Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([F:13])[C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[C:19]([F:26])=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][NH2:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([F:13])[C@H:9]1[C:14](=[O:16])[NH:22][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([Cl:17])[C:19]=1[F:26])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1cccc(Cl)c1F
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H]1C(=O)NCc1cccc(Cl)c1F
Reaction time: 20 h

Procedure:
To a solution of (2R,3R)-3-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (45.0 mg, 0.193 mmol) in CH2Cl2 (5 mL) were added successively 3-chloro-2-fluorobenzylamine (0.024 mL, 0.193 mmol), HBTU (110 mg, 0.289 mmol) and DIPEA (0.067 mL, 0.386 mmol), and stirring was continued at RT for 20 h. The reaction mixture was then diluted with CH2Cl2, and the organics were washed with 0.1N aqueous HCl (2×), aqueous NaHCO3 (2×) and brine (1×), dried (Phase separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: EtOAc/c-hexane gradient 1:4 to 1:3) to afford the title compound. TLC Rf (EtOAc/c-hexane 1:1)=0.31; MS (LC/MS): 397 [M+Na]+, 319 [MH−tBu]+, 275 [MH−Boc]+; tR (HPLC conditions b): 4.37 min.
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].[CH3:13][C:14]1([CH3:22])[S:18][CH2:17][NH:16][CH:15]1C(O)=O>C1(C)C=CC=CC=1>[CH3:13][C:14]1([CH3:22])[S:18][CH2:17][N:16]2[CH:15]1[CH2:3][CH:2]1[CH:11]2[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]1
Reactant: CC1(C)SCNC1C(=O)O
Reactant: C=CCN(CC=O)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CC3N(CSC3(C)C)C2C1

Procedure:
8.6 g (50 mmol) of ethyl N-allyl-N-(2-oxoethyl)-carbamate are heated under reflux overnight with 8.1 g (50 mmol) of 5,5-dimethylthiazolidine-4-carboxylic acid in 200 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: Cl.[CH2:2]([NH:4][OH:5])[CH3:3].[O:6]=[C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][O:10][C:9]2[CH:18]=[CH:19][C:20]([CH:22]([CH3:26])[C:23](Cl)=[O:24])=[CH:21][C:8]1=2>N1C=CC=CC=1.O1CCCC1>[O:6]=[C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][O:10][C:9]2[CH:18]=[CH:19][C:20]([CH:22]([CH3:26])[C:23]([N:4]([CH2:2][CH3:3])[OH:5])=[O:24])=[CH:21][C:8]1=2
Reactant: CCNO
Reactant: CC(C(=O)Cl)c1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCN(O)C(=O)C(C)c1ccc2c(c1)C(=O)c1ccccc1CO2
Reaction time: 8 h
Yield: 30.6 %

Procedure:
A stirring solution of 10.14 g of N-ethylhydroxylamine hydrochloride in 350 ml of dry pyridine was chilled and treated dropwise over several minutes with a solution of 8.0 g of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)propionyl chloride in 400 ml of tetrahydrofuran. The solution was allowed to equilibrate to room temperature overnight (16 hours) with continued stirring. The reaction was quenched with 500 ml of water and concentrated in vacuo to remove solvents. The product mixture was partitioned against a total of 500 ml of methylene chloride and 1000 ml of 10% HCl (pH of aqueous layers <1). The organic phase was washed with 500 ml of water, dried (Na2SO4) and concentrated in vacuo to an oil. Thin layer analysis indicated a mixture, which was separated twice via preparative HPLC to give 2.65 g of 2-(6,11-dihydro-11-oxodibenz[b,e]-oxepin-2-yl)-N-ethyl-N-hydroxypropanamide, as an oil.
Reaction SMILES: OS(O)(=O)=O.N[C:7]1[N:18]=[C:10]2[C:11]3[C:16]([CH2:17][N:9]2[N:8]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.N([O-])=O.[Na+].O[PH2]=O.C(N)=O.C(O)(=O)C.N1CCCCC1>O>[N:18]1[CH:7]=[N:8][N:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=12
Reactant: Nc1nc2n(n1)Cc1ccccc1-2
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: O=[PH2]O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: NC=O
Product: c1ccc2c(c1)Cn1ncnc1-2
Temperature: 1.5 °C
Yield: 63 %

Procedure:
To a solution of 2 ml of 10% H2SO4 in 12 ml of water, a solution of 0.69 g (0.004 mole) of 2-amino -5H-s-triazolo[5,1-a]isoindole in 20 ml of water containing 4 ml of 10% H2SO4 is added. Under cooling to a 0-3°C, 8 ml of 0.5 N NaNO2 is dropped into the solution and 7.8 ml of 50% H3PO2 is successively added. After heating to about 40°C for 30 minutes, the mixture is filtered and the filtrate is brought to pH 8 with Na2CO3. The aqueous phase is extracted several times with ethyl ether and the organic extract is evaporated to dryness. The residual crude product is purified by crystallization from isopropyl ether. Yield 0.32 g (50%). M.p. 116- 7°C. The same compound may be obtained by heating at 140°C for 16 hours N-aminophthalimidine with an excess of formamide in the presence of a catalytic amount of piperidine acetate. Yield 63%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25](Cl)=[O:26])[CH2:13]2)[CH3:11])=[N:7][CH:8]=1)#[N:2].CCN(CC)CC.[NH:35]1[CH2:40][CH2:39][CH:38]([C:41]#[N:42])[CH2:37][CH2:36]1>C(Cl)Cl>[C:41]([CH:38]1[CH2:39][CH2:40][N:35]([C:25]([N:14]2[CH2:15][CH:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH:12]([CH:10]([O:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)[CH3:11])[CH2:13]2)=[O:26])[CH2:36][CH2:37]1)#[N:42]
Reactant: CC(Oc1ccc(C#N)cn1)C1CN(C(=O)Cl)CC1c1ccc(Cl)c(Cl)c1
Reactant: N#CC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(C#N)cn1)C1CN(C(=O)N2CCC(C#N)CC2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 69 %

Procedure:
To a stirred solution of (3RS,4SR)-3-[(SR)-1-(5-Cyano-pyridin-2-yloxy)-ethyl]-4-(3,4-dichloro-phenyl)-pyrrolidine-1-carbonyl chloride (30 mg, 0.070 mmol) in CH2Cl2 (4 mL) were added Et3N (0.015 mL, 0.11 mmol) and piperidine-4-carbonitrile (commercially available) (9 mg, 0.084 mmol). Stirring was continued overnight, and the reaction mixture was concentrated under vacuo and directly purified by flash chromatography (SiO2, EtOAc) to yield 24 mg (69%) the title compound as light yellow oil. ES-MS m/e: 498.0 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[Mg]Br.Br[C:14]1[C:15](=[O:31])[NH:16][C:17](=[O:30])[C:18]=1[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[NH:21][CH:20]=1>C1C=CC=CC=1.C(OCC)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:14]2[C:15](=[O:31])[NH:16][C:17](=[O:30])[C:18]=2[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=3)[NH:21][CH:20]=2)=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COc1ccc2[nH]cc(C3=C(Br)C(=O)NC3=O)c2c1
Agent: C[Mg]Br
Solvent: c1ccccc1
Solvent: CCOCC
Product: COc1ccc2[nH]cc(C3=C(c4c[nH]c5ccccc45)C(=O)NC3=O)c2c1
Reaction time: 0.5 h
Yield: 2.7 %

Procedure:
To a suspension of 105 mg of indole in 20 ml of benzene were added 0.6 ml of a 3M solution of methylmagnesium bromide in diethyl ether under nitrogen. The mixture was stirred for 0.5 hour. 100 mg of 3-bromo-4-(5-methoxy-3-indolyl)-1H-pyrrole-2,5-dione were added and the mixture was heated to reflux for 5 days. After cooling the residue was partitioned between dichloromethane and 2M hydrochloric acid. The organic extracts were washed with water, dried and evaporated. The residue was purified on silica gel with 1% methanol in dichloromethane and then with 50% methanol/0.1% trifluoroacetic acid/water on Spherisorb to give 3 mg of 3-(3-indolyl)-4-(5-methoxy-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 280° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][CH2:21][OH:22])[N:15]=[CH:14]3)=[C:6]([CH:9]=1)[C:7]#[N:8].[BH4-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>CO>[NH2:8][CH2:7][C:6]1[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][CH2:21][OH:22])[N:15]=[CH:14]2
Reactant: N#Cc1cc(F)ccc1Oc1ccc2c(cnn2CCO)c1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NCc1cc(F)ccc1Oc1ccc2c(cnn2CCO)c1
Reaction time: 3 h

Procedure:
To a solution of (5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzonitrile (1.0 g, 3.36 mmol) and NiCl26H2O (148 mg, 0.336 mmol) in MeOH (30 mL) was added NaBH4 (636 mg, 16.8 mmol) in portions (2-3), and the reaction was stirred for 3 hours. A solution of saturated Na2CO3 (15 mL) was slowly added and the mixture was stirred for 75 minutes, during which a fine solid formed. The reaction mixture was filtered thru GF/F and the cake was washed with MeOH (20 mL). The filtrate was concentrated to about 15 mL under vacuum, isopropyl acetate (20 mL) was added, and the mixture was concentrated. To the concentrate was added isopropyl acetate (20 mL) and the mixture was stirred for 5 minutes. The phases were separated, and the organic layer was washed with 10% brine (20 mL). Citric acid (0.1 M, 20 mL) was added and the phases were vigorously mixed. The organic layer was removed and the aqueous was washed with isopropyl acetate (20 mL) and EtOAc (20 mL). To the aqueous layer was added isopropyl acetate (20 mL) and 50% NaOH (1 mL) was added. The phases were vigorously mixed and the aqueous was removed. The organic was washed with 10% brine (20 mL), dried over Na2SO4 and concentrated to 850 mg (85%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([NH:18][C@H:19]([C:21]([OH:23])=[O:22])[CH3:20])=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O.N[C@H](C(O[CH2:69][CH2:70][O:71][C:72]1[CH:77]=[CH:76][C:75]([C:78]2[C:83]([C:84]#[N:85])=[C:82]([N:86]3[CH2:90][CH2:89][CH2:88][CH2:87]3)[N:81]=[C:80]([S:91][CH2:92][C:93]3[N:94]=[C:95]([C:98]4[CH:103]=[CH:102][C:101]([Cl:104])=[CH:100][CH:99]=4)[S:96][CH:97]=3)[C:79]=2[C:105]#[N:106])=[CH:74][CH:73]=1)=O)C>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([NH:18][C@H:19]([C:21]([O:23][CH2:69][CH2:70][O:71][C:72]1[CH:73]=[CH:74][C:75]([C:78]2[C:83]([C:84]#[N:85])=[C:82]([N:86]3[CH2:87][CH2:88][CH2:89][CH2:90]3)[N:81]=[C:80]([S:91][CH2:92][C:93]3[N:94]=[C:95]([C:98]4[CH:99]=[CH:100][C:101]([Cl:104])=[CH:102][CH:103]=4)[S:96][CH:97]=3)[C:79]=2[C:105]#[N:106])=[CH:76][CH:77]=1)=[O:22])[CH3:20])=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@H](N)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
257 mg (0.724 mmol) of N-(tert-butoxycarbonyl)-L-histidyl-L-alanine together with 151 mg (0.790 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 151 mg (0.988 mmol) of 1-hydroxy-1H-benzotriazole hydrate and 0.574 ml (3.293 mmol) of N,N-diisopropylethylamine were dissolved in 10 ml of DMF, after which 500 mg (0.659 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl)phenoxy}ethyl L-alaninate trifluoroacetate were added. The reaction mixture was stirred at room temperature overnight and then purified twice by preparative HPLC (acetonitrile/water). This gave 169 mg (28% of theory) of the target compound.
Reaction SMILES: C[O-].[Na+].[CH2:4]([N:6]([CH2:32][CH3:33])[CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18](OC)=[O:19])=[CH:12][C:11]=1[NH:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:5].[OH:34][NH:35]Cl.Cl.CO>CO>[CH2:4]([N:6]([CH2:32][CH3:33])[CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:35][OH:34])=[O:19])=[CH:12][C:11]=1[NH:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:5]
Reactant: CCN(CC)CCSc1ccc(/C=C/C(=O)OC)cc1NCCCc1ccccc1
Reactant: ONCl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCN(CC)CCSc1ccc(/C=C/C(=O)NO)cc1NCCCc1ccccc1
Reaction time: 0.46 h
Yield: 2.2 %

Procedure:
Under stirring, sodium methoxide (30% in methanol; 2.72 g, 15.1 mmol) was added to a methanol (1.6 mL) solution of (E)-methyl 3-(4-(2-(diethylamino)ethylthio)-3-(3-phenylpropylamino)phenyl)acrylate (229 mg, 0.54 mmol) and hydroxylamino hydrochloride (750 mg, 10.8 mmol). The resulted mixture was kept at room temperature for 5-50 min, then a pre-cooled HCl-MeOH solution was added and pH was adjusted to 7. Solvent was removed under reduced pressure. The product was purified by chromatography. 5 mg of (E)-3-(4-(2-(diethylamino)ethylthio)-3-(3-phenylpropylamino)-phenyl)-N-hydroxy-acrylamide (I) was obtained. Yield: 2%. TLC: Rf=0.23 (DCM:MeOH=9:1); HPLC: 93.1%; tR=8.16 min (LC/PDA: Diamonsil C18 5μ 150×4.6 mm, flow rate 1.0 mL/min, grade: 10-100% B, 20 minutes; mobile phase A: H2O; mobile phase B: acetonitrile; UV254); 1HNMR (400 MHz, DMSO-δ6) δ: 10.68 (1H, s), 9.00 (1H, s), 7.17-7.37 (6H, m), 6.77 (1H, d, J=8.0 Hz), 6.72 (1H, s), 6.40 (1H, d, J=16.0 Hz), 5.45 (1H, br), 3.20 (2H, q, J=6.4 Hz), 2.86 (2H, br), 2.69 (3H, t, 8.0 Hz), 1.90 (2H, m, 3.2 Hz), 0.92 (6H, br). MS (m/z): 428 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:19]([CH3:20])[C:14]2[CH2:15][NH:16][CH2:17][CH2:18][C:13]=2[CH:12]=1)=[O:10].CCN(CC)CC.[N+](C1C=CC([O:37][C:38](=O)[O:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH3:49])[CH:41]=2)=CC=1)([O-])=O>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:19]([CH3:20])[C:14]2[CH2:15][N:16]([C:38]([O:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH3:49])[CH:41]=3)=[O:37])[CH2:17][CH2:18][C:13]=2[CH:12]=1)=[O:10]
Reactant: Cn1c(C(=O)Nc2ccccc2N)cc2c1CNCC2
Reactant: COc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1OC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(OC(=O)N2CCc3cc(C(=O)Nc4ccccc4N)n(C)c3C2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2-aminophenyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (1.0 eq) obtained in step IX of example 228, in DMF was added Et3N (3.0 eq.) followed by carbonic acid 3,4-dimethoxy-phenyl ester 4-nitro-phenyl ester (1.0 eq) and stirred at room temperature overnight. Reaction mixture was then quenched with water and extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][C:24](O)=[O:25])=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.C(OCC)(=O)C>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][C:24]([NH:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13])=[O:25])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: NC1CCc2ccccc2NC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)NC1CCc2ccccc2NC1=O
Reaction time: 1 h
Yield: 78.6 %

Procedure:
To a solution of 50 mg (0.28 mmol) 3-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1; Step A) in 2 mL methylene chloride at room temperature was added 56 mg (0.30 mmol, 1.05 eq) 3-(t-butoxycarbonylamino)propanoic acid followed by 0.1 mL diisopropylethylamine (74 mg, 0.57 mmol, 2 eq) and 190 mg (0.43 mmol, 1.5 eq) benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate. After 1 hour at room temperature, the mixture was added to 20 mL ethyl acetate and washed with 1M aqueous citric acid, saturated aqueous sodium bicarbonate and brine. The organic layer was removed, dried over magnesium sulfate, filtered and solvents removed in vacuo. The residue was purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate/hexane (2:1) to afford 76 mg (0.22 mmol, 77%) of product as a white solid. 1H NMR (200 MHz, CDCl3): 1.40 (s,9H), 1.95 (m,1H), 2.40 (t,6 Hz,2H), 2.6-3.0 (m,3H), 3.36 (q,6 Hz, 2H), 4.52 (m,1H), 5.15 (br t,1H), 6.58 (br d,1H), 7.0-7.3 (m,4H), 7.6 (br s,1H). FAB-MS: calc. for C18H25N3O4 347; found 348 (M+H,35%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH:22]([CH2:25][OH:26])[CH2:21][CH2:20]1.C(N(CC)CC)C>ClCCl.O>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH:22]([CH:25]=[O:26])[CH2:21][CH2:20]1
Reactant: OCC1CCC(COC2CCCCO2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=CC1CCC(COC2CCCCO2)CC1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
A solution of 19.04 g of oxalyl chloride in 200 mL of dichloromethane was cooled to −78° C. under a nitrogen atmosphere. To the solution was added dropwise a solution of 11.72 g of dimethyl sulfoxide in 50 mL of dichloromethane over 20 minutes, followed by stirring at −50° C. for 30 minutes. To the reaction mixture was added dropwise a solution of 22.83 g of 4-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]cyclohexanemethanol (trans/cis=6/4) in 50 mL of dichloromethane over 30 minutes, followed by stirring at −50° C. for 40 minutes. To the mixture was added dropwise 30.36 g of triethylamine over 40 minutes. The reaction mixture was stirred at room temperature for 18 hours. To the reaction mixture was added 100 mL of water. An organic layer was separated and then extracted twice with 100 mL of chloroform. The combined organic layer was washed sequentially with 150 mL of a 1 N aqueous hydrochloric acid solution, 150 mL of a saturated aqueous sodium hydrogen carbonate solution and then 150 mL of water, dried over sodium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 20.04 g of 4-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]cyclohexanecarbaldehyde represented by the following formula:
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([CH2:12][CH3:13])[CH:9]2[C:14]([OH:16])=[O:15])C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH2:12]([CH:10]1[CH2:11][NH:8][CH:9]1[C:14]([OH:16])=[O:15])[CH3:13]
Reactant: [H][H]
Reactant: CCC1CN(C(c2ccccc2)c2ccccc2)C1C(=O)O
Agent: [Pd]
Solvent: CCO
Product: CCC1CNC1C(=O)O

Procedure:
8 g of 2B, 100 ml of ethanol and 70 g of 5% palladium charcoal catalyst was hydrogenated at ambient temperature at a hydrogen pressure of between 3 and 4 atomospheres absolute for 10 hours in a Parr apparatus. The resulting mixture was filtered, evaporated to dryness and partitioned between methylene chloride and water. The aqueous phase was separated, evaporated to a low bulk and poured onto a Dowex 8-50 x(H) resin column. Isolation of the imino acid was achieved by eluting the washed column with a 2M ammonia solution. Evaporation of the washings left a white solid which on recrystallization from ethanol deposited an isomer mixture [1α:3β] of 2. Evaporation of the recrystallizing medium left additional 2, having a different isomer composition [2α:3β].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:10]2[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:16].C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH2:25]([CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH2:26][CH2:27][CH3:28]>CCCCCCC.CCOC(C)=O>[CH2:25]([CH:29]1[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][N:5]2[C:10]3[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]2=[O:16])[CH2:31][CH2:30]1)[CH2:26][CH2:27][CH3:28]
Reactant: Cc1cccc2c1N(CCCCl)C(=O)CO2
Reactant: CCCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCC1CCN(CCCN2C(=O)COc3cccc(C)c32)CC1
Yield: 52.7 %

Procedure:
4-(3-Chloropropyl)-5-methyl-4H-benzo[1,4]oxazin-3-one (81MF941b) (1.08 g, 4.48 mmol), K2CO3 (1.24 g, 8.95 mmol), NaI (1.34 g, 8.95 mmol) and 4-butylpiperidine (0.66 g, 4.70 mmol) were mixed according to GP11. CC (SiO2; Heptane/EtOAc 10:1-4) gave the title compound (81MF941x) (0.814 g, 53%). 1H NMR (CDCl3) δ 6.97-6.83 (m, 3H), 4.41 (s, 2H), 4.07 (t, J=7.2 Hz, 2H), 2.67 (d, J=10.8 Hz, 2H), 2.39 (s, 3H), 2.18 (t, J=7.2 Hz, 2H), 1.76 (t, J=10.8 Hz, 2H), 1.69-1.62 (m, 2H), 1.58 (d, J=10.0 Hz, 2H), 1.30-1.06 (m, 9H), 0.87 (t, J=6.8 Hz, 3H); 13C NMR (CDCl3) δ 168.3, 150.0, 129.2, 128.9, 126.8, 124.8, 114.8, 69.5, 55.7, 54.2, 42.6, 36.4, 35.9, 32.6, 29.2, 25.3, 23.0, 20.9, 14.2.
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:13][C:14]1[C:22]([CH3:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:15]=1[C:16](Cl)=[O:17].S(=O)(=O)(O)O>C(O)C.C(Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1.O>[Cl:13][C:14]1[C:22]([CH3:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:15]=1[C:16]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:17]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1c(F)c(F)cc(C(=O)Cl)c1Cl
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)c(C)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Separately, metallic magnesium (0.38 g) is suspended in anhydrous ethanol (0.8 ml) and thereto is added a few drops of carbon tetrachloride. When the reaction is started, a mixture of diethyl malonate (2.3 ml), anhydrous ethanol (1.5 ml) and anhydrous toluene (6 ml) is added portionwise at 50°-60° C. Thereto is added dropwise a solution of the above 2-chloro-4,5-difluoro-3-methylbenzoyl chloride (3.3 g) in anhydrous toluene (5 ml) at 0° C. After the addition, the mixture is stirred at room temperature for 30 minutes. To the reaction mixture is added a mixture of conc. sulfuric acid (0.4 ml) and water (8 ml) and the mixture is extracted with diethyl ether. The extract is dried over magnesium sulfate and the solvent is then distilled off to give diethyl 2-chloro-3-methyl-4,5-difluorobenzoylmalonate (5.1 g).
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O.N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[C:3]([C:2](=[O:1])[CH2:9][CH2:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: O=Cc1ccccc1Cl
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCCC(=O)C(=Cc1ccccc1Cl)C(=O)OCC

Procedure:
A solution of ethyl 3-ketohexanoate (7.5 g), 2-chlorobenzaldehyde (6.6 g), piperidine (1.2 g) and acetic acid (2.25 g) in benzene (50 ml) was heated under reflux for 5 hours, and the reaction mixture was dehydrated using a Dean-Stark condenser. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent (hexane-ethyl acetate (3:1)) to give ethyl 2-(2-chlorophenyl)methylen-3-oxohexanoate ((E)/(Z)=1:1 mixture) as a yellow oil. A solution of ethyl 2-(2-chlorophenyl)methylene-3-oxohexanoate ((E)/(Z)=1:1 mixture, 2.8 g), 3-amino-1-methylpyrazole (0.25 g) and p-toluenesulfonic acid (25 mg) in toluene (5 mL) and dimethylsulfoxide (0.5 mL) was heated under reflux for one day. The solvent was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate (10 mL) and washed with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent (ethyl acetate-methanol (10:1))) to give the title compound as colorless crystals.