Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:34])[CH2:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([O:27][CH2:28][CH3:29])=[CH:25][CH:26]=3)=[CH:17][C:16]=2[CH2:30][NH:31][CH2:32][CH3:33])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:3].C(N(CC)C(C)C)(C)C.[CH:44]1([C:47](Cl)=[O:48])[CH2:46][CH2:45]1>ClCCl.O>[CH2:2]([O:4][C:5](=[O:34])[CH2:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([O:27][CH2:28][CH3:29])=[CH:25][CH:26]=3)=[CH:17][C:16]=2[CH2:30][N:31]([C:47]([CH:44]2[CH2:46][CH2:45]2)=[O:48])[CH2:32][CH3:33])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:3]
Reactant: CCNCc1cc(-c2ccc(OCC)nc2)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc(OCC)nc3)cc2CN(CC)C(=O)C2CC2)c1
Temperature: 25 °C

Procedure:
To [4′-(6-ethoxy-pyridin-3-yl)-2′-ethylaminomethyl-6-methoxy-biphenyl-3-yl]-acetic acid ethyl ester hydrochloride (0.357 g, 0.736 mmol) and N,N-diisopropylethylamine (0.75 mL, 4.3 mmol) in dichloromethane (4 mL) was added cyclopropanecarbonyl chloride (0.074 mL, 0.814 mmol), and the reaction was stirred at room temperature. Once no starting material was seen by analytical LCMS, the mixture was diluted with dichloromethane and water, and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated, and the residue was purified by silica gel chromatography (ethyl acetate in hexanes gradient) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:8]=2)[N:3]=1.CCN(C(C)C)C(C)C.O>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: COC(=O)c1ccc2c(Cl)nc(Cl)nc2c1
Agent: [Pd]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2cnc(Cl)nc2c1
Reaction time: 1 h

Procedure:
To a solution of methyl 2,4-dichloroquinazoline-7-carboxylate (1250 mg, 4.86 mmol) in EtOAc (100 mL) at R.T. was added Hunig's base (0.847 mL, 4.86 mmol) to form a pale yellow solution. The Pd catalyst was added and the mix hydrogenated with a H2 balloon for 1 hour. Water (20 mL) was added to solubilize salts, and mix filtered to remove Pd. The aqueous layer separated and organics dried over MgSO4, filtered and stripped to yield a residue (yellow solid) that was purified by Biotage 40M chromatography (loaded in DCM) eluting with 15-60% EtOAc/Hex over 2000 mL to afford the title compound as a pale yellow solid, 724 mg, 67%. 1H NMR (400 MHz, DMSO-D6) δ ppm 9.75 (1H, s) 8.45 (1H, s) 8.37 (1H, d, J=8.34 Hz) 8.13-8.30 (1H, m) 3.96 (3H, s); MS (API+) for C10H7N2ClO2 m/z 223.1 (M+H)+.
Reaction SMILES: [Na].[C:2]([CH:4]([C:9]#[N:10])[C:5]([O:7][CH3:8])=[O:6])#[N:3].[ClH:11]>[Pd].CO>[ClH:11].[ClH:11].[NH2:3][CH2:2][CH:4]([CH2:9][NH2:10])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(C#N)C#N
Agent: [Pd]
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COC(=O)C(CN)CN
Reaction time: 24 h

Procedure:
A stirring suspension of 10% palladium on carbon (2.0 g) in a solution of the sodium salt of methyl dicyanoacetate (1.00 g, 6.20 mmol) in methanol (100 mL) containing concd hydrochloric acid (32%, 2.0 mL) was hydrogenated at 5 bar and rt. for 24 h. The catalyst was removed by filtration and the solvent was evaporated in vacuo. The residue was treated with methanol (50 mL) and the precipitated sodium chloride was removed by filtration. The solution was concentrated to a low volume in vacuo and then EtOAc was added to precipitate the bis-hydrochloride 12 as an off-white solid (1.20 g).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][CH2:11][CH2:12][N:13]([CH3:43])[C@@H:14]1[CH2:21][N:20]2[C:22]3[CH:23]=[C:24]([C:35]([O:37]C)=[O:36])[CH:25]=[CH:26][C:27]=3[C:28]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[C:19]2[C:18]2[CH:39]=[CH:40][CH:41]=[CH:42][C:17]=2[O:16][CH2:15]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO.C1COCC1>[C:3]([O:7][C:8]([NH:10][CH2:11][CH2:12][N:13]([CH3:43])[C@@H:14]1[CH2:21][N:20]2[C:22]3[CH:23]=[C:24]([C:35]([OH:37])=[O:36])[CH:25]=[CH:26][C:27]=3[C:28]([CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)=[C:19]2[C:18]2[CH:39]=[CH:40][CH:41]=[CH:42][C:17]=2[O:16][CH2:15]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCNC(=O)OC(C)(C)C)COc1ccccc1-3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(CCNC(=O)OC(C)(C)C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
2N NaOH (aq) (6 eq) was added to a solution of methyl (7R)-7-[{2-[(tert-butoxycarbonyl)amino]ethyl}(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.02 M) in MeOH/THF (3/1) and the reaction stirred vigorously at 60° C. for 4 h. The reaction was allowed to cool to RT before reducing the volume of MeOH/THF in vacuo. The residue was partitioned between 1N HCl (aq) and EtOAc, ensuring the aqueous phase was acidic. The aqueous was extracted a second time with EtOAc and the combined organics washed with water, brine before being dried (Na2SO4), filtered and concentrated in vacuo. The material was taken on without further purification. MS (ES+) m/z 548 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.[Cl:16][C:17]1[N:18]=[C:19](Cl)[C:20]2[N:26]=[CH:25][N:24]=[C:23]([Cl:27])[C:21]=2[N:22]=1.O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([NH:5][C:19]2[C:20]3[N:26]=[CH:25][N:24]=[C:23]([Cl:27])[C:21]=3[N:22]=[C:17]([Cl:16])[N:18]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Clc1nc(Cl)c2ncnc(Cl)c2n1
Reactant: Cc1cccc(N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cccc(Nc2nc(Cl)nc3c(Cl)ncnc23)c1
Reaction time: 1.5 h

Procedure:
0.45 g of 3-methylaniline and 0.42 g of triethylamine are added to 1.0 g of 2,4,8-trichloro-pyrimido[5,4-d]pyrimidine in 20 ml of methylene chloride at 0° to -10° C. and the mixture is stirred at this temperature for 1.5 hours. Water is then added and the organic phase is separated off, dried and concentrated. The residue is purified by chromatography over an aluminium oxide column with petroleum ether/ethyl acetate (10:2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=O.CN.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:23][CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 47.5 %

Procedure:
Under a nitrogen atmosphere, a suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid, 6.0 g (0.021 mole) and 1,1'-carbonyldiimidazole (3.39 g, 0.021 mole) in tetrahydrofuran (150 ml) was refluxed, with stirring, for 2.5 hrs. The mixture was cooled to room temperature and a solution of 3.6 g (0.116 mole) of monomethylamine in tetrahydrofuran (60 ml) was added dropwise and the reaction mixture was stirred at room temperature overnight. The tetrahydrofuran was evaporated and the residue was triturated in water (150 ml). The solid was filtered and rinsed with water. The solid was dissolved in hot isopropyl alcohol, treated with charcoal, filtered, and allowed to cool. Solid formed, and water was added to precipitate more. The solid was filtered and dried under vacuum to give 3.0 g (47.5%) of title compound, mp 238°-238.5° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1.[H][H]>[Pd].C(OCC)(=O)C>[CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=1
Reactant: CC(C)CCOc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)CCOc1ccc(N)cc1
Reaction time: 4 h
Yield: 99.8 %

Procedure:
5% Palladium on charcoal (100 mg) was added in one portion to a stirred solution of 1-[(3-methylbutyl)oxy]4-nitrobenzene (intermediate 4, 2.00 g, 9.56 mmol) in ethyl acetate (40 mL) at room temperature under a nitrogen atmosphere. The nitrogen was replaced with hydrogen and stirring was continued for 4 h. The hydrogen was replaced with nitrogen then the crude reaction mixture was filtered through a plug of celite. The solute was evaporated to dryness to give the title compound as a colourless oil (1.71 g, 100%) which was used without purification. LC/MS: 2.29 min; z/e 180, calcd (M+1) 180. 1H NMR (400 MHz; CDCl3): 0.95 (6H), 1.65 (2H), 1.85 (1H), 3.10 (2H), 3.90 (2H), 6.65 (2H), 6.75 (2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[O:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][N:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[N:19]1>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:17][N:18]1[C:22]([C:2]2[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[O:5][CH:6]=2)=[CH:21][CH:20]=[N:19]1
Reactant: COC(=O)c1cc(Br)co1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)co1
Reaction time: 1 h
Yield: 26.2 %

Procedure:
A solution of methyl 4-bromo-2-furancarboxylate (470 mg, 2.29 mmol), potassium carbonate (1584 mg, 11.46 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (525 mg, 2.52 mmol)[prepared according to Preparation 7] and bis-(tri-t-butylphosphine)Palladium (0) (58.6 mg, 0.12 mmol) in 1,4-dioxane (9.55 ml) and water (1.9 ml) was stirred at 80° C. After 1 hr, the solution was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (30% EtOAc in hexanes) affording the title compound (124 mg, 0.60 mmol, 26% yield) as a white powder: LCMS (ES) m/e 206 (M+H)+.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13].[C:14]1([CH2:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>ClCCl>[F:5][C:6]1[CH:11]=[C:10]([C:21](=[O:22])[CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:7]=1[O:12][CH3:13]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)Cc2ccccc2)cc1F
Temperature: -10 °C

Procedure:
To a stirring suspension consisting of aluminum trichloride (15.9 g) in dichloromethane (200 mL) cooled to an internal temperature of −10° C. under a nitrogen atmosphere is added 2-fluoroanisole (10 g) over one minute. Phenylacetyl chloride (11.6 mL) is subsequently added to the mixture at a rate that maintained the internal temperature below 0° C. The reaction mixture is allowed to warm to room temperature overnight. Water (100 mL) is cautiously added to the stirring mixture. The layers are subsequently separated and the dichloromethane layer is concentrated under reduced pressure. The concentrate is dissolved in ethyl acetate and washed with water, 1 M sodium hydroxide, water, and brine. The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the synthetic intermediate 1-(3-fluoro-4-methoxy-phenyl)-2-phenyl-ethanone (14.1 g.)
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10]C)=[O:9])=[C:4]([NH:14][C:15](OCC)=O)[CH:3]=1.Br.BrC[C:23]([C:25]1[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=1)=[O:24]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6]([CH2:7][C:8]([OH:10])=[O:9])=[C:15]([C:23]([C:25]3[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=3)=[O:24])[NH:14]2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)OC
Reactant: Cn1ccnc1C(=O)CBr
Agent: Br
Product: Cn1ccnc1C(=O)c1[nH]c2cc(Cl)ccc2c1CC(=O)O

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 31 from methyl trans-4-chloro-2-(ethoxycarbonylamino)cinnamate (Example 31, step 1) and 2-bromoacetyl-1-methylimidazole hydrobromide*.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][NH2:25])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[F:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](Cl)=[O:42])=[CH:36][CH:35]=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][NH:25][C:41](=[O:42])[CH2:40][C:37]1[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=1)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)NN)c(OCc1ccccc1)c2=O
Reactant: O=C(Cl)Cc1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OCCn2c1nc(C(=O)NNC(=O)Cc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.1 %

Procedure:
To stirred solution of 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carbohydrazide (0.170 g, 0.49 mmol) and Et3N (0.14 mL, 1 mmol) in CH2Cl2 (10 mL) was added 2-(4-fluorophenyl)acetyl chloride (69 mL, 0.5 mmol) and the mixture stirred 2 h at room temperature. The reaction mixture was purified by preparative HPLC on a C18 column using water/MeOH containing 0.1% TFA as eluent to afford the title compound (0.078 g, 33% yield) as a white solid. 1HNMR (500 MHz, CDCl3) δ: 9.97 (1H, d, J=7.0 Hz), 8.42 (1H, d, J=6.7 Hz), 7.54 (2H, d, J=6.7 Hz), 7.35-7.27 (5H, m), 7.05 (2H, t, J=8.6 Hz), 5.36 (2H, s), 4.04-3.98 (4H, m), 3.64 (2H, s), 1.60 (6H, s). HRMS (M+H) calcd for C25H26N4O5F: 481.1887. found: 481.1866.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:21])[N:11]([NH:13]C(=O)OC(C)(C)C)[CH:12]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:21])[N:11]([NH2:13])[CH:12]=1
Reactant: Cc1nc(-c2ccccc2F)cn1NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2ccccc2F)cn1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound C2 (17.4 g, 59.7 mmol) in dichloromethane (120 mL) was treated with trifluoroacetic acid (23.0 mL, 299 mmol) and allowed to stir for 18 hours at room temperature. Excess 1 N aqueous sodium hydroxide solution was added, and the mixture was stirred vigorously for 15 minutes. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the product as a brown solid. Yield: 9.95 g, 52.0 mmol, 87%. LCMS m/z 192.3 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1([CH3:30])[C:21]2[C:16](=[CH:17][C:18]([CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:23][OH:24])=[CH:19][CH:20]=2)[O:15][CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl>[CH3:11][C:12]1([CH3:30])[C:21]2[C:16](=[CH:17][C:18]([CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:23]=[O:24])=[CH:19][CH:20]=2)[O:15][CH2:14][CH2:13]1
Reactant: CCCCCC(CO)c1ccc2c(c1)OCCC2(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC(C=O)c1ccc2c(c1)OCCC2(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 73.8 %

Procedure:
To a solution of oxalyl chloride (0.15 mL) in 9 mL of dichloromethane at −78° C. was added 0.19 mL of DMSO. The mixture was stirred at −78° C. for 5 minutes and then a solution of 2-(4,4-dimethyl-chroman-7-yl)-heptan-1-ol (0.22 g, 0.79 mmole, from Example 1) in 3 mL of dichloromethane was added. The mixture was stirred at −78° C. for 15 minutes then 0.56 mL of triethylamine was added. Stirring was continued at −78° C. for another 15 minutes then at room temperature for two hours. The reaction mixture was quenched by the addition of 20 mL of water, extracted with three 20 mL portions of dichloromethane and the combined organic extracts were washed with two 20 mL portions of water and 20 mL of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by flash chromatography (SiO2, 10% ethyl acetate in hexanes) to afford 0.16 g of 2-(4,4-dimethyl-chroman-7-yl)-heptanal as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[C:4](=[O:35])[C:5]1[CH:10]=[CH:9][C:8]([C@H:11]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25](=[O:34])[CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:19]=2)[N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].NC1C=C(C(C2C=CC(C(N(CC)CC)=O)=CC=2)N2CCN(C(OC(C)(C)C)=O)CC2)C=CC=1>>[CH2:36]([N:3]([CH2:1][CH3:2])[C:4](=[O:35])[C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25](=[O:34])[CH2:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:19]=2)[N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:37]
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(NC(=O)CCc3ccccc3)c2)N2CCNCC2)cc1
Agent: CCN(CC)C(=O)c1ccc(C(c2cccc(N)c2)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(NC(=O)CCc3ccccc3)c2)N2CCNCC2)cc1

Procedure:
Synthesized according to the method used for COMPOUND 41 except that INTERMEDIATE 5a was used. The residue was purified by flash chromatography, eluting 25% methanol in dichloromethane, rising to 40% methanol in dichloromethane. The product was converted to the hydrochloride salt using 2M HCl in diethyl ether to give COMPOUND 65 as a colourless solid. Purity (HPLC): >99%; Optical purity (Chiral HPLC): >99%; 1H NMR (400 MHz, CD3OD) 1.06 (t, J=6.64 Hz, 3H), 1.19 (t, J=6.88 Hz, 3H), 2.61 (t, J=7.66 Hz, 2H), 2.56-2.67 (m, 4H), 2.95 (t, J=7.66 Hz, 2H), 3.18-3.26 (m, 6H), 3.45-3.53 (m, 2H), 4.41 (s, 1H), 7.13-7.16 (m, 2H), 7.19-7.24 (m, 6H), 7.30 (d, J=8.30 Hz, 2H), 7.52 (d, J=8.20 Hz, 2H), Found: C, 61.14; H, 6.86; N, 9.10. C31H38N4O2×2.9HCl×0.3H2O has C, 61.06; H, 6.86; N, 9.19%. [a]D20=−0.96 deg [c 0.73, MeOH].
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][C:4]=2[CH:3]=[C:2]1[C:17]([O:19]CC)=[O:18].[OH-].[Na+]>C(O)C>[C:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][C:9]2[NH:1][C:2]([C:17]([OH:19])=[O:18])=[CH:3][C:4]=2[CH2:5]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: CCOC(=O)c1cc2c([nH]1)CCN(C(=O)OC(C)(C)C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2[nH]c(C(=O)O)cc2C1

Procedure:
To a solution of 5-tert-butyl 2-ethyl 1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-2,5-dicarboxylate (1 eq.) obtained in step I of example 212 in ethanol was added NaOH (2.00 eq.) and refluxed for 6 hrs. Reaction mixture was concentrated under reduced pressure and neutralized to get desired compound 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid.
Reaction SMILES: [O:1]=[C:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[CH2:13]1CCN2C(=NCCC2)CC1.IC.Cl>CN(C=O)C>[O:1]=[C:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:13])=[O:4]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)C(=O)Cc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C(=O)Cc1ccccc1
Temperature: 0 °C

Procedure:
2-Oxo-3-phenylpropanoic acid (20 g), DMF (100 ml) and DBU (18.2 ml) were combined at 0° C. under N2 atmosphere, and the mixture was stirred at 0° C. for an hour. Then iodomethane (15.2 ml) was added to the solution at 0° C. The reaction mixture was stirred at r.t. for 3 hours, and poured into 1N—HCl. The mixture was extracted with AcOEt (twice). The combined organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with CHCl3/AcOEt (30:1) as an eluent, and triturated with IPE/n-Hexane to give methyl 2-oxo-3-phenylpropanoate (11.2 g) as a pale yellow wax.
Reaction SMILES: [NH4+:1].C([O-])(=O)C.[Cl:6][C:7]1[CH:12]=[C:11]([N:13]2[C:18](=[O:19])[NH:17][C:16](=[O:20])[CH:15]=[N:14]2)[CH:10]=[CH:9][C:8]=1[C:21]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)([CH3:25])[C:22](Cl)=[O:23]>CC(=O)C>[Cl:6][C:7]1[CH:12]=[C:11]([N:13]2[C:18](=[O:19])[NH:17][C:16](=[O:20])[CH:15]=[N:14]2)[CH:10]=[CH:9][C:8]=1[C:21]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)([CH3:25])[C:22]([NH2:1])=[O:23]
Reactant: CC(C(=O)Cl)(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(C)=O
Product: CC(C(N)=O)(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.4 %

Procedure:
Acetic acid, ammonium salt (3 g) was added at RT to a solution of (±)-2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-α-methylbenzeneacetyl chloride (0.007 mol) in 2-propanone (30 ml). The mixture was stirred at RT for 5 hours. Acetic acid, ammonium salt was filtered off and the solvent was evaporated. The residue was taken up in CH2Cl2, washed with water, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3). The pure fractions were collected and the solvent was evaporated, yielding 1.6 g (57%) of (±)-2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-α-methylbenzeneacetamide (comp. 1.18).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2C=CC=1.C[CH2:40][N:41]=[C:42]=[N:43]CCCN(C)C.Cl.NCC#N.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=1)[CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](=[O:25])[N:41]([C:42]#[N:43])[CH3:40])=[CH:22][CH:21]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(=O)O)cc1)c1ccc(C(C)(C)C)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N#CCN
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C#N)C(=O)c1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 500.8 %

Procedure:
4-{[tert-Butoxycarbonyl-(4-tert-butylphenyl)amino]methyl}benzoic acid (4.1 g, 10.7mmol) was dissolved in DMF (40 ml). Hydroxybenzotriazole (1.59 g, 11.8 mmol) and EDAC (2.25 g, 1.8 mmol) were added and the reaction mixture was stirred at room temperature for 30 min. Aminoacetonitrile hydrochloride (1.38 g, 15 mmol) and diisopropylethylamine (2.55 ml, 15 mmol) were added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (150 ml) and extracted with water (125 ml). The aqueous phase was extracted with ethyl acetate (50 ml). The combined organic phases were washed with hydrochloric acid (0.2 N, 3×50 ml) and a mixture of water and saturated sodium chloride (1:1, 3×50 ml), dried (magnesium sulphate) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (150 g) using ethyl acetate/n-heptane (3:7) as eluent to afford 3.8 g of N-(4-tert-butylphenyl)-N-[4-(cyano-methylcarbamoyl)benzyl]carbamic acid tert-butyl ester.