Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:4]1[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([N:3]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:4]1[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCC(=O)N1CC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN1C(=O)CC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 99.3 %

Procedure:
Ethyl 1-ethyl-5-oxoprolinate (1.33 g, 7.18 mmol) was dissolved in ethanol (10 ml) and cooled to 0° C. in an ice bath. To this was added 12.5M aqueous sodium hydroxide solution (1.72 ml, 21.53 mmol) and the mixture was stirred for ˜4 hours at 0° C. The ethanol was evaporated under vacuum and the aqueous residue was acidified with 2N aqueous hydrogen chloride to pH1. The volume of the aqueous phase was reduced to ˜3 ml under vacuum and then extracted with a 3:1 mixture of chloroform and isopropanol using a phase separator. The combined organic layers were concentrated to a pale yellow oil which on drying in vacuo crystallized to give 1-ethyl-5-oxoproline as a white solid (1.12 g).
Reaction SMILES: N[C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N([O-])=[O:24].[Na+].[C-:27]#[N:28].[K+]>Cl>[C:16]([O:15][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:2]=1[C:27]#[N:28])[C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])(=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=N[O-]
Reactant: [C-]#N
Reactant: Nc1ccc(C(=O)CCC(=O)O)cc1OCc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Product: N#Cc1ccc(C(=O)CCC(=O)O)cc1OC(=O)c1ccccc1

Procedure:
3-(4-Amino-3-benzyloxybenzoyl)propionic acid was diazotised in aqueous hydrochloric acid with sodium nitrite and the resultant solution was treated with cuprous cyanide in aqueous potassium cyanide solution to give 3-(3-benzoyloxy-4-cyanobenzoyl)propionic acid.
Reaction SMILES: C[C:2]1(C)OC(=O)CC(=O)[O:3]1.N1C=CC=CC=1.[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:25][C:26](=[O:32])[CH2:27][C:28]([O:30][CH3:31])=[O:29]>>[Cl:17][C:18]1[C:23]([Cl:24])=[C:22]([O:3][CH3:2])[CH:21]=[CH:20][C:19]=1[CH2:25][C:26](=[O:32])[CH2:27][C:28]([O:30][CH3:31])=[O:29]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COC(=O)CC(=O)Cc1cccc(Cl)c1Cl
Solvent: c1ccncc1
Product: COC(=O)CC(=O)Cc1ccc(OC)c(Cl)c1Cl

Procedure:
24.1 g (0.17 mol) of Meldrum's acid, 30.4 g (0.38 mol) of pyridine and the acyl chloride described under Intermediate 8.4 were reacted by the method of Intermediate 1. Yield: quantitative;
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:11][C@H:10]([NH2:12])[C:9](=[O:13])[N:8]([CH3:14])[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]1=2)(=[O:4])[CH3:3].[C:19](O)(=[O:23])[C@H:20]([CH3:22])[OH:21]>>[C:2]([N:5]1[CH2:11][C@H:10]([NH:12][C:19](=[O:23])[C@@H:20]([OH:21])[CH3:22])[C:9](=[O:13])[N:8]([CH3:14])[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]1=2)(=[O:4])[CH3:3]
Reactant: C[C@H](O)C(=O)O
Reactant: CC(=O)N1C[C@H](N)C(=O)N(C)c2ccccc21
Agent: Cl
Product: CC(=O)N1C[C@H](NC(=O)[C@H](C)O)C(=O)N(C)c2ccccc21

Procedure:
In an analogous manner to that described in Example 53 c), the condensation of (S)-5-acetyl-3-amino-1-methyl-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one hydrochloride with L-(+)-lactic acid yielded the title compound as a yellow foam; MS: m/e=306 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH3:17])=[O:14].[CH3:18][O:19][C:20]1[N:25]=[C:24]([O:26][CH3:27])[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][N:21]=1.ClCCl>C(OCC)(=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[C:24]([O:26][CH3:27])=[N:25][C:20]([O:19][CH3:18])=[N:21][CH:22]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH3:17])=[O:14]
Reactant: CCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCNC(=O)c1nnc2c(-c3cnc(OC)nc3OC)cccc2c1N
Temperature: 90 °C
Reaction time: 4 h

Procedure:
The title compound was prepared from 4-amino-8-bromo-N-ethyl-cinnoline-3-carboxamide (200.0 mg, 0.678 mmol) and 2,4-dimethoxyprimidine-5-boronic acid pinacol ester (363.1 mg, 1.362 mmol) according to Method B except that the reaction was heated at 90° C. to fully dissolve the starting materials. After 4 hours, additional 2,4-dimethoxyprimidine-5-boronic acid pinacol ester (363.1 mg, 1.362 mmol) was added and the reaction was refluxed overnignt. A third addition of 2,4-dimethoxyprimidine-5-boronic acid pinacol ester (363.1 mg, 1.362 mmol) and an additional 5 mol % tetrakis(triphenylphospine)palladium(0) were required to force the reaction to completion. The reaction was then worked up as described in Method B using dichloromethane rather than ethyl acetate for the extraction and crystallizing the material obtained from the flash column from chloroform/hexanes to afford the title compound as a white solid (89.5 mg, 37%). 1H NMR (300.132 MHz, CDCl3) δ 8.47 (s, 1H), 8.32 (s, 1H), 7.90 (dd, J=7.6, 2.1 Hz, 1H), 7.78-7.70 (m, 2H), 4.07 (s, 3H), 3.93 (s, 3H), 3.53 (dq, J=5.7, 7.3 Hz, 2H), 1.28 (t, J=7.3 Hz, 3H). MS APCI, m/z=354 (M+H). HPLC 2.07 min.
Reaction SMILES: [F:1][CH:2]([F:31])[C:3]1[C:4]2[N:5]([C:9]([C:12]3[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]([NH:20][CH:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]O)[CH:24]=4)[CH3:22])[N:13]=3)=[CH:10][N:11]=2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.C(=O)([O-])O.[Na+].[N-:51]=[N+:52]=[N-:53].[Na+]>C(Cl)(Cl)Cl.CN(C)C=O>[N:51]([CH2:29][C:25]1[CH:24]=[C:23]([CH:21]([NH:20][C:14]2[N:13]=[C:12]([C:9]3[N:5]4[CH:6]=[CH:7][CH:8]=[C:3]([CH:2]([F:31])[F:1])[C:4]4=[N:11][CH:10]=3)[C:17]([C:18]#[N:19])=[CH:16][N:15]=2)[CH3:22])[CH:28]=[CH:27][CH:26]=1)=[N+:52]=[N-:53]
Reactant: CC(Nc1ncc(C#N)c(-c2cnc3c(C(F)F)cccn23)n1)c1cccc(CO)c1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncc(C#N)c(-c2cnc3c(C(F)F)cccn23)n1)c1cccc(CN=[N+]=[N-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
125 mg of the 4-[8-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl]-2-({1-[3-(hydroxymethyl)phenyl]ethyl]amino]pyrimidin-5-carbonitrile [101-1] and 259 μL of N,N-diisopropylethylamine were dissolved in 3 mL of chloroform, then 69 μL of methanesulfonyl chloride was added under an ice-cold condition, and stirred at the same temperature for 30 minutes. Thereto, a saturated aqueous solution of sodium hydrogen carbonate was added, and extracted with chloroform. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The insolubles were filtered and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was dissolved in 3 mL of N,N-dimethylformamide. Thereto, 97 mg of sodium azide was added, and stirred at 80° C. for 1 hour. The reaction solution was cooled back to room temperature, then a saturated aqueous solution of sodium hydrogen carbonate was added, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The insolubles were filtered and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative thin-layer chromatography, and 87 mg of 2-({1-[3-(azidomethyl)phenyl)ethyl}amino)-4-[8-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-5-carbonitrile [102-1] was obtained as a light brown oily product.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13]([S:17][Na])([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[C:13]([S:17][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)S[Na]
Reactant: CCOC(=O)c1ccc(F)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(SC(C)(C)C)cc1
Temperature: 80 °C

Procedure:
Ethyl 4-fluorobenzoate (5.00 g, 29.7 mmol) and tert-butylsulfanylsodium (6.67 g, 59.5 mmol) were combined in DMF (50 mL). The reaction mixture was heated at 80° C. for 67 hours. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield ethyl 4-tert-butylsulfanylbenzoate. The aqueous layer was acidified with hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3×100 mL), and the combined organic layer was washed with water (1×50 mL) and brine (1×50 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield 4-(tert-butylthio)benzoic acid as an off-white solid. 1H NMR (400 MHz, DMSO) δ 13.10 (s, 1H), 7.93 (d, J=8.2 Hz, 2H), 7.61 (d, J=8.2 Hz, 2H), 1.28 (s, 9H). ESI-MS m/z calc. 210.1, found 211.1 (M+1)+; Retention time: 1.64 minutes (3 min run).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][OH:28])=[CH:23][CH:22]=3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:1][S:2]([O:28][CH2:27][CH2:26][O:25][C:24]1[CH:23]=[CH:22][C:21]([C:20]#[C:19][C:16]2[CH:15]=[N:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=3)=[CH:18][N:17]=2)=[CH:30][CH:29]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1ccc(C#Cc2cnc(-c3ccc(Cl)cc3)cn2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1ccc(C#Cc2cnc(-c3ccc(Cl)cc3)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.62 mL (7.98 mmol) of methanesulfonic acid chloride was added dropwise at RT to a solution of 700 mg (2.00 mmol) of 2-{4-[5-(4-chlorophenyl)pyrazin-2-ylethynyl]phenoxy}ethanol and 0.65 mL (7.98 mmol) of pyridine in 20 mL of DCM and the mixture was then stirred overnight at RT. After the addition of another 0.33 mL (3.99 mmol) of pyridine and 0.32 mL (4.12 mmol) of methanesulfonic acid chloride, the reaction mixture was stirred for a further 2 hours at RT in the ultrasound bath. The solution was diluted with 30 mL DCM, and the organic phase was separated off, washed three times with 60 mL of water, and dried over magnesium sulfate. After the desiccant and solvent had been eliminated, the residue was purified by chromatography (silica gel, DCM). Yield: 600 mg (70% of theoretical); C21H17ClN2O4S (M=428.889); calc.: molpeak (M+H)+:429/431 (Cl); found: molpeak (M+H)+:429/431 (Cl); Rf value: 0.30 (silica gel, DCM/MeOH 9:1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:13]1([CH2:23][NH:24][CH2:25][C@@H:26]([NH:31][C:32](=[O:48])[CH2:33][C:34]2[N:38]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=3)[CH:37]=[N:36][CH:35]=2)[C@@H:27]([CH3:30])[CH2:28][CH3:29])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([N:24]([CH2:23][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH2:25][C@@H:26]([NH:31][C:32](=[O:48])[CH2:33][C:34]1[N:38]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=2)[CH:37]=[N:36][CH:35]=1)[C@@H:27]([CH3:30])[CH2:28][CH3:29])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC[C@H](C)[C@@H](CNCc1cccc2ccccc12)NC(=O)Cc1cncn1Cc1ccc(C#N)cc1
Product: CC[C@H](C)[C@@H](CN(Cc1cccc2ccccc12)C(=O)CNC(=O)OC(C)(C)C)NC(=O)Cc1cncn1Cc1ccc(C#N)cc1

Procedure:
The title compound was prepared using the protocol described in Example 1 step H using N-t-butoxycarbonyl glycine and N-naphth-1-ylmethyl-2(S)-{(1-(4-cyanobenzyl)-1H-imidazol-5-ylacetyl}amino-3(S)-methyl pentanamine from Example 2.
Reaction SMILES: [CH2:1]([N:8](C(OC(C)(C)C)=O)[CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][C:18]([O:20][C:21]3[C:26]([C:27]#[N:28])=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(OCC)(=O)C>[CH2:1]([NH:8][CH:9]1[CH2:10][C:11]2[CH:19]=[C:18]([O:20][C:21]3[C:26]([C:27]#[N:28])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=[CH:16][C:12]=2[CH2:13][CH2:14][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CCCc2ccc(Oc3ncccc3C#N)cc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1cccnc1Oc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To N-benzyl-N-[3-(3-cyanopyridin-2-yloxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-tert-butoxycarbonylamine (480 mg) was added 4N hydrogen chloride in ethyl acetate (5 ml) at room temperature, and the mixture was stirred at the same temperature for 1 hour. After evaporation in vacuo, the residue was dissolved into a mixture of saturatd aqueous sodium hydrogencarbonate and ethyl acetate, followed by being made basic with saturated aqueous sodium hydrogencarbonate. After separation, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo to give 2-(8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)oxy-3-cyanopyridine (359 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5]Cl)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:14][C:15]1([CH3:20])[CH2:19][CH2:18][CH2:17][NH:16]1>C(O)C.C(OCC)C>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][N:16]1[CH2:17][CH2:18][CH2:19][C:15]1([CH3:20])[CH3:14])[CH3:2]
Reactant: CCOC(=O)CCl
Reactant: CC1(C)CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)CN1CCCC1(C)C
Yield: 61.5 %

Procedure:
Ethylchloroacetate (0.15 ml, 1.37 mmol), potassium carbonate (416 mg, 1.5 mmol) and 2,2-dimethyl-pyrolidine (0.280 mg, 2.06 mmol) were suspended in ethanol (3 ml) and subjected to microwave irradiation at 120° C. for 45 min. The resultant mixture was suspended in diethyl ether (30 ml), extracted with 2M hydrochloric acid (30 ml) and the organic layer discarded. The aqueous layer was treated with a slight excess of 4N sodium hydroxide solution and extracted with diethyl ether (3×30 ml). The organic layers were combined, dried over sodium sulfate, filtered and solvent removed under reduced pressure to afford (2,2-dimethyl-pyrrolidin-1-yl)-acetic acid ethyl ester (156 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:27][C@H:28]([C:32]([O:34]C)=[O:33])[CH:29]([CH3:31])[CH3:30])=[O:26])=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.CO.[Li+].[OH-].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:27][C@H:28]([C:32]([OH:34])=[O:33])[CH:29]([CH3:31])[CH3:30])=[O:26])=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)[C@@H](NC(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)c(F)c2)cc1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)c(F)c2)cc1)C(=O)O
Temperature: 50 °C

Procedure:
Methyl N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-valinate (84.2 mg, 0.17 mmol) was suspended in THF (2.5 mL), MeOH (2.5 mL) and water (1 mL), and LiOH (40.7 mg, 1.70 mmol) was added. The reaction mixture was heated at 50° C. for 2 h. Upon cooling to rt, the reaction mixture was brought to pH 3 with 1N HCl and was extracted with EtOAc (3×25 mL). The combined organic phases were washed with water (2×50 mL) and brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo. This yielded 72.3 mg (88%) of the title compound as a white solid. LC/MS m/z 482.3 (MH+), retention time 3.46 min. 1H NMR (400 MHz, DMSO-d6) δ 0.99 (dd, 6H), 2.19-2.24 (m, 1H), 4.30 (dd, H), 7.18 (t, 1H), 7.60-7.84 (m, 6H), 7.88 (d, 2H), 8.42 (d, 1H), 8.66 (t, 1H), 10.42 (s, 1H).
Reaction SMILES: CO[C:3](=[O:42])[N:4]=[C:5](SC)[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH2:29][CH2:30][O:31][Si](C(C)(C)C)(C)C)=[CH:22][C:21]=1[F:39])=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=C(C)O[N:15]=2)=[CH:10][CH:9]=1.Cl.[NH:44]([C:46]1[CH:54]=[CH:53][CH:52]=[CH:51][C:47]=1[C:48]([OH:50])=[O:49])[NH2:45].COC(=O)N=C(SC)C(C1C=C(OC)C=C(OCCF)C=1F)=NC1C=CC(C2N=C(C)ON=2)=CC=1.N(C1N=CC=CN=1)N>>[C:14]([C:11]1[CH:10]=[CH:9][C:8]([NH:7][C@@H:6]([C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH2:29][CH2:30][OH:31])=[CH:22][C:21]=2[F:39])[C:5]2[NH:4][C:3](=[O:42])[N:44]([C:46]3[CH:54]=[CH:53][CH:52]=[CH:51][C:47]=3[C:48]([OH:50])=[O:49])[N:45]=2)=[CH:13][CH:12]=1)(=[NH:18])[NH2:15]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OCCO[Si](C)(C)C(C)(C)C)cc1F
Reactant: NNc1ccccc1C(=O)O
Agent: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OCCF)c1F
Agent: Cl
Agent: NNc1ncccn1
Product: COc1cc([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)c(F)cc1OCCO

Procedure:
The same procedure was carried out as in Examples (3f)-(3h), except that (2-{4-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene)carbamic acid methyl ester and 2-hydrazinobenzoic acid hydrochloride were used instead of respectively the {2-[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in Example (3f) and 2-hydrazinopyrimidine in Example (3f), to give the title compound as a white solid.
Reaction SMILES: [CH:1]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:2]=1[CH2:3][C:4]1[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=12.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C>[CH:1]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:2]=1[CH2:3][C@@H:4]1[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C@@H:5]12
Reactant: c1ccc2c(c1)Cc1c-2[nH]c2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: c1ccc2c(c1)C[C@@H]1c3ccccc3N[C@H]21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of 5,10-dihydroindeno[1,2-b]indole 9.16 g, 93 mmol in glacial acetic acid (300 cm3) was added portionwise over half an hour, sodium cyanoborohydride (24 g, 400 mmol). The mixture was stirred for 3 hours, until all the material had dissolved. The solution was poured into ice water (500 cm3) and stirred for 1 hour to break down the borohydride complex. The clear solution was carefully neutralised with sodium hydroxide causing a white precipitate to form. This was filtered and washed with water until the washings were free from cyanide ion. Drying yielded the title compound as a white solid. Yield: 19 g, (98%). M.p. 107° C. 1H NMR (CDCl3) δ: 3.20 (1H, dd,), 3.51 (1H, dd), 3.99 1H, br,) 4.18 (1H, ddd,), 5.25 (1H, d), 6.60 (1H, d,), 6.74 (1H, dd,), 6.99 (1H, dd,), 7.15-7.22 (4H, m,), 7.32 (1H, d,),
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH2:12][OH:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CCOCC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1c[nH]c(-c2ccccc2)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: O=Cc1c[nH]c(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.6 %

Procedure:
To a solution (45 mL) of (5-phenyl-1H-pyrrol-3-yl)methanol (1.51 g) in acetonitrile were added tetra-n-propylammonium perruthenate (0.46 g), N-methylmorpholine N-oxide (2.36 g) and molecular sieves 4A powder (4.5 g), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→1:1) to give the title compound as a pale-yellow powder (yield 0.92 g, 62%).
Reaction SMILES: CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[OH:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:16]([O:18][CH3:19])=[O:17].Br[CH2:26][CH2:27][Cl:28]>O>[Cl:28][CH2:27][CH2:26][O:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(OCCCl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
To DMF (40 mL) was added potassium carbonate (9.1 g, 65.9 mmol) and methyl 3-hydroxy-4-methoxybenzoate (10.0 g, 54.9 mmol) and the mixture stirred 30 minutes at room temperature 1-bromo-2-chloroethane (11.0 g, 76.8 mmol) was added and the mixture was heated at 60° C. overnight at which point excess 1-bromo-2-chloroethane (5.5 g, 38.4 mmol) was added and heating continued for 8 hours. After cooling to room temperature, the mixture was diluted with H2O, filtered, and the solid washed with EtOAc to give methyl 3-(2-chloroethoxy)-4-methoxybenzoate (4.04 g, 16.6 mmol, 30%). 1H NMR (300 MHz, DMSO-d6) δ 7.63 (d, 1H), 7.47 (s, 1H), 7.11 (d, 1H), 4.29 (t, 2H), 3.95 (t, 2H), 3.86 (s, 3H), 3.81 (s, 3H); LC-MS (ESI) m/z 245 (M+H)+.
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.[CH:19]([NH:22]C(C)C)(C)[CH3:20].C(N)C>CO>[NH2:11][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH2:5][C:3]([NH:22][CH2:19][CH3:20])=[O:4]
Reactant: COC(=O)CC[C@H](N)C(=O)O
Reactant: CC(C)NC(C)C
Agent: CCN
Solvent: CO
Solvent: CC(=O)CC(C)=O
Product: CCNC(=O)CC[C@H](N)C(=O)O
Temperature: 60 °C
Yield: 75.9 %

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 3.1 g (31 mmol) of diisopropylamine 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 4.1 g of theanine (yield: 75.9%). The obtained theanine had the same purity as high as in Example 1.
Reaction SMILES: [CH2:1]([N:5]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32]CC)=[O:31])=[C:26]([CH3:37])[CH:25]=1)[C:6]1[C:11]([CH3:12])=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([N:5]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[C:26]([CH3:37])[CH:25]=1)[C:6]1[C:11]([CH3:12])=[C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=2)[N:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1ncnc(-c2ccc(C(F)(F)F)cc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1ncnc(-c2ccc(C(F)(F)F)cc2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a solution of ethyl {4-[(butyl{5-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)methyl]-2-methylphenoxy}acetate (190 mg, 0.37 mmol) in methanol (4 mL) and tetrahydrofuran (4 mL) was added 2M sodium hydroxide (4 mL). The resulting mixture was stirred at room temperature for 2 h. The solvents were removed in vacuo and the residue was diluted with water (20 mL), acidified with 2M HCl and extracted ethyl acetate (50 mL). The organic solution was washed with brine (20 mL), dried (MgSO4) and the solvents removed in vacuo, to afford the title compound as a white foam (180 mg).
Reaction SMILES: [C:1]([O:4][C@H:5]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][C:7]#[N:8])(=[O:3])[CH3:2]>C(Cl)(Cl)Cl>[C:1]([O:4][CH:5]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][C:7]#[N:8])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H](CC#N)c1cccs1
Solvent: ClC(Cl)Cl
Product: CC(=O)OC(CC#N)c1cccs1

Procedure:
Yield of (S)-3-acetyloxy-3-(2-thienyl) propanenitrile (S-2) 43%, ee >99%, [α]30D=−82.1 (c 1, CHCl3).