Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[C@@H:13]2[C@H:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@:9]1([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:10]([O:23][CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1>[Pd]>[F:37][C:35]([F:36])([F:38])[C:27]1[CH:26]=[C:25]([CH2:24][O:23][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:15][C@H:14]3[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: [Pd]
Product: CC(C)(C)OC(=O)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65371.9 %

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 24; 240 mg, 0.39 mmol), 10% palladium on charcoal (470 mg, 0.40 mmol) ethanol (10 ml) was stirred under hydrogen atmosphere (1 atm) at +65° C. for 1 hour and at room temperature overnight. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate 0-25%) to give the title compound (135 g, 66%).
Reaction SMILES: [NH2:1]O.[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][CH:10]=[O:11])=[CH:6][CH:5]=1.ClC1C=CC(C=O)=CC=1.CC=O>CCO>[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][C:10]#[N:1])=[CH:6][CH:5]=1.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][CH:10]=[O:11])=[CH:12][CH:13]=1
Reactant: NO
Agent: CC=O
Agent: O=CC=Cc1ccc(Cl)cc1
Agent: O=Cc1ccc(Cl)cc1
Solvent: CCO
Product: N#CC=Cc1ccc(Cl)cc1

Procedure:
Hydroxylamine hydrochloride (13.0 g.) was dissolved in dry methanol (100 ml.) and neutralised to phenolphthalein with a solution of sodium (6 g.) in methanol (60 ml.). The precipitated sodium chloride was filtered off and the filtrate was refluxed with p-chlorocinnamonitrile (9.4 g.) for 2 hrs. Thin layer chromatography showed the reaction to be complete after this time. The reaction mixture was evaporated to dryness in vacuo and the residue was crystallised from ethanol to produce colourless of crystals of p-chlorocinnamamidoxime, 4.16 g. (37%) m.p. 102°-4° λmax (EtOH), 273 nm., ε17500, τ(CDCl3) 2.68 (aromatic), 3.00 (OH), 5.16 (NH2), 3.13 (doublet, J=16 c./sec.), 3.58 (doublet, J=16 c./sec.). p-Chlorocinnamonitrile was prepared by NH2OH treatment and dehydrations of p-chlorocinnamaldehyde (J. Chem. Soc., 1965, 1564). p-Chlorocinnamaldehyde was prepared from p-chloro benzaldehyde and CH3CHO cf. G. Cigarella, E. Occelli, and E. Testa, (J. Med. Chem., 1965, 8, 326).
Reaction SMILES: OC1C(=O)N=C(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)N2CCNC(=O)C=12.C([O:37][C:38]1[C:43](=[O:44])[N:42]=[C:41]([CH2:45][C:46]2([C:51]3[C:60]4[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=4)[CH:54]=[CH:53][CH:52]=3)[CH2:50][CH2:49][CH2:48][CH2:47]2)[N:40]2[CH2:61][CH2:62][N:63]([CH:66]3[CH2:68][CH2:67]3)[C:64](=[O:65])[C:39]=12)C1C=CC=CC=1>>[CH:66]1([N:63]2[CH2:62][CH2:61][N:40]3[C:41]([CH2:45][C:46]4([C:51]5[C:60]6[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=6)[CH:54]=[CH:53][CH:52]=5)[CH2:47][CH2:48][CH2:49][CH2:50]4)=[N:42][C:43](=[O:44])[C:38]([OH:37])=[C:39]3[C:64]2=[O:65])[CH2:67][CH2:68]1
Reactant: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4cccc5ccccc45)CCCC3)n2CCN1C1CC1
Agent: O=C1NCCn2c(CC3(c4cccc5ccccc45)CCCC3)nc(=O)c(O)c21
Product: O=C1c2c(O)c(=O)nc(CC3(c4cccc5ccccc45)CCCC3)n2CCN1C1CC1

Procedure:
This compound was prepared by following the same method as described for pure 9-hydroxy-6-(1-naphthalen-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (349) from 9-benzyloxy-2-cyclopropyl-6-(1-naphthalen-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (356) (100 mg, 0.18 mmol). The yield was 40 mg, 52% of a white solid.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[CH:4][C:3]=1[O:13][CH:14]([CH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH3:25])[CH2:19][CH2:18]1)[C:15]#[CH:16].[F-].[K+].O.Cl>C(N(CC)C1C=CC=CC=1)C>[F:12][C:11]1[C:2]([F:1])=[C:3]2[C:4]([CH:16]=[CH:15][CH:14]([CH:17]3[CH2:18][CH2:19][CH:20]([CH2:23][CH2:24][CH3:25])[CH2:21][CH2:22]3)[O:13]2)=[C:5]2[CH2:6][CH2:7][CH2:8][O:9][C:10]=12
Reactant: C#CC(Oc1cc2c(c(F)c1F)OCCC2)C1CCC(CCC)CC1
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CCN(CC)c1ccccc1
Solvent: O
Product: CCCC1CCC(C2C=Cc3c4c(c(F)c(F)c3O2)OCCC4)CC1

Procedure:
6.0 g (17.2 mmol) of 7,8-difluoro-6-[1-(4-propylcyclohexyl)prop-2-ynyloxy]-chroman are heated at 200° C. for 6 h together with 2.0 g (34.4 mmol) of potassium fluoride in 55 ml of N,N-diethylaniline. After cooling, water is added, and the mixture is acidified using 25% hydrochloric acid. The batch is extracted with MTBE, and the organic phase is washed with saturated sodium chloride solution. The solution is dried using sodium sulfate and evaporated to dryness. The crude product is purified by column chromatography (SiO2, 1-chlorobutane), giving 5,6-difluoro-8-(4-propylcyclohexyl)-1,2,3,8-tetrahydropyrano[3,2-f]chromene as a pale-brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:43][C:44]([F:47])([F:46])[F:45])(=O)=O.O>CS(C)=O>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:43][C:44]([F:47])([F:46])[F:45])[CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=C(NC(COCC1CCNCC1)c1ccccc1Cl)c1ccc2c(Cl)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(NC(COCC1CCN(CC(F)(F)F)CC1)c1ccccc1Cl)c1ccc2c(Cl)c[nH]c2c1
Yield: 29.6 %

Procedure:
To a solution of 3-chloro-N-[1-(2-chlorophenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (700 mg, 1.6 mmol) in 5 mL of DMSO was added potassium carbonate (1.0 g, 7.9 mmol) and 2,2,2-trifluoroethyl trifluoromethane-sulfonate (364 mg, 1.6 mmol). The reaction was allowed to stir at room temperature overnight after which time water was added and the resulting precipitate was isolated by filtration. Purification of the filtrate (SiO2: 30% EtOAc in hexane) provided 250 mg (30%) of the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[S:31]([CH3:30])(=[O:33])=[O:32])[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@H]1CCCN1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@H]1CCCN1S(C)(=O)=O
Yield: 76 %

Procedure:
Using a similar process to that described in Example 29, 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2R)-pyrrolidin-2-ylmethoxy]quinazoline hydrochloride (300 mg) was reacted with methane sulfonyl chloride to give the title product (250 mg, 76%); 1H NMR Spectrum: (DMSO d6) 1.88-2.12 (m, 4H); 2.99 (s, 3H); 3.30-3.34 (m, 2H); 3.94 (s, 3H); 4.02 (m, 1H); 4.15 (m, 2H); 7.15-7.30 (m, 2H); 7.40-7.55 (m, 2H); 7.81 (s, 1H); 8.36 (s, 1H); 9.62 (s, 1H); Mass Spectrum: (M+H)+ 481.
Reaction SMILES: [N+]([C:4]1C=CC=CC=1O)([O-])=O.[Cl:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][C:13]=1[OH:21].C(=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[Cl:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][C:13]=1[O:21][CH3:4]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: O=[N+]([O-])c1cccc(O)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
The nitrophenol starting material C2 (1.3 g; 7.49 mmol) was dissolved in DMF (10 mL) and to this solution was added ground cesium carbonate (2.92 g; 8.96 mmol), followed by MeI (1.4 mL; 22.5 mmol). The mixture was stirred at room temperature overnight. The DMF was evaporated in vacuo and the residue taken up in ether (150 mL), washed with water (150 mL), brine (4×100 mL), and then dried over (MgSO4). The organic phase was filtered and evaporated to afford the crude 2-chloro-3-nitroanisole C3 (98%; 1.38 g) as an orange solid.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:4]([C:14]([OH:16])=O)[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:29]([NH2:32])([CH3:31])[CH3:30]>C(#N)C>[O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][CH:4]([C:14]([NH:32][CH:29]([CH3:31])[CH3:30])=[O:16])[CH2:3]1
Reactant: CC(C)N
Reactant: O=C(O)C1CC(=O)N(Cc2ccccc2)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(C)NC(=O)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 60 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
To a solution of 16.4 g (75.0 mmole) of 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid in 150 ml of acetonitrile was added 13.8 g (85.0 mmole) of 1,1-'carbonyldiimidazole. The reaction was heated to 60° C. for one hour, cooled to room temperature and treated with 5.0 g (85 mmole) of isopropylamine. The reaction was stirred at room temperature for 18 hours, the solvent removed in vacuo and the residue partitioned between chloroform and water. The organic layer was washed with water, 1N hydrochloric acid, dried over magnesium sulfate, and evaporated in vacuo to give 18.6 g of 5-oxo-1-(phenylmethyl)-N-(2-propyl)-3-pyrrolidinecarboxamide, mp 122-124° C.
Reaction SMILES: [Cl-].[Cl:2][CH2:3][C:4]([CH2:6]Cl)=[O:5].C(OCC)C.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl-:2].[Cl:2][CH2:3][C:4](=[O:5])[CH2:6][N+:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(CCl)CCl
Reactant: c1ccncc1
Agent: [Cl-]
Solvent: CCOCC
Product: O=C(CCl)C[n+]1ccccc1
Reaction time: 8 h

Procedure:
66.9 g of 1,3-dichloroacetone chloride are introduced into a three-necked flask containing 800 cm3 of diethyl ether. 28 cm3 of pyridine are added dropwise and the mixture is kept stirring overnight. The precipitate obtained is filtered, washed with twice 100 cm3 of diethyl ether and then dried at 40° C. under 90 Pa to give 29.2 g of 1-(3-chloro-2-oxopropyl)-pyridinium chloride in the form of a cream-coloured solid melting at 92° C. and which is used as it is.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:29])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH2:24][O:25]C(=O)C)=[O:23])=[CH:17][CH:16]=1)=[N:8]2.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:29])[NH:6][C:7]([C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:23])[CH2:24][OH:25])=[CH:19][CH:20]=1)=[N:8]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(NC(=O)COC(C)=O)cc3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(NC(=O)CO)cc3)nc2c1
Yield: 26.2 %

Procedure:
The yellow solid was triturated with ether and methanol to provide acetic acid [4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-phenylcarbamoyl]-methyl ester (112 mg, 37%). To a solution of acetic acid [4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-phenylcarbamoyl]-methyl ester (0.23 g, 0.59 mmol) in THF/methanol mixture (3.5 mL/3.5 mL) was added potassium carbonate (0.41 g, 2.95 mmol). The reaction mixture was heated at reflux overnight and the solvent was concentrated under vacuum and diluted with water (60 mL) to obtain a precipitate. The yellow solid was filtered, washed with water (20 mL), methanol and dried under vacuum to provide crude compound. The yellow solid was triturated with ether and methanol to provide the desired compound N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-2-hydroxyacetamide (55 mg, 55%). Selected data: MS (ES) m/z: 356.1; mp 318-319° C.
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:3][CH2:2]1.[C:18](OC(=O)C)(=[O:20])[CH3:19].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1C=CC=CC=1>[CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([O:15][C:18](=[O:20])[CH3:19])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: CN1CCC(O)N(c2nnc(C3CC3)s2)C1=O
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccccc1
Product: CC(=O)OC1CCN(C)C(=O)N1c1nnc(C2CC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.1 mole), acetic anhydride (0.11 mole), toluenesulfonic acid (0.05 gram) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is heated on a steam bath with stirring for a period of about 2 hours. After this time the reaction mixture is cooled to room temperature and is stripped of solvent under reduced pressure leaving a residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-acetyloxy-2(1H)-pyrimidinone.
Reaction SMILES: C(OC([N:8]1[CH2:15][C@H:14]2[N:16](C(OC(C)(C)C)=O)[C@H:10]([CH2:11][C:12]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][C:37]4[C:42]([Cl:43])=[CH:41][C:40]([CH3:44])=[CH:39][C:38]=4[Cl:45])=[CH:29][CH:28]=3)=[C:13]2[C:24]([OH:26])=O)[CH2:9]1)=O)(C)(C)C.[CH:46]1([NH:49][CH2:50][C:51]2[CH:56]=[C:55]([CH2:57][CH2:58][CH2:59][O:60][CH3:61])[CH:54]=[CH:53][C:52]=2[CH3:62])[CH2:48][CH2:47]1>>[CH:46]1([N:49]([CH2:50][C:51]2[CH:56]=[C:55]([CH2:57][CH2:58][CH2:59][O:60][CH3:61])[CH:54]=[CH:53][C:52]=2[CH3:62])[C:24]([C:13]2[C@@H:14]3[NH:16][C@H:10]([CH2:11][C:12]=2[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][C:37]4[C:42]([Cl:43])=[CH:41][C:40]([CH3:44])=[CH:39][C:38]=4[Cl:45])=[CH:29][CH:28]=2)[CH2:9][NH:8][CH2:15]3)=[O:26])[CH2:47][CH2:48]1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(C3=C(C(=O)O)[C@H]4CN(C(=O)OC(C)(C)C)C[C@@H](C3)N4C(=O)OC(C)(C)C)cc2)c(Cl)c1
Reactant: COCCCc1ccc(C)c(CNC2CC2)c1
Product: COCCCc1ccc(C)c(CN(C(=O)C2=C(c3ccc(OCCOc4c(Cl)cc(C)cc4Cl)cc3)C[C@@H]3CNC[C@H]2N3)C2CC2)c1

Procedure:
This compound was synthesized from (1R,5S)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester and cyclopropyl-[5-(3-methoxy-propyl)-2-methyl-benzyl]-amine as for compound L1, and then Example 1. MS (ESI, Q+) m/z 678.2.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(O[C@@H:23]1[O:40][C@H:39]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[C@H:34]([O:35][C:36](=[O:38])[CH3:37])[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]1[O:25][C:26](=[O:28])[CH3:27])(=O)C>ClCCl>[C:26]([O:25][C@@H:24]1[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@@H:34]([O:35][C:36](=[O:38])[CH3:37])[C@@H:39]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[O:40][C@H:23]1[O:1][C:2]1[C:7]2[C:8]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: Oc1cccc2occ(CCc3ccccc3)c12
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(CCc4ccccc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
To a solution of 4-hydroxy-3-(2-phenylethyl)benzofuran (0.11 g) and 1,2,3,4,6-penta-O-acetyl-β-D-galactopyranose (0.37 g) in dichloromethane (5 mL) was added boron trifluoride-diethyl ether complex (0.12 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1-3/2) to give 4-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-3-(2-phenylethyl)benzofuran (0.13 g). This material was dissolved in methanol (5 mL). To the solution was added sodium methoxide (28% methanol solution, 0.043 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give the title compound (24 mg).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([C:15]#[N:16])=[C:13]([S:17][CH3:18])[S:12][C:11]=2[C:19]([OH:21])=[O:20])=[CH:6][CH:5]=1)([OH:3])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:34]([NH2:37])([CH3:36])[CH3:35].O.Cl>C(Cl)Cl>[C:15]([C:14]1[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1](=[O:3])[NH:37][CH:34]([CH3:36])[CH3:35])=[CH:5][CH:6]=2)=[C:11]([C:19]([OH:21])=[O:20])[S:12][C:13]=1[S:17][CH3:18])#[N:16]
Reactant: CSc1sc(C(=O)O)c(-c2ccc(C(=O)O)cc2)c1C#N
Reactant: CC(C)N
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: CSc1sc(C(=O)O)c(-c2ccc(C(=O)NC(C)C)cc2)c1C#N
Reaction time: 8 h
Yield: 27 %

Procedure:
Combine 3-(4-Carboxy-phenyl)-4-cyano-5-methylsulfanyl-thiophene-2-carboxylic acid (0.1 g, 1.0 eq) in CH2Cl2 (5.0 mL) and stir. Add carbonyldiimidazole (2.0 eq). Stir the mixture overnight. Add isopropylamine (1.0 eq) and stir overnight at room temperature. Add 1N HCl water solution. Filter the precipitate to provide the title compound (0.03 g, Yield 27%). MS (ES+, m/e): 361 (M+1).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[F:26][C:27]([F:33])([F:32])[CH2:28][C:29](O)=[O:30]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:29](=[O:30])[CH2:28][C:27]([F:33])([F:32])[F:26])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)CC(F)(F)F
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(CC(F)(F)F)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (17.4 mg, 49.4%), MS (ISP) m/z=441.0 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (29.4 mg, 0.080 mmol) and 3,3,3-trifluoropropanoic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]([CH3:22])([CH3:21])[CH:19]=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C[Si](C)(C)[C:31]([F:34])([F:33])[F:32].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:32][C:31]([F:34])([F:33])[CH:19]([OH:20])[C:18]([CH3:22])([CH3:21])[CH:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C=O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanal (from Ex 109(b), (140 mg, 0.376 mmol) in THF (3 ml) at 0° C. was added trimethyl(trifluoromethyl)silane (267 mg, 1.88 mmol) and tetrabutyl-ammonium fluoride in THF (0.376 ml, 0.376 mmol, 1M THF solution). The reaction mixture was stirred at 0° C. for 30 minutes, and then at room temperature overnight. After quenching with 4N HCl, the reaction was stirred for 30 minutes and was extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and concentrated to give the crude 1,1,1-trifluoro-4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3,3-dimethyl-4-phenylbutan-2-ol. The crude alcohol in DCM (1 ml) was treated with commercially available Dess-Martin periodinane (187 mg, 0.440 mmol). The reaction was complete in 45 minutes and was filtered through a plug of SiO2 using DCM and concentrated to give the crude product. The crude material was purified via chromatography on silica gel eluting with 10% ethyl acetate in hexane to afford the compound of Example 6 as a colorless viscous oil (90 mg, 70% yield). 1H NMR (400 MHz, MeOD) δ ppm 8.21 (1 H, s) 7.85 (1 H, s) 7.70 (2 H, dd, J=9.16, 4.58 Hz) 7.63 (1 H, d, J=8.65 Hz) 7.43 (1 H, dd, J=8.90, 1.78 Hz) 7.37 (2 H, d, J=7.12 Hz) 7.27-7.33 (4 H, m) 7.22 (1 H, t, J=7.12 Hz) 4.80 (1 H, s) 1.43 (6 H, d, J=5.09 Hz). LC/MS (m/z) 441.24 [(M+H)+]; HPLC Rt: 4.066 min.
Reaction SMILES: CO[C:3]([CH2:5][CH2:6][C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[O:4].C(CC(=O)C)(=O)C.[CH2:19]([N:23](CCCC)CCCC)[CH2:20]CC.C(N)C>CO>[NH2:11][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH2:5][C:3]([NH:23][CH2:19][CH3:20])=[O:4]
Reactant: COC(=O)CC[C@H](N)C(=O)O
Reactant: CCCCN(CCCC)CCCC
Agent: CCN
Solvent: CC(=O)CC(C)=O
Solvent: CO
Product: CCNC(=O)CC[C@H](N)C(=O)O
Temperature: 60 °C
Yield: 66.7 %

Procedure:
First, 5.0 g (31 mmol) of L-glutamic acid-γ-methyl ester was suspended in 15 mL of methanol. To this, 3.4 g (34 mmol) of acetylacetone and 5.7 g (31 mmol) of tri-n-butylamine were added. The mixture was heated at 60° C. for 2 hours. Subsequently, 20 g (310 mmol) of 70% ethylamine was added to the mixture and the same procedure as in Example 1 was performed to obtain 3.6 g of theanine (yield: 66.7%). The obtained theanine had the same purity as high as in Example 1.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C@H:18]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:21][CH2:20][S:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[CH3:38][NH:39][CH2:40][CH2:41][OH:42]>>[C:29]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:28]=[CH:27][C:26]([S:23]([N:22]2[CH2:21][CH2:20][S:19][C@H:18]2[C:16]([NH:15][C@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][N:39]([CH2:40][CH2:41][OH:42])[CH3:38])=[O:17])(=[O:24])=[O:25])=[CH:31][CH:30]=1
Reactant: CNCCO
Reactant: CS(=O)(=O)OCC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Product: CN(CCO)CC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1

Procedure:
Following the general method A as outlined in Example 16, starting from (3S)-3-({[(2S)-3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and 2-(methylamino)ethanol, the title compound was obtained in 94.3% purity by HPLC.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:8]=[CH:7][O:6][CH:5]=1.[Li]CCCC.CCCCCC.[CH3:21][Si:22](Cl)([CH3:24])[CH3:23]>C1COCC1>[O:6]1[CH:7]=[CH:8][C:4]([C:3]#[C:2][Si:22]([CH3:24])([CH3:23])[CH3:21])=[CH:5]1
Reactant: C[Si](C)(C)Cl
Reactant: BrC(Br)=Cc1ccoc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccoc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 141 %

Procedure:
To a stirred and cooled (−78° C.) solution of the dibromofuran 10 (2.0 g, 7.9 mmol) in THF (20 mL) was added 1.6 M n-BuLi in hexane (10.2 mL, 16.3 mmol) over 3 min. After 1 h the cooling bath bath was removed and the mixture allowed to warm to r.t. Following a further 1.5 h the mixture was cooled back to −78° C. and then TMSCl (3.0 mL, 23.8 mmol) was added dropwise. The mixture was allowed to gradually warm up to r.t. After 19 h the mixture was poured into ice-cold Et2O-saturated aqueous NaHCO3 solution. The organic layer was separated and the aqueous layer extracted with Et2O (2×). The combined organic solutions were dried (MgSO4), filtered and concentrated to afford the crude acetylene 11 (1.83 g) as a yellow oil. This material was used in the next step without purification. 1H NMR (400 MHz; CDCl3) inter alia δ 0.23 (s, 9H), 6.44 (m, 1H), 7.34(m, 1H) and 7.63 (m, 1H).