Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([Br:24])=[CH:7][C:8]([F:23])=[C:9]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[NH:13][C:12]2=[O:22])[CH:10]=1)[CH:2]=[CH2:3].CI.[C:27](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:4][C:5]1[C:6]([Br:24])=[CH:7][C:8]([F:23])=[C:9]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[N:13]([CH3:27])[C:12]2=[O:22])[CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A crude product (16.67 g) of 3-(5-allyloxy-4-bromo-2-fluorophenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, methyl iodide (7.18 g) and potassium carbonate (7.03 g) were suspended in DMF (80 ml), and the mixture was stirred at room temperature for 8 hours. After the reaction, DMF was distilled off under reduced pressure, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off, and the resulting oily substance was purified by chromatography on silica gel (ethyl acetate:n-hexane=1:3 v/v), and the resulting oily substance was crystallized from ethyl acetate-n-hexane to obtain the objective 3-(5-allyloxy-4-bromo-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (5.42 g).
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([F:13])[C:5](=[O:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[Cl-].[NH4+]>C1COCC1>[F:3][CH:4]([F:13])[C:5]([CH:6]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:12]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)CC(=O)C(F)F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C(=O)OCC)C(=O)C(F)F
Reaction time: 0.08 h

Procedure:
0.52 g (14.296 mmol) of sodium hydride (60% in mineral oil) was initially charged in THF (30 ml), and at 0° C. a solution of 2.00 g (11.437 mmol) of ethyl 4,4-difluoro-3-oxobutyrate in THF (20 ml) was then added dropwise. After warming to RT and a further 30 min at this temperature, 2.865 g (17.156 mmol) of ethyl bromoacetate in THF (15 ml) were added and the mixture was then heated at reflux overnight. After cooling, saturated aqueous ammonium chloride solution was added and the mixture was then extracted three times with ethyl acetate. The combined organic phases were dried with sodium sulphate, filtered and concentrated. After 5 min at high vacuum, the title compound obtained in this manner (3.00 g, about 50% pure) was used without further purification for the next step.
Reaction SMILES: N1C=CC=CC=1.CS(C)=O.[OH:11][CH2:12][CH:13]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15][N:14]1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:12]([CH:13]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:16][CH2:15][N:14]1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(CO)C1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C=O)C1
Temperature: 0 °C
Yield: 100 %

Procedure:
To SO3-pyr complex (5.84 g, 36.69 mmol) was added pyridine (2.90 mL, 36.66 mmol) and DMSO (7.20 mL, 101.37 mmol). Slurry was stirred at room temperature 10 min before DCM (30 mL) was added and mixture was cooled to 0° C. Then solution of 1-benzyl 4-tert-butyl 2-(hydroxymethyl)piperazine-1,4-dicarboxylate (6.44 g, 18.37 mmol), Hunig's base (11.0 mL, 63.15 mmol) and DMSO (7.20 mL, 101.37 mmol) in DCM (70 mL) was added over 10 min. Reaction mixture was stirred at 0° C. 30 min and TLC showed complete consumption of starting material. Reaction was washed subsequently with H2O (50 mL), cold aqueous 1N HCl (until aqueous phase stayed acidic), then NaHCO3 (aqueous saturated, 50 mL) and finally NaCl (aqueous saturated, 50 mL). Organic phase was dried over Na2SO4 and solvent concentrated. Crude 1-benzyl 4-tert-butyl 2-formylpiperazine-1,4-dicarboxylate (˜6.40 g, quant) was obtained as colorless oil and was taken directly into the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([OH:14])[CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CN(C)C1C=CN=CC=1.CN(C1C=CN=CC=1)C.[CH3:33][C:34]1[CH:39]=[C:38]([CH3:40])[CH:37]=[C:36]([CH3:41])[C:35]=1[CH2:42][C:43](Cl)=[O:44]>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([O:14][C:43](=[O:44])[CH2:42][C:35]2[C:34]([CH3:33])=[CH:39][C:38]([CH3:40])=[CH:37][C:36]=2[CH3:41])[CH2:7][CH2:8][N:9]([O:12][CH3:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(O)CCN(OC)CC1
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOC(=O)C1(OC(=O)Cc2c(C)cc(C)cc2C)CCN(OC)CC1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
To a solution of 4-hydroxy-1-methoxy-piperidine-4-carboxylic acid ethyl ester (0.5 g, 2.46 mmol) in 15 ml pyridine under argon was added 4-dimethylaminopyridine DMAP (0.11 g, 0.9 mmol). The solution was cooled down to 0° C., then (2,4,6-trimethylphenyl)-acetyl chloride (0.58 g, 2.95 mmol) was added dropwise. The reaction mixture was warmed up to room temperature and left stirring for 3 days. Then the reaction mixture was concentrated and cold (0° C.) water was added. The aqueous phase was thoroughly extracted three times with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography on silica gel (ethyl acetate/cyclohexane 1:4) to give pure 1-methoxy-4-[2-(2,4,6-trimethyl-phenyl)-acetoxy]-piperidine-4-carboxylic acid ethyl ester (compound P3.6) as light yellow oil. Yield: 610 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[C:15]([Cl:21])[CH:14]=1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:7]([C:6]2[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)=[O:9])=[C:15]([Cl:21])[CH:14]=1
Reactant: COc1ccc(C(=O)O)cn1
Reactant: Clc1cc(Br)ccc1CBr
Product: COc1ccc(C(=O)Cc2ccc(Br)cc2Cl)cn1

Procedure:
In analogy to Example 165, step 1, 6-methoxynicotinic acid was converted to the acid chloride and subsequently reacted with 4-bromo-1-bromomethyl-2-chloro-benzene to give the title compound (not completely pure) as a light yellow solid.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH:4](I)[CH3:5].[N-:9]=[N+:10]=[N-:11].[Na+]>C(O)C>[N:9]([CH:4]([CH3:5])[CH2:3][C:2]([F:8])([F:7])[F:1])=[N+:10]=[N-:11]
Reactant: CC(I)CC(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: CC(CC(F)(F)F)N=[N+]=[N-]

Procedure:
1,1,1-Trifluoro-3-iodobutane (20.00 g, 0.084 mol) was added slowly to a stirred solution of sodium azide (13.00 g, 0.200 mol) in aqueous ethanol (60% ethanol, 200 ml) contained in a 500 ml flask (3-necked) with an argon lute, then refluxed for 11 h. The solution was extracted with ether (250 ml), which was washed and dried, and shown by g.l.c. analysis (2 m D.N.P. at 60°) to contain one major product, 3-azido-1,1,1-trifluorobutane, [approximately 9 g (estimated from g.l.c. analysis), 0.059 mol, 70%] which was not isolated because of the explosive hazard.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([O:18]C)=[O:17])=[C:13]([CH3:23])[N:12]=[C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:10]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([OH:18])=[O:17])=[C:13]([CH3:23])[N:12]=[C:11]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:10]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc(C)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1ccc(C)cc1F
Yield: 86.5 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-(2-fluoro-4-methylphenyl)-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.067 g; 0.171 mmol), sodium hydroxide 10N (0.171 mL; 1.71 mmol) in methanol (1.7 mL) to afford 0.056 g (86%) of the title compound as a white solid.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[C:10]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH:22]([OH:30])[CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:16][C:15]=1[NH:31][C:32](=[O:48])[CH2:33][CH:34]1[C:47]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[O:41][C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[Ca+2].O>C1C=CC=CC=1>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH:22]([O:30][C:3](=[O:4])[NH2:5])[CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[CH:16][C:15]=1[NH:31][C:32](=[O:48])[CH2:33][CH:34]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=2[O:41][C:42]2[C:47]1=[CH:46][CH:45]=[CH:44][CH:43]=2)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1ccc(CCC(O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)c1ccc(CCC(CC2CCCCC2)OC(N)=O)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reaction time: 0.17 h
Yield: 45.6 %

Procedure:
64 μl (0.54 mmol) of trichloroacetyl isocyanate, were added to a solution of 272 mg (0.52 mmol) of N-[2-t-butyl-5-(4-cyclohexyl-3-hydroxybutyl)phenyl]-2-(9H-xanthen-9-yl) acetamide (prepared as described in Example 12) in 6 ml of benzene, and the resulting mixture was stirred for 10 minutes. At the end of this time, a methanolic solution of calcium carbonate was then added, whilst stirring. The reaction mixture was then mixed with water, and the organic phase was separated and dried. The solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 50 g of silica gel, using a 15:85 by volume mixture of ethyl acetate and methylene chloride as the eluent, to give 135 mg (yield 46%) of the title compound as a foam-like material.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[Cl:17][C:18]1[CH:23]=[C:22]([N+]([O-])=O)[CH:21]=[CH:20][N:19]=1>>[Cl:17][C:18]1[CH:23]=[C:22]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:21]=[CH:20][N:19]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Cl)c2)CC1
Yield: 83.8 %

Procedure:
Using the method of Example 3, Step A, tert-butyl 4-hydroxypiperidine-1-carboxylate (1.90 g, 9.46 mmol), 60% sodium hydride in mineral oil (378 mg, 9.46 mmol), and 2-chloro-4-nitropyridine (1.50 g, 9.46 mmol) were reacted to provide tert-butyl 4-(2-chloropyridin-4-yloxy)piperidine-1-carboxylate (2.48 g, 84% yield) as an oil. 1H NMR (CDCl3) δ 8.19 (d, 1H), 6.83 (s, 1H), 6.74 (d, 1H), 4.56 (m, 1H), 3.68 (ddd, 2H), 3.37 (ddd, 2H), 1.94 (dddd, 2H), 1.77 (dddd, 2H), 1.47 (s, 9H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:39](=[O:40])[N:13]3[C:14]([C:23]([O:25][CH:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:24])=[C:15](OS(C)(=O)=O)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].CO.[N:46]1[CH:51]=[CH:50][C:49]([C:52]2[N:53]=[C:54]([SH:57])[S:55][CH:56]=2)=[CH:48][CH:47]=1.C(O)(=O)C>O1CCCC1.O.CO>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:39](=[O:40])[N:13]3[C:14]([C:23]([O:25][CH:26]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[O:24])=[C:15]([S:57][C:54]4[S:55][CH:56]=[C:52]([C:49]5[CH:50]=[CH:51][N:46]=[CH:47][CH:48]=5)[N:53]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Reactant: Sc1nc(-c2ccncc2)cs1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Sc3nc(-c4ccncc4)cs3)CS[C@H]12
Temperature: -3 °C
Reaction time: 1.5 h

Procedure:
Benzhydryl 7β-[(phenylacetyl)amino]-3-[(methylsulfonyl)oxy]-3-cephem-4-carboxylate-(900 g, 1.56 mol) was dissolved in tetrahydrofuran (3.6 L) and cooled to −3° C. While maintaining the same temperature, 28% sodium methylate-methanol solution (360 g, 1.87 mol) of 4-(4-pyridyl)-1,3-thiazole-2-thiol (362.5 g, 1.87 mol) obtained in the same manner as in Reference Example 29, and tetrahydrofuran (720 mL) solution were added. The mixture was stirred for 1.5 hr. Acetic acid (18.7 g) was added and after stirring for 30 min, methanol (9 L) and water (5.4 L) were added. The mixture was stirred for 2 hr. The precipitated crystals were collected by filtration, washed with methanol (16 L) and dried in vacuo. yield: 884 g (84%)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH:4]=[CH:3]1.[Na].[OH-].[Na+]>C(O)(=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc2ccn(C)c2c1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)N(C)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
To a mixture of methyl N-methylindole-6-carboxylate (1.5 g) and acetic acid (22.5 ml) was added sodium cyanoboride (1.62 g), followed by stirring at room temperature for 1 hour. The reaction mixture was poured into ice-water (100 ml), and sodium hydroxide (pellet) was added thereto to adjust the pH to about 10, followed by extraction with ethyl acetate (60 ml). The organic layer was washed with a saturated sodium bicarbonate solution three times, and saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was then removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain methyl N-methylindoline-6-carboxylate (900 mg) as a pale yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C[O-].[Na+].Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CCOC(=O)CCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CCCSc1ccc(Cl)cc1
Yield: 92.7 %

Procedure:
14.5 g (0.1 mol) of p-chlorothiophenol are added at 0° C to a solution of 5.4 g (0.1 mol) of sodium methylate in 50 ml of methanol and thereafter 19.5 g (0.1 mol) of ethyl γ-bromobutyrate dissolved in 40 ml of methanol are added dropwise at 20° C, whilst stirring. The mixture is heated for 2 hours to the reflux temperature and is then evaporated in vacuo, the residue is extracted with ether, the extract is washed with water and dried, and the ether is evaporated. 24 g (93%) of a white oil are obtained.
Reaction SMILES: B(O)(O)O.[NH2:5][C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][C:9](=[O:11])[NH2:10].[CH2:15](N)[CH3:16]>>[NH2:5][C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][C:9]([NH:10][CH2:15][CH3:16])=[O:11]
Reactant: CCN
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: OB(O)O
Product: CCNC(=O)CC[C@H](N)C(=O)O
Reaction time: 22 h

Procedure:
Glutaminase in an amount of 0.3 U per 1 ml of the buffer was added to boric acid buffer (disodium borate-sodium hydroxide, pH 11) containing 0.3 M glutamine and 1.5 M ethylamine, and the mixture was incubated at 30° C. for 22 hours to react the components. Two-hundred and twenty-five millimoles of theanine was isolated from 1 L of the reaction mixture. Incidentally, a by-product, glutamic acid, was 20 mmol. Theanine was isolated and purified from the reaction mixture by applying the reaction mixture to a Dowex 50×8, Dowex 1×2 column chromatography and eluting with ethanol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:20][C:21]4[N:26]5[C:27](=[O:30])[NH:28][N:29]=[C:25]5[CH2:24][O:23][C:22]=4[N:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:39](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:20][C:21]4[N:26]5[C:27](=[O:30])[N:28]([CH3:39])[N:29]=[C:25]5[CH2:24][O:23][C:22]=4[N:31]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(n[nH]c3=O)CO4)cc2)CCC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cn1nc2n(c1=O)-c1cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc1OC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of tert-butyl(1-(4-(1-oxo-8-phenyl-2,4-dihydro-1H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (26 mg, 0.05 mmol) in dry DMF (1 ml) was added potassium carbonate (21 mg, 0.15 mmol) and methyliodide (10 μl, 0.15 mmol) under nitrogen. The resulting mixture was stirred overnight at room temperature. Water was added and the mixture was extracted with EtOAc (3×5 ml). The combined organic phases were dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 40% EtOAc in cyclohexane) to give the title compound (22 mg, 82%). 1H NMR (500 MHz, CDCl3): 8.50 (1H, s), 7.25 (2H, d), 7.20-7.19 (5H, m), 7.15-7.12 (2H, m), 5.21 (2H, s), 5.00 (1H, br s), 3.46 (3H, s), 2.55-2.25 (4H, m), 2.10-2.03 (1H, m), 1.86-1.78 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[Cl:5][C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([C:15]([NH:17][C@@H:18]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:19]([OH:23])[C:20]([OH:22])=O)=[O:16])[NH:12][C:9]2=[CH:10][N:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.[Cl-].[Na+].O>[CH2:24]([C@H:18]([NH:17][C:15]([C:13]1[NH:12][C:9]2=[CH:10][N:11]=[C:6]([Cl:5])[CH:7]=[C:8]2[CH:14]=1)=[O:16])[C@@H:19]([C:20](=[O:22])[N:3]([CH3:4])[CH3:2])[OH:23])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc2cc(Cl)ncc2[nH]1
Reaction time: 12 h

Procedure:
Dimethylamine hydrochloride (7 mg, 0.085 mmol) was added to a solution of 3-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-2-(S)-hydroxy-4-phenylbutyric acid (EXAMPLE 124, 30 mg, 0.080 mmol), HOBt (14 mg, 0.091 mmol), DIPEA (31 μL, 0.18 mmol) and EDCI (18 mg, 0.094 mmol) in DMF (3 mL). After the addition of DIPEA (14 ml, 0.080 mmol) the mixture was stirred for 12 h before adding to diluted brine (100 mL, water/brine: 1/1). Extraction with ethyl acetate (4×25 mL), washing of the combined extracts with brine (50 mL) and drying (MgSO4) gave, after concentration, a residue which was purified by preparative LCMS to give the title compound as a colourless solid. m/z (ES+)=401.28 [M+H]+; RT=3.06 min.
Reaction SMILES: CI.[CH3:3][C:4]1([CH3:28])[C:23]2=[CH:24][CH:25]=[N:26][CH:27]=[C:22]2[C:7]2[C:8]([OH:21])=[CH:9][C:10]([CH:12]([CH:14]([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:13])=[CH:11][C:6]=2[O:5]1.[CH3:29]N(C)C=O.C[O-].[Na+]>O>[CH3:28][C:4]1([CH3:3])[C:23]2=[CH:24][CH:25]=[N:26][CH:27]=[C:22]2[C:7]2[C:8]([O:21][CH3:29])=[CH:9][C:10]([CH:12]([CH:14]([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:13])=[CH:11][C:6]=2[O:5]1
Reactant: CN(C)C=O
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCCCCC(C)C(C)c1cc(OC)c2c(c1)OC(C)(C)c1ccncc1-2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl iodide (5.11 g., 0.036 mole) was added dropwise to a stirred solution of 10.59 g. (0.03 mole) of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-5H-[1]benzopyrano [3,4-d]pyridine in 300 ml. of N,N-dimethylformamide containing 1.78 g. (0.033 mole) of sodium methoxide. The mixture was stirred at room temperature for 18 hours and 300 ml. of water was added and extracted with petroleum ether (30°-60°). The combined petroleum ether extracts were washed with water, dried with anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by chromatography on a Florisil® column with chloroform or by distillation under reduced pressure to give the pure product.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13](=[O:15])[CH2:12][N:11]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[CH:22]=1.CN(C)C=O.Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>C1(C)C=CC=CC=1>[CH3:33][O:32][C:30](=[O:31])[CH2:29][N:14]1[C:8]2[CH:7]=[CH:6][C:5]([Cl:4])=[CH:22][C:9]=2[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:11][CH2:12][C:13]1=[O:15]
Reactant: COC(=O)CBr
Reactant: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Reaction time: 8 h
Yield: 42 %

Procedure:
Sodium methoxide (5.95 g., 0.11 mole) is added to a solution of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (27 g., 0.1 mole) in 200 ml. of dimethylformamide and the mixture is stirred and heated on a steambath for about 20 minutes. To this mixture is added a solution of methyl bromoacetate (16.7 g., 0.11 mole) in 165 ml. of toluene during 1 hour while stirring and heating are continued. The mixture is heated for an additional 2 hours, allowed to stand overnight at room temperature (about 25° C.) and evaporated to dryness in vacuo. The residue is stirred with 500 ml. of water until a suspension results. The suspension is filtered and the solid thus obtained is crystallized first from ether and then from ethanol to give 14.5 g. (42% yield) of 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-acetic acid methyl ester of melting point 137°-138° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=O)[O:17]C3C=CC=CC=3)=[CH:11][CH:10]=2)[O:3]1.[CH3:26][NH2:27].C1COCC1>C1COCC1>[CH3:26][NH:27][C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:25])([CH3:1])[C:6]([CH3:8])([CH3:7])[O:5]2)=[CH:10][CH:11]=1)=[O:17]
Reactant: CC1(C)OB(c2ccc(NC(=O)Oc3ccccc3)cc2)OC1(C)C
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
A mixture of phenyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (26 g, 76.6 mmol)), 2.0M Methylamine/THF (265 mL, 530 mmol) in 150 mL of THF was stirred at room temperature for 6 hours, then excess solvent was distilled off from the reaction mixture; residue was dissolved into water, extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure. The crude product was purified by silica gel column chromatography by using 5-60% ethyl acetate in pet-ether as an eluent. to give 1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]urea. (20 g, 88% yield) as white solid.