(4-fluorophenyl)-5-[(1-methylethyl)oxy]-1-benzofuran-3-carboxylate.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:15]1([C:21]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:29]3[C@H:25]([CH2:26][NH:27][CH2:28]3)[C@H:24]([OH:30])[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:13][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([N:27]1[CH2:26][C@H:25]2[C@H:29]([C:21]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:22][CH2:23][C@H:24]2[OH:30])[CH2:28]1)=[O:12]
Reactant: O[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Reactant: CN(C)c1ccccc1CC(=O)O
Agent: Cl
Product: CN(C)c1ccccc1CC(=O)N1C[C@@H]2[C@H](O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Yield: 31.8 %

Procedure:
By carrying out the procedure according to that described in the Example of use 9, using 0.26 g of 2-dimethylaminophenylacetic acid and 0.50 g of (3aR,4R,7aR)-7,7-diphenyl-4-perhydroisoindolol hydrochloride, 0.21 g of (3aR,4R,7aR)-2-[(2dimethylaminophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolol is obtained in the form of a white solid; melting point 204° C., [α]20D =-212° (c =0.5, methanol).
Reaction SMILES: [OH-].[Na+].[C:3]1([C:10]([O-:12])=[O:11])([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4]1>CO>[CH3:9][O:8][C:6]([C:3]1([C:10]([OH:12])=[O:11])[CH2:5][CH2:4]1)=[O:7]
Reactant: COC(=O)C1(C(=O)[O-])CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
1.45 liters of 1N sodium hydroxide solution are added to a solution, cooled to 5° C., of 1.45 ml of methyl 1,1-cyclopropanedicarboxylate in 2.5 liters of methanol. After stirring for 4 days at ambient temperature, the mixture is three-quarters concentrated, extracted with ether and then treated in customary manner, allowing the expected product to be isolated.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](O)[CH2:10][C@H:9]1[CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:53].CCCCCC>C1COCC1>[Br:53][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([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)[CH2:10]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1C[C@@H](Br)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a stirred solution of trans-1-tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy) methyl-4-hydroxypyrrolidine (910 mg, 2.0 mmol) and Ph3P (628 mg, 2.4 mmol) in THF (20 ml) was added CBr4 (993 mg, 3.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 0.5 hr. n-Hexane (40 ml) was added thereto. The resulting solid was filtered off, and dried in vacuo. The residue was purified by column chromatography on silica gel with n-hexane to n-hexane-EtOAc (3:2, v/v) as eluent to give cis-4-bromo-1-tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy)methylpyrrolidine (1.0 g, quant.) as a pale yellow oil. 1H-NMR (CDCl3) δ 1.06 (s, 9H), 1.31 and 1.45 (each s, 9H), 2.63 (m, 2H), 3.49 (m, 1H), 3.89–4.14 (m, 5H), 7.35–7.42 (m, 6H), 7.64–7.66 (, 4Hm).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]2[N:24]([CH2:25][C:26]3[C:31]([OH:32])=[CH:30][CH:29]=[C:28]([CH3:33])[N:27]=3)[C:23]3[CH:34]=[C:35]([CH3:39])[CH:36]=[C:37]([CH3:38])[C:22]=3[N:21]=2)[CH2:15][CH2:14]1)C.O.C(OC(=O)C)C>O1CCCC1>[OH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]2[N:24]([CH2:25][C:26]3[C:31]([OH:32])=[CH:30][CH:29]=[C:28]([CH3:33])[N:27]=3)[C:23]3[CH:34]=[C:35]([CH3:39])[CH:36]=[C:37]([CH3:38])[C:22]=3[N:21]=2)[CH2:15][CH2:14]1
Reactant: CCOC(=O)CCN1CCC(Nc2nc3c(C)cc(C)cc3n2Cc2nc(C)ccc2O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c2nc(NC3CCN(CCCO)CC3)n(Cc3nc(C)ccc3O)c2c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
LiAlH4 (0.0002 mol) was added at 5° C. to a mixture of 3-{4-[1-(3-Hydroxy-6-methyl-pyridin-2-ylmethyl)-4,6-dimethyl-1H-benzoimidazol-2-ylamino]-piperidin-1-yl}-propionic acid ethyl ester (0.00009 mol; melting point: 172° C.; prepared according to the procedure described in variant 2) in tetrahydrofuran (10 ml) under N2 flow. The mixture was stirred at 5° C. for 1 hour, then at room temperature for 3 hours. A minimum of H2O and ethylacetate were added. The organic layer was separated, dried (over MgSO4), filtered and the solvent was evaporated until dryness. The residue was crystallized from 2-propanone/CH3CN/diisopropylether. The precipitate was filtered off and dried, yielding 0.026 g of 2-{2-[1-(3-hydroxy-propyl)-piperidin-4-ylamino]-4,6-dimethyl-benzoimidazol-1-ylmethyl}-6-methyl-pyridin-3-ol (compound 4, 68%, melting point: 209° C.).
Reaction SMILES: [C:1]1([C:11](Cl)=[O:12])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:14][C@H:15]([C:21]([C:23]1[C:24]([C:30]#[N:31])=[N:25][CH:26]=[C:27]([NH2:29])[CH:28]=1)=[O:22])[CH2:16][CH2:17][C:18](=[O:20])[OH:19].C([O-])(O)=O.[Na+]>O1CCCC1.O>[C:1]1([C:11]([NH:14][C@H:15]([C:21]([C:23]2[C:24]([C:30]#[N:31])=[N:25][CH:26]=[C:27]([NH2:29])[CH:28]=2)=[O:22])[CH2:16][CH2:17][C:18](=[O:19])[OH:20])=[O:12])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1cccc2c1CCCC2
Reactant: N#Cc1ncc(N)cc1C(=O)[C@@H](N)CCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ncc(N)cc1C(=O)[C@H](CCC(=O)O)NC(=O)c1cccc2c1CCCC2
Reaction time: 0.25 h
Yield: 53.8 %

Procedure:
A solution of 1.91 g (0.009 mol) of 5,6,7,8-tetrahydro-1-naphthoyl chloride in anhydrous tetrahydrofuran (50 cm3) is added dropwise to a solution of 1.5 g (0.0064 mol) of alpha-L-glutamyl-5-aminopyridine-2-carbonitrile and 5.05 g (0.06 mol) of NaHCO3 in 50 cm3 of water. After stirring for 15 minutes at 20 C., the tetrahydrofuran is removed under vacuum and the remaining aqueous solution is acidified to pH 2-3 with a 6 N solution of HCl to give a precipitate of 1.4 g of N-5,6,7,8-tetrahydro-1-naphthoyl-alpha-L-glutamyl-5-aminopyridine-2-carbonitrile (yield: 55%, melting point: 141° C. in the amorphous state) after filtration and trituration in hexane. The sweetening potency of this compound, on a weight basis, is approximately 40,000 (forty thousand) times that of sucrose by comparison with a 2% solution of sucrose, 30,000 (thirty thousand) times by comparison with a 5% solution of sucrose and 20,000 (twenty thousand) times by comparison with a 10% solution of sucrose. This is tantamount to saying that an aqueous solution of 5 mg/1 of the compound has an intense sweet taste equivalent to that of a 10% solution of sucrose, corresponding to the sweetening intensities generally used in food preparations.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].Cl[S:8]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)(=[O:10])=[O:9].C(=O)(O)[O-].[Na+].CO>O>[S:8]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=1)([OH:10])=[O:9]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(S(=O)O)cc1
Temperature: 25 °C
Yield: 78.3 %

Procedure:
Sodium sulfite (15.3 g, 121.45 mMole), was dissolved in water (100 mL) and while stirring at room temperature, methyl 4-chlorosulfonylbenzoate (3), (19.0 g, 80.97 mMole) was added a little at a time to the solution. Sodium bicarbonate was added simultaneously in small portions keeping the solution at approximately pH 8. As the reaction proceeds, periodic addition of a little methanol from a wash bottle minimizes foaming. A total of 20 g of sodium bicarbonate were needed to complete the reaction. After complete addition of the reagents, the mixture was then stirred at room temperature for about 30 minutes. The mixture was then filtered. The clear solution was acidified with concentrated hydrochloric acid and treated with sufficient solid sodium chloride to precipitate the product. The white solid was filtered off and air-dried to give 12.7 g of methyl 4-sulfinobenzoate.