Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:6]([NH:8][CH2:9][C:10]([O:12]CC)=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[OH-].[Na+].Cl>CO>[NH:1]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[C@H:2]([C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: CCOC(=O)CNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Temperature: 25 °C
Yield: 88.2 %

Procedure:
BOC-Val-Gly-OEt (10 g) was dissolved in 20 ml of methanol and 40 ml of 1 M sodium hydroxide was added thereto under cooling. The mixture was stirred with cooling for 15 minutes and at room temperature for an additional 45 minutes. The pH of the reaction mixture was adjusted to a pH of about 7 with 1 N hydrochloric acid and concentrated in vacuo. Water was then addedto the residue and the mixture was washed with diethyl ether. The pH of thewater layer was adjusted to a pH of about 2 with 1 N hydrochloric acid and the layer was extracted with ethyl acetate. The ethyl acetate layer was washed well with water, dried over magnesium sulfate and concentrated in vacuo. The resultant oily residue was solidified by addition of n-hexane and recrystallized from ethyl acetate-n-hexane to obtain 8.0 g (yield: 89%) of the desired material having a melting point of 101°-104° C.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH:12]2[CH2:14][CH2:13]2)[C:9]2[CH:15]=[C:16]([Br:21])[C:17]([O:19][CH3:20])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.[Cl-].[Na+].O>[Br:21][C:16]1[C:17]([O:19][CH3:20])=[CH:18][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH:12]3[CH2:14][CH2:13]3)[C:9]=2[CH:15]=1
Reactant: COc1cc2c(cc1Br)C(C1CC1)CN(C(=O)C(F)(F)F)CC2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1Br)C(C1CC1)CNCC2
Reaction time: 2 h
Yield: 73 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-1-cyclopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.014 g, 0.037 mmol) in methanol (1 mL) was treated with 15% aqueous NaOH (1 mL), and stirred for 2 hours at 50 C. The product mixture was diluted with brine (10 mL), extracted twice with EtOAc (10 mL), dried with MgSO4, and concentrated to give 0.008 g of a clear oil. 1H NMR (400 MHz, CD3OD) d 7.26 (s, 1H), 6.78 (s, 1H), 3.83 (s, 3H), 3.02 (m, 2H), 2.92 (m, 2H), 2.67 (s, 2H), 0.91 (m, 2H), 0.85 (m, 2H). MS calculated for C13H16BrNO+H: 282, observed: 282.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].C(Br)(Br)(Br)[Br:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P>ClCCl>[Br:21][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)CCCCCCCCCCCCCCO
Reactant: BrC(Br)(Br)Br
Agent: P
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)CCCCCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a solution of methyl 15-hydroxypentadecanoate (4.2 g, 15.6 mmol, 1.0 eq) and carbon tetrabromide (5.7 g, 17.1 mmol, 1.1 eq) in dichloromethane (15 mL) cooled to 0° C., was added triphenyl phosphine (4.3 g, 17.1 mmol, 1.1 eq) in portions over 30 min with vigorous stirring. Upon addition of the phosphine, the colourless solution turned a pale brown colour and was stirred for an additional 2 hours at room temperature. The mixture was concentrated in vacuo (using a rotary evaporator attached to a diaphragm pump) to a brown oil. Hexane (200 mL) was quickly added and the resulting mixture was stirred for 15 minutes. The resultant white precipitate was removed by filtration, and the filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (20:1 hexane:ethyl acetate), yielding methyl 15-bromopentadecanoate (4.6 g, 90%) as a colourless solid.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[N:17][N:18]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH:19]=2)[CH2:10][C@H:9]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([CH3:36])[CH:30]=1)=[O:7].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[F:43][C:40]([F:41])([F:42])[C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:45])[F:44])[CH:39]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[N:17][N:18]([CH2:20][C:21]([OH:23])=[O:22])[CH:19]=2)[CH2:10][C@H:9]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([CH3:36])[CH:30]=1)=[O:7]
Reactant: Cc1ccc(C[C@@H]2CN(Cc3cnn(CC(=O)OC(C)(C)C)c3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C[C@@H]2CN(Cc3cnn(CC(=O)O)c3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Yield: 101.9 %

Procedure:
A solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[[1-(tert-butoxycarbonylmethyl)-1H-pyrazol-4-yl]methyl]-2-(3,4-dimethylbenzyl)piperazine (425 mg) in dichloromethane (2.5 ml) was treated with trifluoroacetic acid (2.5 ml) at room temperature for 1 hour. The mixture was adjusted to pH 7.4 with aqueous sodium bicarbonate solution and evaporated under reduced pressure. The residue was washed with a mixture of dichloromethane and methanol (9:1), and the solution was evaporated under reduced pressure and purified by column chromatography on a silica gel using a mixture of methanol and chloroform (1:9) as eluent and subsequent crystallization from ethyl acetate, isopropyl ether, and hexane to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[[1-(carboxymethyl)-1H-pyrazol-4-yl]methyl]-2-(3,4-dimethylbenzyl)piperazine (395 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[C:12]([CH:30]([CH3:32])[CH3:31])[N:11]=[N:10]1.C(=O)([O-])[O-:34].[K+].[K+].OO>CS(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([NH2:29])=[O:34])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[C:12]([CH:30]([CH3:32])[CH3:31])[N:11]=[N:10]1
Reactant: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc(C(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64171.7 %

Procedure:
To a solution of 4′-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-biphenyl-4-carbonitrile (0.150 mg) in dimethyl sulfoxide (1.2 mL) is added potassium carbonate (0.03 g) and 50% aqueous hydrogen peroxide (0.2 mL). The reaction mixture is allowed to stir at room temperature for 30 minutes. The reaction mixture is diluted with water (55 mL), cooled to 0° C., and filtered. The resulting solids are washed with cold (−78° C.) hexanes. The white solids are allowed to dry under reduced pressure to give the title compound (0.100 g, 64%). 1H NMR (300 MHz, CDCl3) δ 7.9 (d, 2H), 7.6 (d, 2H), 7.5 (m, 5H), 6.9 (d, 2H), 5.0 (s, 2H), 3.3 (p, 1H), 1.5 (d, 6H);′ APCI/MS m/e 481 (M+1), HPLC purity 98.5%.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28]>>[OH:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][NH:24][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: CC(C)(CN)CO
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCC(C)(C)CO)cn1
Yield: 59 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (310 mg, 1.0 mmol) was converted, using 3-amino-2,2-dimethyl-1-propanol instead of methylamine, to the title compound (235 mg, 59%) which was obtained as a white solid. MS: m/e=396.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[C:5]([NH:7][NH:8][C:9](=[O:12])[CH2:10][Cl:11])=O.C(Cl)(OCC1C=CC=CC=1)=O>C(Cl)Cl>[Cl:11][CH2:10][C:9]1[O:12][C:5]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:15]=[C:14]([Cl:16])[CH:13]=2)=[N:7][N:8]=1
Reactant: O=C(CCl)NNC(=O)c1cc(Cl)cc(Cl)c1
Agent: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: ClCc1nnc(-c2cc(Cl)cc(Cl)c2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of compound 6 (1.0 g, 6.36 mmol) and Et3 N (0.96 g, 9.50 mmol) in DCM, was added CbzCl (1.30 g, 7.64 mmol) slowly. The mixture was stirred at ambient temperature overnight. Then TLC showed-compound 6 had disappeared. The mixture was washed with brine, dried with Na2SO4 and concentrated to give crude product 7 as a colorless oil which was used in the next step without any purification.
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:17]=1[O:18][C:19]1[CH:27]=[CH:26][C:25]([C:28]([CH3:32])([CH3:31])[CH2:29][CH3:30])=[CH:24][C:20]=1[C:21]([O-:23])=[O:22].[F:41][C:42]([F:57])([F:56])[C:43]1[CH:44]=[C:45]([N:53]=[C:54]=[O:55])[CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1>N1C=CC=CC=1>[CH:1]([OH:14])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:41][C:42]([F:56])([F:57])[C:43]1[CH:44]=[C:45]([NH:53][C:54](=[O:55])[NH:15][C:16]2[CH:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=[CH:33][C:17]=2[O:18][C:19]2[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:32])[CH2:29][CH3:30])=[CH:24][C:20]=2[C:21]([O-:23])=[O:22])[CH:46]=[C:47]([C:49]([F:52])([F:50])[F:51])[CH:48]=1
Reactant: CCC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2N)c(C(=O)[O-])c1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: OC(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CCC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2NC(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(C(=O)[O-])c1

Procedure:
Benzhydrol-2-(2-amino-4-trifluoromethylphenoxy)-5-(1,1-dimethylpropyl)benzoate (200 mg, 0.0004 mol) and 3,5-di(trifluoromethyl)phenyl isocyanate (300 μL 0.002 mol) were mixed in pyridine, under argon, at room temperature for 16 h. The solvent was evaporated and the residue flash chromatographed (silica gel, ethyl acetate/hexane) to yield the title compound. 1H NMR (250 MHz, CDCl3) δ8.69 (d, 2H), 7.97 (d, 1H), 7.59 (s, 2H), 7.48 (d, 2H), 7.20-7.39 (m, 9H), 7.08 (d, 1H), 6.95 (s, 1H), 6.82 (dd, 2H), 2.05 (d, 1H), 1.64 (dd, 2H), 1.32 (s, 6H), 0.99 (d, 1H), 0.72 (t, 3H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([CH3:14])[C@@H:9]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])C1C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)C>[CH3:14][C@@H:10]1[O:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)[C@H]1[C@H](C)OCCN1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)[C@@H]1NCCO[C@H]1C
Yield: 90.6 %

Procedure:
(2S,3R)-Ethyl 4-benzyl-2-methylmorpholine-3-carboxylate (648 mg, 2.461 mmol), ethanol (5 ml), and Pd(OH)2 (34.6 mg, 0.246 mmol) were combined in a round-bottomed flask. The mixture was vigorously stirred and purged of air using house vacuum and recharged with H2 (three times). The reaction was stirred at 20° C. for 16 h. Transferred to a Parr® shaker and pressurized to 50 psi (345 kPa) of H2 for and shaken for 2 hours. The suspension was filtered over a pad of Celite® and washed with ethanol (5 ml). The filtrate was concentrated in vacuo to afford (2S,3R)-ethyl 2-methylmorpholine-3-carboxylate (386 mg, 2.229 mmol, 91% yield) as yellow crystal upon standing.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([CH3:15])[C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([Cl:16])[N:3]=1.Br[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CCO>[Cl:16][C:4]1[N:3]2[CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:1]=[C:2]2[CH:14]=[C:13]([CH3:15])[C:5]=1[C:6]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Cc1cc(N)nc(Cl)c1C(=O)OC(C)(C)C
Solvent: CCO
Product: CCOC(=O)c1cn2c(Cl)c(C(=O)OC(C)(C)C)c(C)cc2n1
Temperature: 25 °C
Yield: 86.9 %

Procedure:
A solution of tert-butyl 6-amino-2-chloro-4-methylnicotinate (9.4 g, 38.7 mmol, 1 equiv) and ethyl bromopyruvate (6.5 mL, 46.5 mmol, 1.2 equiv) in EtOH (194 mL) was heated to reflux for 2 h. Upon cooling to ambient temperature, the solution was concentrated in vacuo. The residue was triturated in ether and filtered to provide the product (11.4 g, 70%) as a cream colored solid. LCMS (ESI, M+1): 339.1.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][CH2:13][O:14][C:7]3=[CH:6][C:5]=2[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-])=O)([C:15]([O:17]C)=O)[C:3]1=[O:28]>[Pd].CO>[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][CH2:13][O:14][C:7]3=[CH:6][C:5]=2[C:4]2([C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:25][C:15]2=[O:17])[C:3]1=[O:28]
Reactant: COC(=O)C1(c2ccccc2[N+](=O)[O-])C(=O)N(C)c2cc3c(cc21)OCCO3
Agent: [Pd]
Solvent: CO
Product: CN1C(=O)C2(C(=O)Nc3ccccc32)c2cc3c(cc21)OCCO3
Reaction time: 20 h
Yield: 40.2 %

Procedure:
A suspension of methyl 6-methyl-8-(2-nitrophenyl)-7-oxo-2,3,7,8-tetrahydro-6H-[1,4]dioxino[2,3-f]indole-8-carboxylate (0.21 g, 0.54 mmol) and 10% w/w palladium on carbon (0.1 g) in methanol (20 mL) was hydrogenated at 1 atm and at ambient temperature for 20 h. The mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated in vacuo. The residue was subjected to column chromatography to afford 6-methyl-2,3-dihydrospiro[1,4-dioxino[2,3-f]indole-8,3′-indole]-2′,7(1H,6H)-dione (0.07 g, 40%): MS (ES+) m/z 323.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:9])=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:13][CH2:12]1.CS(C)=O>C(OCC)(=O)C>[C:21]([O:20][C:19](=[O:25])[NH:18][CH2:17][C@H:14]1[CH2:13][CH2:12][C@H:11]([NH:10][C:5]2[CH:4]=[C:3]([I:9])[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:16][CH2:15]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: Fc1cc(I)c(Cl)cn1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](N)CC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Nc2cc(I)c(Cl)cn2)CC1
Temperature: 95 °C
Reaction time: 26 h

Procedure:
A mixture of 5-chloro-2-fluoro-4-iodopyridine (517 mg, 2.008 mmol), tert-butyl (trans-4-aminocyclohexyl)methylcarbamate (550 mg, 2.410 mmol), DMSO (2 ml) and TEA (0.336 ml, 2.410 mmol) reaction mixture was stirred at about 95° C. for about 26 hours. The crude reaction mixture mixture was cooled to room temperature, mixed with 125 ml ethyl acetate, washed with saturated sodium bicarbonate (2×), water (3×), saturated salt solution (1×), dried sodium sulfate, filtered and concentrated under reduced pressure to yield a residue. The residue was purified by silica gel chromatography using a 40 g column, eluting from 0%-35% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, yielding 656 mg of titled compound as free base. LCMS (m/z): 466.1 (MH+), retention time=0.93 min.
Reaction SMILES: C(OC(=O)[C@H]1C[C@H](OS(C2C=CC(C)=CC=2)(=O)=O)CN1C(OCC1C=CC=CC=1)=O)C.[C-]#N.[Na+].C(Cl)(Cl)Cl.[CH2:39]([O:41][C:42](=[O:60])[C@@H:43]1[CH2:47][C@H:46]([C:48]#[N:49])[CH2:45][N:44]1[C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH3:40]>CS(C)=O>[CH2:39]([O:41][C:42](=[O:60])[C@H:43]1[CH2:47][C@@H:46]([C:48]#[N:49])[CH2:45][N:44]1[C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH3:40]
Reactant: CCOC(=O)[C@@H]1C[C@H](C#N)CN1C(=O)OCc1ccccc1
Agent: CCOC(=O)[C@H]1C[C@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OCc1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: CCOC(=O)[C@H]1C[C@@H](C#N)CN1C(=O)OCc1ccccc1

Procedure:
The tosylate 12 (2.02 g, 4.53 mmol) was treated with NaCN in DMSO at 80° C. to provide, after workup, the cis nitrile ester (0.88 g, 64%) as a colorless oil: [α]25D +32° (c 1.04, CHCl3); Spectra were identical in all respects to those of the enantiomer N-(benzyloxycarbonyl)-cis-4-cyano-L-proline ethyl ester; HRMS (EI, 22 eV) m/e 302.1255 (302.1266 calcd for C16H18NO4).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.Cl.CN.[CH2:14]([N:16](CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:16][CH3:14])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
To a stirred solution of 6-chloropyridine-3-carbonyl chloride (1.5 g, 8.52 mmol) in DCM (10 ml) at 0° C. was added methylamine hydrochloride (1.73 g, 25.5 mmol) followed by drop wise additional of triethylamine (3.55 ml, 25.5 mmol) over 10 mins. The reaction mixture was stirred at RT for 2 h then quenched by addition of brine (15 ml) and saturated Na2CO3 (5 ml). The organic layer was collected and the aqueous layer extracted with DCM (2×20 ml). The combined organic phase was washed with brine (10 ml), dried (Na2SO4), filtered and evaporated to dryness. Recrystallisation from hot DCM (˜10 ml) provided the title compound (0.995 g, 5.8 mmol, 68%) as white crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:13]([OH:15])=[O:14])([O-:3])=[O:2].[CH:16](OC)(OC)OC.S(=O)(=O)(O)O>CO>[C:13]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH3:16])=[O:8])([OH:15])=[O:14]
Reactant: COC(OC)OC
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1C(=O)O
Temperature: 62 °C
Yield: 94.7 %

Procedure:
3-Nitrophthalic acid [NPA] (660 kg), trimethyl orthoformate (400 kg), concentrated sulfuric acid (115 kg) and methanol (1180 kg) were mixed, and the mixture was stirred with heating (59 to 65° C.) for about 15 to 20 hours under reflux. The reaction solution was cooled, and concentrated at 40° C. or lower under reduced pressure. The residue was cooled to 30° C. or lower, water (900 L) was added, and the mixture was cooled to 5° C. or lower. The precipitated crystals were separated by a centrifuge, washed with water, and dried at 50° C. for about 50 hours to give methyl 2-carboxy-3-nitrobenzoate [MNA] (666.8 kg, 94.7%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][N:7]([CH:18]1[CH2:23][CH2:22][N:21]([CH:24]([CH3:38])[CH2:25][CH2:26][NH:27][C:28]([C:30]2[C:31]([CH3:37])=[N:32][CH:33]=[N:34][C:35]=2[CH3:36])=[O:29])[CH2:20][CH2:19]1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:17])C)=[CH:10][CH:9]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].[CH3:48][N:49](C)[C:50](Cl)=O>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][N:7]([CH:18]1[CH2:23][CH2:22][N:21]([CH:24]([CH3:38])[CH2:25][CH2:26][NH:27][C:28]([C:30]2[C:35]([CH3:36])=[N:34][CH:33]=[N:32][C:31]=2[CH3:37])=[O:29])[CH2:20][CH2:19]1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:17])[N:49]([CH3:50])[CH3:48])=[CH:10][CH:9]=1)#[N:2]
Reactant: CN(C)C(=O)Cl
Reactant: CC(=O)Oc1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(OC(=O)N(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
To a solution of COMPOUND 138 (43 mg, 0.084 mmol) in DMF (1 mL) were added K2CO3 (38 mg, 0.27 mmol) followed by dimethylcarbamoyl chloride (15 μL, 0.16 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 146 as a white solid (27 mg, 53%) following work-up and purification. 1H NMR (CDCl3) δ 0.86-1.13 (m, 2H), 1.02 (d, 3H, J=6.6 Hz), 1.52-1.59 (m, 1H), 1.75-1.79 (m, 3H), 2.16 (t, 1H, J=11.4 Hz), 2.52 (s, 6H), 2.57 (t, 1H, J=10.5 Hz), 2.73-2.88 (m, 3H), 2.98 (s, 3H), 3.05 (s, 3H), 3.28-3.36 (m, 1H), 3.53-3.60 (m, 1H), 3.83-3.87 (m, 1H), 3.87 (s, 2H), 6.53 (d, 2H, J=9.0 Hz), 6.88 (d, 2H, J=9.0 Hz), 7.40-7.45 (m, 1H), 7.50-7.56 (m, 3H), 8.65-8.66 (m, 1H), 8.84 (s, 1H). 13C NMR (CDCl3) δ 14.72, 23.24, 30.49, 31.68, 32.01, 37.66, 37.95, 41.32, 44.90, 49.82, 53.32, 58.14, 61.53, 113.83, 115.91, 120.24, 123.71, 130.55, 131.32, 131.88, 132.15, 132.37, 143.13, 144.63, 146.97, 156.73, 158.83, 164.36, 167.61. ES-MS m/z 584 (M+H). Anal. Calcd. for C33H41N7O3.1.4H2O: C, 65.09; H, 7.25; N, 16.10. Found. C, 65.27; H, 6.88; N, 15.76.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[C:11]([NH:21][C@H:22]([C:34]([N:36]1[CH2:43][CH2:42][CH2:41][C@H:37]1[C:38](O)=[O:39])=[O:35])[CH:23]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:24](=[O:26])[OH:25])([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[N+:7]([C:6]1[CH:5]=[CH:4][C:3]([O:10][C:38](=[O:39])[C@@H:37]2[CH2:41][CH2:42][CH2:43][N:36]2[C:34](=[O:35])[C@H:22]([CH:23]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:24](=[O:25])[OH:26])[NH:21][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:2][CH:1]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(N[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(N[C@H](C(=O)N1CCC[C@H]1C(=O)Oc1ccc([N+](=O)[O-])cc1)C(Cc1ccccc1)C(=O)O)OCc1ccccc1
Reaction time: 2 h

Procedure:
p-Nitrophenol (3.0 Kg) is added to the concentrated ethyl acetate solution of N-carbobenzoxy-β-benzyl-L-aspartyl-L-proline prepared as described in Example II above. The solution is cooled below 5° C. Dicyclohexylcarbodiimide (4.5 Kg) is dissolved in ethyl acetate (10-20 L) and added, maintaining the temperature below 5° C. The solution is stirred at reduced temperature for two hours and then for three hours at 20°-30° C. The dicyclohexylurea is removed by filtration and washed with ethyl acetate (20-30 L). The filtrate is concentrated in vacuo below 60° C. The concentrate is dissolved in hot isopropyl alcohol (50-70 L) and cooled below 25° C. The solids are collected on a filter, rinsed with isopropyl alcohol and dried below 40° C. Melting point=88°-91° C.; specific rotation=-70° to -73° (C=1, ethyl acetate).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.S(C)C.[O:12]=[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]1[C:19]1[CH:26]=[CH:25][C:22]([CH2:23]O)=[CH:21][CH:20]=1>C(Cl)Cl>[O:12]=[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]1[C:19]1[CH:26]=[CH:25][C:22]([CH2:23][Br:8])=[CH:21][CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1ccccn1-c1ccc(CO)cc1
Solvent: ClCCl
Solvent: CSC
Product: O=c1ccccn1-c1ccc(CBr)cc1
Temperature: 0 °C

Procedure:
A solution of NBS (1.59 g, 8.94 mmol) and CH2Cl2 was cooled to 0°. To this solution (under Ar) was added Me2S (10.72 mmol, 0.78 mL) via syringe. This mixture was then cooled to -20° and added to a solution of the benzyl alcohol from Step 2 (1.2 g, 5.96 mmol) in CH2Cl2 via pipette. The reaction mixture was warmed to 0° and stirred for several hours. The residue was poured into ice water and extracted with CH2Cl2 (3×). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to give the title compound as a yellow solid, which will be used in the next step without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]([CH3:7])[CH3:6].[NH:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:17]=[O:18])[C:11]=2[CH:10]=[CH:9]1>>[CH3:6][C:5]([CH3:7])=[CH:4][CH2:3][CH2:2][N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:17]=[O:18])[C:11]=2[CH:10]=[CH:9]1
Reactant: CC(C)=CCCBr
Reactant: O=Cc1cccc2[nH]ccc12
Product: CC(C)=CCCn1ccc2c(C=O)cccc21
Yield: 86.9 %

Procedure:
The same procedures used in Example 7 were repeated except for using 4.59 g of 5-bromo-2-methyl-2-pentene and 2.00 g of indole-4-carbaldehyde as a starting material to give 2.72 g of 1-(4-methyl-3-pentenyl)indole-4-carbaldehyde as a brown oily substance. The yield thereof was found to be 87%.