Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=1.[C:12]([O:23][CH3:24])(=[O:22])[C:13]1[CH:21]=[CH:20][C:18]([OH:19])=[C:15]([O:16][CH3:17])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:24][O:23][C:12](=[O:22])[C:13]1[CH:21]=[CH:20][C:18]([O:19][CH2:2][C:3]2[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=2)=[C:15]([O:16][CH3:17])[CH:14]=1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: Cc1nc(C)c(CBr)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OCc2nc(C)c(C)nc2C)c(OC)c1
Temperature: 85 °C
Yield: 69.3 %

Procedure:
Adding 2-bromomethyl-3,5,6-trimethylpyrazine (0.5 g, 2.33 mmol), methyl vanillate (0.6 g, 3.30 mmol), anhydrous potassium carbonate (1.0 g, 7.25 mmol), and DMF (40 mL) into a 100 mL three-necked bottle in turn, heating to 85° C. with oil bath, stifling to react for 8 hours, TLC [V(cyclohexane):V(ethyl acetate)=3:1 as developing agent] detecting shows that reaction is complete, (Rf of raw material=0.6, Rf of product=0.35), filtering to obtain filtrate, adding 30 mL water, extracting with chloroform (3×30 mL), incorporating the chloroform layer and wishing with water (2×20 mL), drying with anhydrous sodium sulfate, recycling chloroform under reduced pressure to obtain a light yellow oily matter, separating with a silica column, wherein eluant is V(petroleum ether):V(ethyl acetate)=3:1, collecting product, recycling the solution under reduced pressure to obtain solid, 0.51 g white crystalloid of 4-((3,5,6-trimethylpyrazine-2-yl)methoxyl)-3-methoxybenzoic methyl ester, a yield is 69.3%, m.p. 129.8-130.4° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]C)=[O:26])=[CH:20][CH:19]=2)[CH:7]=[CH:8][C:9]=1[CH2:10][O:11][C:12]1([CH3:15])[CH2:14][CH2:13]1)([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.O1CCCC1>[CH:1]([C:4]1[CH:5]=[C:6]([C:16]#[C:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:22][CH:23]=2)[CH:7]=[CH:8][C:9]=1[CH2:10][O:11][C:12]1([CH3:15])[CH2:13][CH2:14]1)([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(COC3(C)CC3)c(C(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)c1cc(C#Cc2ccc(CC(=O)O)cc2)ccc1COC1(C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure I; a solution methyl {4-[3-isopropyl-4-(1-methyl-cyclopropoxymethyl)-phenylethynyl]-phenyl}-acetate (Compound 140, 70.0 mg, 0.19 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (240.0 mg, 6.0 mmols, 2.0 mL of a 3N aqueous solution) and stirred overnight at room temperature. Work-up and purification by HPLC (Partisil 10-pac, 10% H2O/CH3CN) afforded of the title compound as a colorless solid.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:18]([CH:19]=1)=[N:17][C:16]1[C:11](=[CH:12][CH:13]=[C:14]([O:20][CH2:21][CH2:22]Cl)[CH:15]=1)[CH:10]=2.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[ClH:2].[ClH:1].[ClH:2].[CH:24]([NH:27][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:18]([CH:19]=1)=[N:17][C:16]1[C:11](=[CH:12][CH:13]=[C:14]([O:20][CH2:21][CH2:22][NH:17][CH:16]([CH3:11])[CH3:15])[CH:15]=1)[CH:10]=2)([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: ClCCOc1ccc2cc3ccc(OCCCl)cc3nc2c1
Agent: Cl
Product: CC(C)NCCOc1ccc2cc3ccc(OCCNC(C)C)cc3nc2c1

Procedure:
The compound is prepared from 3,6-bis(2-chloroethoxy)acridine hydrochloride and isopropylamine as described in Example 15, giving 1.1 g. of the desired product as yellow crystals, m.p. 232°-234° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23]([O:25]CC)=O)[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][NH:33][CH3:34]>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:33]([CH2:32][CH2:31][N:30]([CH3:35])[CH3:29])[CH3:34])=[O:25])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CNCCN(C)C
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: CCO
Product: CN(C)CCN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 85 °C
Yield: 154.1 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl)-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (560 mg, 1.42 mmol) in ethanol (2 ml) was treated with N,N,N′-trimethylethylenediamine (900 l, 0.91 mmol) and the resulting mixture was heated at 85° C. in a sealed tube for 4.5 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a system of 95:5:0.5 (dichloromethane:methanol:ammonia) to afford the title compound as a colourless oil (632 mg).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[NH:5][CH:4]=[C:3]1[C:16]#[N:17].P(Cl)(Cl)([Cl:20])=O>CN(C)C=O>[Cl:20][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1c[nH]c2cc3ccccc3cc2c1=O
Solvent: CN(C)C=O
Product: N#Cc1cnc2cc3ccccc3cc2c1Cl
Yield: 49.5 %

Procedure:
A reaction mixture of 3.5 g (16 mmol) of 4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile in 35 mL of phosphorus oxychloride and 22 drops of N,N-dimethylformamide (DMF) is heated at 100–110° C. for 5 hours. After cooling, the mixture is concentrated to dryness in vacuo to give a dark residue. The residue is partitioned between methylene chloride and ice-cooled saturated aqueous sodium carbonate solution. The organic layer is washed with ice-cooled brine and dried over sodium sulfate. The organic solvent is passed through a short column of silica gel, and further eluted with additional methylene chloride. Removal of the solvent yields 1.89 g (49.5%) of the product as a bright yellow solid, mp 253–255° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:8]=2[CH:9]=1)=[O:4].[H][H]>C1COCC1.[Pd]>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1cc2cc([N+](=O)[O-])ccc2o1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cc2cc(N)ccc2o1
Yield: 98.9 %

Procedure:
The product from step (a) (6.9 g) was dissolved in THF (200 mL), followed by the addition of 10% Pd/C (1 g), and the resulting reaction mixture was hydrogenated under 50 psi of hydrogen for 2 hours. The catalyst was removed by filtration through celite, and the solvent was removed in vacuo to provide 5.9 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:16])[C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([O-:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([O:21][C:22]([NH:24]O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:1]([O:5][C:6]([N:8]([CH3:16])[C@@H:9]([CH:13]([CH3:14])[CH3:15])[C:10]([O:12][NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H](C(=O)[O-])N(C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NO
Product: CC(C)[C@@H](C(=O)ONC(=O)OC(C)(C)C)N(C)C(=O)OC(C)(C)C

Procedure:
[(tert-Butoxy)carbonyl]amino (2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}-3-methylbutanoate is prepared from (25)-2-{[(tert-butoxy)carbonyl](methyl)amino}-3-methylbutanoate and N-tert-butoxycarbonyl hydroxylamine according to Scheme 6. The compound exists as rotomers and is reported as such. (1.18 g, 42%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.50-8.11 (1H, m), 4.02-4.94 (1H, m), 3.49-3.50 (3H, m), 2.07-2.41 (1H, m), 1.37-1.55 (18H, m), 0.83-1.17 (6H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH:24]4[O:29][CH2:28][CH2:27][NH:26][CH2:25]4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:30]=O>C(O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH:24]4[O:29][CH2:28][CH2:27][N:26]([CH3:30])[CH2:25]4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=O
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCC1CNCCO1
Solvent: O
Solvent: O=CO
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCC1CN(C)CCO1
Temperature: 95 °C
Yield: 91 %

Procedure:
To a solution of N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(morpholin-2-ylmethyl)oxy]quinazolin-4-amine (3.32 g, 7.7 mmol) in formic acid (33.2 mL) was added a 37 wt % solution of formaldehyde in water (3.32 mL), and the reaction mixture was heated at 95° C. for 2.5 h. After cooling to room temperature, the reaction mixture was concentrated. The residue was dissolved in methanol and treated with Bio-Rad AG®1-X8 hydroxide form resin until pH 8. Filtration and concentration in vacuo afforded 3.11 g (91%) of the title compound as a yellow-brown solid. 1H NMR (400 MHz, d4-MeOH): 8.46 (s, 1H), 8.14 (d, 1H), 7.73 (dd, 1H), 7.68 (s, 1H), 7.48 (d, 1H), 7.13 (s, 1H), 4.21-4.09 (m, 2H), 4.02 (s, 3H), 4.01-3.91 (m, 3H), 2.96 (m, 1H), 2.75 (m, 1H), 2.35 (s, 3H), 2.22 (m, 1H), 2.11 (t, 1H); MS (EI) for C21H22N4O3Cl2: 449 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:19]#[N:20])=[CH:7][N:8]2[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Cl[C:22]([O:24][CH2:25][CH2:26][CH3:27])=[O:23].C(N(CC)CC)C>CCO>[CH2:25]([O:24][C:22](=[O:23])[NH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:19]#[N:20])=[CH:7][N:8]2[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1)[CH2:26][CH3:27]
Reactant: CCCOC(=O)Cl
Reactant: COc1ccc(-n2cc(C#N)c3ccc(N)cc32)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCOC(=O)Nc1ccc2c(C#N)cn(-c3ccc(OC)cc3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Amino-1-(4-methoxyphenyl)-1H-indole-3-carbonitrile (30 mg, 0.12 mmol), is suspended in EtOH (300 μL). Propyl chloroformate (168 μL, 1.5 mmol) is added, and this mixture is stirred at room temperature overnight. The addition of triethylamine (300 μL), followed by another hour of stirring at room temperature, completes the reaction. This reaction mixture is loaded directly onto a silica column, and is eluted with CH2Cl2. Another silica column (3/2, ether/hexanes) is needed to fully purify the product, [3-cyano-1-(4-methoxy-phenyl)-1H-indol-6-yl]-carbamic acid propyl ester (19 mg, 45%), as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([N+:20]([O-:22])=[O:21])[C:12]=1[NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[C:5]([O:7][CH2:8][CH3:9])=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33]>CC#N>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([N+:20]([O-:22])=[O:21])[C:12]=1[N:13]([CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])[C:14](=[O:19])[C:15]([F:17])([F:18])[F:16])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CC(C)=CCBr
Reactant: CCOC(=O)c1cc(Br)c(NC(=O)C(F)(F)F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)c(N(CC=C(C)C)C(=O)C(F)(F)F)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
To a solution of ethyl 3-bromo-5-nitro-4-[(trifluoroacetyl)amino]benzoate (D214) (12.0 g, 31.3 mmol, 1 equiv) in CH3CN (100 ml) was added K2CO3 (5.6 g, 40 mmol, 1.3 equiv) and 1-bromo-3-methyl-2-butene (5.1 ml, 43.8 mmol, 1.4 equiv) and the resulting mixture was refluxed for 1 h then cooled to room temperature. The precipitate formed was filtered off through a pad of celite and washed with CH3CN. The combined organic layers were concentrated in vacuo and the residue diluted with AcOEt. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOEt: 9/1 to 4/1) gave ethyl 3-bromo-4-[(3-methyl-2-buten-1-yl)(trifluoroacetyl)amino]-5-nitrobenzoate (D215) (12.9 g, 91%) as an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](B(O)O)=[CH:8][C:7]=2[CH:14]=1.I[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.CCO>[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][C:16]([C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][C:7]=3[CH:8]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc2oc(B(O)O)cc2c1
Reactant: COC(=O)c1ccc(I)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2cc3cc(OC)ccc3o2)cc1
Reaction time: 2 h
Yield: 31.9 %

Procedure:
A solution of 5-Methoxy-benzofuran-2-boronic acid (1.9 g, 10 mmol), Methyl 4-iodobenzoate (2.61 g, 10 mmol), Pd(Ph3)4 (0.25 g), and 2M NaCO3 (10 ml) in toluene (40 ml) and EtOH (10 ml) was heated to reflux. After 2 hr, the reaction was cooled and the organic layer was separated dried, and concentrated to give a solid. The solid was triturated with MeOH, filtered to give 127 (0.90 g, 32%) which was used without further purification or characterization for the next step.
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH2:16]N1C=NN=C1.CS(C)=O.CC(C)([O-])C.[Li+]>C(O)(=O)C>[NH2:16][C:8]1[C:9]([N+:10]([O-:12])=[O:11])=[C:2]([CH3:1])[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]=1[C:6]#[N:7]
Reactant: Nn1cnnc1
Reactant: Cc1c([N+](=O)[O-])cc(C#N)cc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: Cc1c([N+](=O)[O-])cc(C#N)c(N)c1[N+](=O)[O-]
Temperature: 22.5 °C
Reaction time: 2 h

Procedure:
A solution of 4-methyl-3,5-dinitrobenzonitrile (10.5 kg; preparation see U.S. Pat. No. 3,162,675), 4-amino-4H-1,2,4-triazole (17.0 kg) and dimethyl sulfoxide (68.6 kg) was dosed into a mixture of lithium tert-butoxide (12.2 kg) and dimethyl sulfoxide (106.6 kg) over about 50 min, while maintaining the temperature of each solution at 20-25° C. After aging at 20-25° C. for about 2 h, acetic acid (8.9 kg) was dosed into the reaction mixture at about 20° C. over about 10 min. The product was crystallized by dosing water (158 L) into the reaction mixture over about 1.5 h at about 20° C. The product slurry was cooled to 10-15° C. and held at this temperature for about 45 min. The resultant slurry was filtered, and washed with water (106 L). The wet cake obtained was dried in a vacuum tray dryer at about 50° C. and 30 Torr to provide 2-amino-4-methyl-3,5-dinitrobenzonitrile as an orange-brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)=[O:25])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([OH:19])=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:43](=[O:50])([O:47][CH2:48][CH3:49])[O:44][CH2:45]Cl>CN(C)C=O>[Cl:1][C:2]1[CH:23]=[C:22]([C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)=[O:25])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([O:19][CH2:45][O:44][C:43]([O:47][CH2:48][CH3:49])=[O:50])=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5]
Reactant: CCOC(=O)OCCl
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)OCOC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 60 °C

Procedure:
A mixture of N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine (Example 303; 1 mmol), potassium carbonate (1.1 mmol), potassium iodide (0.2 mmol), and chloromethyl ethyl carbonate (which is prepared according to Boehme, H. et al. Synthesis 1971, 588-590; 1.1 mmol) in N,N-dimethylformamide (10 mL) is heated at 60° C. for 3 h. The reaction mixture is concentrated to remove N,N-dimethylformamide. Water (50 mL) is added and the mixture is extracted with ethyl acetate (3×50 mL). The combined ethyl acetate layers are washed with brine (100 mL), dried (MgSO4), filtered, evaporated and chromatographed to give N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine, [(ethoxycarbonyl)oxy]methyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12](OC)=[O:13])[CH:5]=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].CC(C[AlH]CC(C)C)C>C(Cl)Cl.CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[N:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: COC(=O)c1cnc(C(F)(F)F)c(C)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(CO)cnc1C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
To a solution of methyl 5-methyl-6-(trifluoromethyl)-3-pyridinecarboxylate (552 mg, 2.52 mmol) in DCM (30 ml) stirred under N2 at 0° C. was added a solution of DIBAL-H (1.5 M solution in toluene, 5.04 ml, 7.56 mmol) dropwise. The reaction mixture was stirred at 0° C. for 2 h and at room temperature overnight. The reaction mixture was diluted with MeOH and concentrated under reduced pressure. The residue was treated with a 1N HCl solution and extracted twice with EtOAc. The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced. Purification by flash chromatography using a 10 g silica gel cartridge, and mixtures of DCM and MeOH as eluent afforded [5-methyl-6-(trifluoromethyl)-3-pyridinyl]methanol (297 mg, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:20][C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[B-](F)(F)(F)F.CN(C(O[N:43]1[C:48](=O)[CH:47]=[CH:46]C=C1)=[N+](C)C)C.CCN(C(C)C)C(C)C.C1(N)CC1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([NH:43][CH:48]3[CH2:46][CH2:47]3)=[O:26])=[CH:28][CH:29]=2)[CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Reaction time: 2 h

Procedure:
rac-4-{[(4-Chloro-benzenesulfonyl)-(2-oxo-azepan-3-yl)-amino]-methyl}-benzoic acid (0.70 g, 1.6 mmol) was dissolved in DMF and activated with the coupling reagent TPTU (0.48 g, 1.6 mmol) and Hünig's base (0.55 ml, 3.2 mmol) for 2 min. ⅛ of this activated mixture was delivered to a reaction tube on a parallel synthesizer containing cyclopropylamine (0.013 g, 0.22 mmol) and a further amount of Hünig's base (0.04 ml, 0.22 mmol) in DMF (3 ml). The reaction mixture was shaken for 2 h, concentrated under reduced pressure and purified directly using preparative RP(C18) chromatography: lyophilisate 40 mg; MS: m/e=476.1 (MH+), 493.1 (MNH4+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[C:11]([NH:15][OH:16])([CH3:14])([CH3:13])[CH3:12]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[N+:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[O-:16])[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc(C=O)c1
Reactant: CC(C)(C)NO
Product: COc1cccc(C=[N+]([O-])C(C)(C)C)c1

Procedure:
The title compound was prepared according to the procedure described in Example 11 using 3-methoxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 56.5% overall yield as a crystalline solid. m.p. 93.4° C.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[I-:10].[Na+].[C:12]([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)(=O)[CH3:13]>C(#N)C>[I-:10].[C:4]1([CH2:3][CH2:2][NH+:17]2[CH:18]=[CH:19][N:15]([CH2:12][CH2:13][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:16]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)n1ccnc1
Reactant: BrCCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: C1=C[NH+](CCc2ccccc2)CN1CCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of (2-bromoethyl)benzene (27.3 ml), sodium iodide (60.0 g), 1-acetylimidazole (22.2 g), and acetonitrile (220 ml) was refluxed 6.5 hrs. under nitrogen. The solution was cooled to 25° C. and the acetonitrile was evaporated. Water and potassium carbonate were added to the oily residue, which was extracted with dichloromethane. Combined extracts were washed with water, dried, filtered, and concentrated to give 1,3-bis(2-phenylethyl)-1H-imidazolium iodide (J, 35.4 g), m.p. 145.5°-147° C. from ethyl acetate.
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:18]3=[N:19][C:20](Cl)=[N:21][CH:22]=[C:17]3[CH2:16][N:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3[F:32])[C:14]2=[O:33])[CH2:9][CH2:8]1)(C)(C)C.[NH2:36][C:37]1[CH:38]=[C:39]([O:45][CH3:46])[C:40]([O:43][CH3:44])=[CH:41][CH:42]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[F:32][C:25]1[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=1[N:15]1[CH2:16][C:17]2[C:18](=[N:19][C:20]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[CH:38]=3)=[N:21][CH:22]=2)[N:13]([C@H:10]2[CH2:11][CH2:12][C@H:7]([OH:6])[CH2:8][CH2:9]2)[C:14]1=[O:33]
Reactant: COc1ccc(N2Cc3cnc(Cl)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)C2=O)c(F)c1
Reactant: COc1ccc(N)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: COc1ccc(N2Cc3cnc(Nc4ccc(OC)c(OC)c4)nc3N([C@H]3CC[C@H](O)CC3)C2=O)c(F)c1
Temperature: 160 °C

Procedure:
A mixture of 1-[trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-7-chloro-3-(2-fluoro-4-methoxy-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.20 g, 0.38 mmol) (from Example 17c supra), 4-amino-veratrole (76.6 mg, 0.50 mmol) (Aldrich) and p-toluenesulfonic acid monohydrate (95.1 mg, 0.50 mmol) (Aldrich) in 2-propanol (4 mL) was placed in a microwave reactor (SmithSynthesizer™). The reaction mixture was heated at 160° C. for 15 minutes. After cooling, it was concentrated under reduced pressure and purified by RP-HPLC (C-18, eluted with acetonitrile-water) to give 3-(2-fluoro-4-methoxy-phenyl)-1-(trans-4-hydroxy-cyclohexyl)-7-(3,4-dimethoxy-phenylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 0.13 g, 63%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[O:9](C(OC(C)(C)C)=O)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:10](=[O:9])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccc(Br)n1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 6-bromopyridin-2-amine (15 g, 86.49 mmol, 1 eq.) in 250 ml of DCM cooled to 0° C. were added DMAP (1.05 g, 8.67 mmol, 0.1 eq.), TEA (9.65 g, 95.36 mmol, 1.1 eq.) and BOC2O (22.70 g, 104.03 mmol, 1.2 eq.) portionwise. The reaction was stirred at 0° C. for 5 h and quenched with sat. aqueous NH4Cl. The aqueous layer was extracted with DCM, and the organics were combined, dried over MgSO4 and concentrated. The crude residue was purified by chromatography on silica gel to give impure tert-butyl (6-bromopyridin-2-yl)carbamate (mix 80/20 of mono and bis BOC) as a white solid. A chemical purification was then done. This solid was dissolved in 250 ml of THF cooled to 0° C. then iPrMgCl.LiCl (2 M, 51.89 ml, 103.78 mmol, 1.2 eq.) was added dropwise. The solution was stirred 30 min and quenched with aqueous sat. NH4Cl. The aqueous layer was separated and extracted with DCM. The organics were combined, dried over MgSO4 and concentrated to give tert-butyl (6-bromopyridin-2-yl)carbamate (15.96 g, 68%) as a white solid.