Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:32])[C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:35][NH2:36]>C(O)C>[CH:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]([N:10]3[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13][N:14]4[C:5]([C:3]([NH:35][NH2:36])=[O:4])=[CH:6][CH:7]=[C:8]4[CH2:9]3)=[O:32])=[CH:21][CH:22]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: NN
Reactant: O=C(c1ccc(C2CCCCC2)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Solvent: CCO
Product: NNC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,2,2-Trichloro-1-[10-cyclohexyl-benzoyl]10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]-1-ethanone of Example 7 (1.3 g) was added to a solution of anhydrous hydrazine (0.24 g) in absolute ethanol (50 mL). After stirring overnight at room temperature, the volatiles were removed in vacuo and the residue extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and filtered through a short column of Magnesol®. Removal of the solvent provided the title compound as a pale yellow amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:29]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30]1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[C:27]([C:31]3[CH:32]=[CH:33][S:29][CH:30]=3)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccsc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Cc2ccc(I)cc2)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Cc2ccccc2-c2ccsc2)cc1
Yield: 72.3 %

Procedure:
Followed the same procedure as that of step 1 in Example 107 with the use of (S)-2-[4-(4-iodo-benzyl)phenoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (2000 mg, 4 mmol), thiophene-3-boronic acid (1200 mg, 8 mmol) to afford the title product, (1300 mg, 74%); 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.79-2.08 (m, 4H), 3.26-3.44 (m, 2H), 3.70-3.95 (m, 1H), 3.93 (s, 2H), 4.03-4.18 (m, 2H), 6.82-6.88 (m, 2H), 7.10 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 7.35-7.41 (m, 3H), 7.50 (d, J=8.0 Hz, 2H):
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:29][C:30]1[N:34]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:32][N:31]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][N:22]([CH2:29][C:30]5[N:34]=[C:33]([C:35]6[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=6)[O:32][N:31]=5)[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Reactant: ClCc1noc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CN(Cc3noc(-c4ccccc4)n3)C2=O)CC1
Yield: 67 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride and 3-(chloromethyl)-5-phenyl-1,2,4-oxadiazole, to give the desired product as a brown oil (67%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([S:20]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][O:31]C)[CH2:25][CH2:24]2)(=[O:22])=[O:21])[C:14]=1[OH:33])=[O:11].FC(F)(F)C(O)=O.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([S:20]([N:23]2[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][OH:31])[CH2:27][CH2:28]2)(=[O:22])=[O:21])[C:14]=1[OH:33])=[O:11]
Reactant: COCCN1CCN(S(=O)(=O)c2c(Cl)ccc(NC(=O)Nc3cccc(F)c3Cl)c2O)CC1
Agent: BrB(Br)Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(S(=O)(=O)N2CCN(CCO)CC2)c1O)Nc1cccc(F)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
Under Ar, to the suspension of 2c trifluoroacetic acid salt (100 mg, 0.16 mmol) in 3 mL of dichloromethane was added boron tribromide (0.63 mL, 0.63 mmol). The mixture was stirred at room temperature overnight. After quenching with methanol, solid produced. The mixture was filtered, solid was collected. Purification upon Gilson HPLC, eluting with acetonitrile/water/0.1% TFA (10/90, v/v to 90/10, v/v, over 10 min) yielding 66 mg (76%) of the title compound 2d. LC-MS (m/z) 507.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][C:3]=1[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][S:7][C:6]1=[O:11].[OH-:20].[Na+]>C1COCC1>[C:16]([C:13]1[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([CH2:4][CH:5]([CH2:10][CH2:9][CH2:8][SH:7])[C:6]([OH:11])=[O:20])[CH:12]=1)([OH:18])=[O:17]
Reactant: COC(=O)c1ccc(Cl)c(CC2CCCSC2=O)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cl)c(CC(CCCS)C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
A solution of 3-(2-Chloro-5-methoxycarbonylbenzyl)-tetrahydrothiopyrane-2-one IV (9.26 g, 31.0 mmol) in THF (70 mL) was purged for 15 minutes with nitrogen. A degassed aqueous sodium hydroxide solution (2.2 M, 70 mL, 154 mmol) was added to the solution and the mixture was stirred at room temperature under nitrogen overnight. The reaction mixture was washed with ether, acidified by 3N HCl at 0° C., and extracted with ether. The extract was dried over MgSO4 and concentrated to afford 5-carboxy-2-chloro-alpha-(3-mercaptopropyl) benzenepropanoic acid 10 (8.42 g, 27.8 mmol, 90%) as a white solid: 1H NMR (CD3OD) δ 1.50-1.80 (m, 4H), 2.35-2.50 (m, 2H), 2.65-2.75 (m, 1H), 2.91 (dd, J=6.2, 13.8 Hz, 1H), 2.96 (dd, J=8.8, 13.8 Hz, 1 H), 7.39 (d, J=8.3 Hz, 1H), 7.76 (dd, J=2.0, 8.3 Hz, 1H), 7.86 (d, J=2.0 Hz, 1H); 13C NMR (CD3OD) δ 25.1, 32.5, 33.2, 37.4, 46.8, 130.8, 131.2, 134.0, 139.1, 140.5, 169.2, 178.9. Anal. Calcd for C13H15ClO4S: C, 51.57; H, 4.99; S, 10.59; Cl, 11.71. Found: C, 51.59; H, 4.94; S, 10.43; Cl, 11.80.
Reaction SMILES: COP([CH2:7][C:8]([O:10][CH3:11])=[O:9])(OC)=O.[H-].[Na+].[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C:16](=O)[CH2:15]2>C1COCC1>[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C:16](=[CH:7][C:8]([O:10][CH3:11])=[O:9])[CH2:15]2
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: O=C1CN2CCC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C=C1CN2CCC1CC2
Reaction time: 1 h

Procedure:
To a solution of methyl 2-(dimethoxyphosphoryl)acetate (2.70 g, 14.8 mmol) in THF (200 ml) at 0° C. was added NaH [60% dispersion in mineral oil] (600 mg, 15.0 mmol). After 1 h of stirring, quinuclidin-3-one (2.00 g, 12.4 mmol) was added and the resultant mixture was stirred at room temperature for 18 h. The reaction was quenched with 50 ml water at 0° C. and the mixture was extracted with EtOAc. The organic layers were combined and concentrated under reduced pressure to afford crude methyl 2-(quinuclidin-3-ylidene)acetate, which was used in next step without purification (1.2 g, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]=[C:7]2[OH:13].[CH3:14][C:15]([NH2:18])([CH3:17])[CH3:16]>C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:18][C:15]([CH3:17])([CH3:16])[CH3:14])[NH:8][C:7]2=[O:13]
Reactant: Oc1nc(Cl)nc2c(Br)cccc12
Reactant: CC(C)(C)N
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)Nc1nc2c(Br)cccc2c(=O)[nH]1
Temperature: 80 °C
Yield: 56.1 %

Procedure:
A mixture of 8-bromo-2-chloroquinazolin-4-ol (407c, 0.20 g, 0.77 mmol) in 2-methylpropan-2-amine (1.62 mL, 15.42 mmol) was sealed and heated to 80° C. overnight. The reaction was transferred to a microwave vessel and heated to 170° C. for 30 min. The reaction was transferred to a flask with DCM/MeOH and concentrated in vacuo. The material was taken up in DCM/MeOH and adsorbed onto 1.3 g silica gel and dried in vacuo. The material was purified by silica gel chromatography (24 g column) using 0-100% EtOAc/hexanes. The product-containing fractions were concentrated to afford 8-bromo-2-(tert-butylamino)quinazolin-4(3H)-one (408a, 0.128 g, 0.432 mmol, 56% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.59 (1H, s), 7.85-7.90 (2H, m), 7.00 (1H, t, J=7.7 Hz), 6.22 (1H, s), 1.48 (9H, s). m/z (ESI, +ve ion) 296.0/298.0 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([CH:19]=O)[N:15]4[CH3:18])=[C:11]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:10]=3)[C:7]3[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[O:31]1[CH2:36][CH2:35][CH:34]([CH:37]2[CH2:40][NH:39][CH2:38]2)[CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:1]1([C:4]2[N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([CH2:19][N:39]5[CH2:40][CH:37]([CH:34]6[CH2:35][CH2:36][O:31][CH2:32][CH2:33]6)[CH2:38]5)[N:15]4[CH3:18])=[C:11]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:10]=3)[C:7]3[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21
Reactant: C1CC(C2CNC2)CCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(CN2CC(C3CCOCC3)C2)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21
Reaction time: 16 h

Procedure:
A mixture of 2-(2-cyclopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.25 mmol), 3-(tetrahydropyran-4-yl)azetidine (37 mg, 0.26 mmol) and 4 Å powdered molecular sieves (250 mg) in DCE (5 mL) was stirred at room temperature for 5 h before the addition of sodium triacetoxyborohydride (233 mg, 0.92 mmol). The reaction mixture was stirred for 16 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%). The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 499 as an orange solid (76 mg, 57%). LCMS (Method I): RT 2.72 min [M+H]+ 529.3. 1H NMR (CDCl3, 400 MHz): δ 7.93 (d, J=7.6 Hz, 1 H); 7.67 (d, J=7.4 Hz, 1 H); 7.27-7.18 (m, 2 H); 4.36 (m, 4 H); 4.00-3.93 (m, 2 H); 3.88-3.83 (m, 9 H); 3.55 (m, 2 H); 3.37 (m, 2 H); 3.06 (m, 2 H); 2.89-2.81 (m, 1 H); 2.34 (m, 1 H); 1.71 (m, 1 H); 1.54 (m, 2 H); 1.38-1.32 (m, 2 H); 1.22 (m, 2 H) and 1.06 (m, 2 H)
Reaction SMILES: [CH:1]1([CH:6]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(C(CC)(OP([CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])(O)=O)C)C.[Br-].[Li+].C(N(CC)CC)C>C1COCC1>[CH:1]1(/[CH:6]=[CH:16]/[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CC1CCCC1
Reactant: CCC(C)(CC)OP(=O)(O)CC(=O)OCc1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(/C=C/C1CCCC1)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of cyclopentanecaboxaldehyde (0.069 g, 0.70 mmol), benzyl (diethylethyl phosphono)acetate (0.100 g, 0.35 mmol), lithium bromide (0.030 g, 0.35 mmol), and triethylamine (0.049 mL, 0.35 mmol) in THF (1 mL) at room temperature was stirred for 16 hours, quenched with water, stirred for 15 minutes, diluted with ethyl acetate, washed sequentially with pH 7 buffer and brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI) m/e 231 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:19])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:19][C:20](=[O:22])[CH3:21])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCCCC(N)(Cn1cncn1)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCC(Cn1cncn1)(NC(C)=O)c1ccc(Cl)cc1
Yield: 32 %

Procedure:
To a stirred, cooled (0° C.) solution of 0.54 g (1.94 mmols) of [2-(4-chlorophenyl)-1-(1,2,4-triazol-1-yl)-2-hexylamine and 0.02 g (0.15 mmols) of N,N-dimethylaminopyridine in 10 mL of methylene chloride under nitrogen was added dropwise 0.50 mL (5.28 mmols) of acetic anhydride. After 5 days the reaction was quenched with the addition of methanol and the solvents were removed to give a white solid. The solid was dissolved in toluene which was removed under reduced pressure to remove any acetic acid. The resultant solid was recrystaltized from chloroform to give 0.2 g (32%) of white crystals, melting point 178.5°-179° C. 1H-NMR 200 MHz (CDCl3, Me4Si) 0.85 (t, J=7.5 Hz, CH2 -CH3), 1.0-1.4 (m, 4H), 1.8-2.2 (m, 2H), 2.05 (s, COCH3), 4.85 (ABq, J=35.3 Hz, JAB =12.5 Hz, CH2 -N), 5.95 (s, NH), 7.05-7.4 (q, aromatic H), 7.8 (s, CH=N), 7.95 ppm (s, CH=N).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[O:31][C:28]1[CH:29]=[CH:30][C:25]([N:22]2[CH2:23][CH2:24][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:20][CH2:21]2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Oc3cc(Cl)ccc3[N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 89.1 %

Procedure:
A mixture of 4-chloro-2-fluoronitrobenzene (2.63 g, 15 mmols), 4-(4-tert-butoxycarbonylpiperazin-1-yl)phenol (4.18 g, 15 mmols), potassium carbonate (2.07 g, 15 mmols) and N,N-dimethylformamide (50 ml) was stirred at 100° C. for 12 hours. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The residue was purified through silica gel column chromatography to give a crystal of tert-butyl 4-[4-(5-chloro-2-nitrophenoxy)phenyl]piperazine-1-carboxylate (5.8 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C@:10]3([C@@H:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=4[F:22])[C@H:13]([C:23]([NH:25][C:26]4[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=4)[C:29](O)=[O:30])=[O:24])[NH:12][C@H:11]3[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:5]2=[CH:4][CH:3]=1.CC[N:43]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH4+].[Cl-]>>[C:29]([C:28]1[CH:27]=[C:26]([NH:25][C:23]([CH:13]2[NH:12][CH:11]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:10]3([C:5]4[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:9]3=[O:40])[CH:14]2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])=[O:24])[CH:34]=[CH:33][CH:32]=1)(=[O:30])[NH2:43]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cccc(C(=O)O)c2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)Nc2cccc(C(N)=O)c2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 22, rac-3-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-benzoic acid (42 mg, 0.072 mmol) was reacted with EDCI (28 mg, 0.14 mmol), HOBt (19 mg, 0.14 mmol), triethyamine (15 mg, 0.14 mmol), and NH4Cl (38 mg, 0.72 mmol) at 80° C. to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (3-carbamoyl-phenyl)-amide as a light yellow solid (Yield, 25 mg, 60%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][CH2:14]Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(P(N(C)C)(N(C)C)=O)C.[Li]CCCC.[N+:32]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([O-:34])=[O:33]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][CH2:14][CH:35]([N+:32]([O-:34])=[O:33])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1CCBr
Reactant: O=[N+]([O-])Cc1ccccc1
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1CCC(c1ccccc1)[N+](=O)[O-]
Temperature: -2 °C
Reaction time: 0.75 h

Procedure:
To a −78° C. solution of 200 mg (1.460 mmol) 2-(2-bromo-ethyl)-pyrrolidine-1-car boxylic acid tert-butyl ester (CAS: 958026-65-8) in 4.3 ml tetrahydrofuran over mol-sieves and 851.0 ul HMPA, was added drop-wise 1.92 ml (3.064 mmol) n-BuLi (1.6 M in hexane). After 45 minutes at −78° C., a solution of 406.2 mg (1.460 mmol) nitromethyl-benzene in 0.6 ml tetrahydrofuran over mol-sieves was added drop-wise. After 1 hour at −78° C., the reaction mixture was allowed to warm up slowly (during 5 hours) to −2° C. The mixture was then cooled again to −78° C. and quenched at this temperature with 0.4 ml of acetic acid, then with 8 ml saturated ammonium chloride. Back to room temperature, the aqueous phase was extracted 2 times with ethylacetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude yellow oil (993 mg) was purified with flash column chromatography on silica eluting from n-heptane and ethyl acetate (0 to 15%) to provide 242 mg (y: 49.6%) of the title compound as a colorless oil. MS (m/e): 335.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]=[CH2:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18](=[O:32])[C@@H:19]([NH2:31])[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.CN(C)CCCN=C=NCC>CN(C=O)C>[CH3:16][O:17][C:18](=[O:32])[C@@H:19]([NH:31][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH:14]=[CH2:15])[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc2ccccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)OC
Reaction time: 3 h
Yield: 83.4 %

Procedure:
To a solution of 2-(S)-tert-butoxycarbonylamino-pent-4-enoic acid (3.8 g, 18.0 mmol) and 2-(S)-amino-3-naphthalen-2-yl-propionic acid methyl ester (4.1 g, 18.0 mmol) in DMF (40 mL) are added 1-hydroxybenzotriazole (3.1 g, 23.4 mmol), N-methylmorpholine (9.1 g, 90.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (4.5 g, 23.4 mmol) consecutively and the reaction mixture is stirred for 3 hours. The reaction is quenched with aqueous NH4Cl and extracted with ethyl acetate. The extract is dried over Na2SO4, filtered and concentrated in vacuo and the residue purified over silica gel (hexanes/ethyl acetate, 1:1) to afford 6.4 g (84% yield) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH:5]([OH:13])[CH:6]([OH:12])[CH2:7][C:8]([O:10][CH3:11])=[O:9].[CH:15](OCC)(OCC)[O:16][CH2:17][CH3:18]>C1(C)C=CC=CC=1>[CH3:11][O:10][C:8](=[O:9])[CH2:7][CH:6]1[CH:5]([CH2:4][C:3]([O:2][CH3:1])=[O:14])[O:13][CH:15]([O:16][CH2:17][CH3:18])[O:12]1
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)CC(O)C(O)CC(=O)OC
Solvent: Cc1ccccc1
Product: CCOC1OC(CC(=O)OC)C(CC(=O)OC)O1
Yield: 97.5 %

Procedure:
To a solution of 3,4-dihydroxy-hexanedioic acid dimethyl ester (Ex-14A, 8.8 g, 43 mmol) in toluene (65 mL) was added triethyl orthoformate (12.6 g, 85.4 mmol) and the mixture was heated at reflux with a Dean-Stark trap for 24 h. The reaction mixture was then distilled to remove toluene and excess triethyl orthoformate and dried in vacuo to give (2-ethoxy-5-methoxycarbonylmethyl-[1,3]dioxolan-4-yl)-acetic acid methyl ester as a colorless oil (11.0 g, 99%). This material used without further purification. 1H-NMR (300 MHz, CDCl3) δ5.80 (s, 1H),4.41 (q, 1H, J=6.3 Hz), 4.28 (q, 1H, J=6.3 Hz), 3.71 (s, 6H), 3.78 (q, 2H, J=7.2 Hz), 2.83 (dd, 1H, J=9.3, 6.7 Hz), 2.70 (dd, 1H, J=6.7, 3.0 Hz), 1.22 (t, 3H, J=7.2 Hz). HRMS (EI) calcd for C11H18O7 (M−H), 261.0974; found, 261.0970.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.[Cu][C:22]#[N:23].N>CN1CCCC1=O>[OH:20][CH2:19][C:4]1[CH:5]=[N:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[C:2]([CH:3]=1)[C:22]#[N:23]
Reactant: OCc1cnc(Oc2cccc(C(F)(F)F)c2)c(Br)c1
Reactant: N#C[Cu]
Agent: N
Solvent: CN1CCCC1=O
Product: N#Cc1cc(CO)cnc1Oc1cccc(C(F)(F)F)c1
Temperature: 150 °C
Reaction time: 24 h
Yield: 107.2 %

Procedure:
To a solution of (5-bromo-6-(3-(trifluoromethyl)phenoxy)pyridin-3-yl)methanol (530 mg, 1.522 mmol) in N-methyl-2-pyrrolidone (NMP) (5 mL) was added copper(I) cyanide (545 mg, 6.09 mmol). The reaction mixture was stirred at 150° C. for 24 h, then poured into aq. NH3 (100 mL) and extracted with ethyl acetate (100 mL). Separated organic part was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. Purification via flash chromatography with (EtOAc/hexanes: 5% to 80%) afforded the title product (480 mg).
Reaction SMILES: C([O:3][C:4](=[O:11])[CH2:5][NH:6][CH2:7][CH2:8][C:9]#[N:10])C.[CH:12](O)=[O:13].[OH-].[K+].O>C(O)C>[C:9]([CH2:8][CH2:7][N:6]([CH:12]=[O:13])[CH2:5][C:4]([OH:3])=[O:11])#[N:10]
Reactant: CCOC(=O)CNCCC#N
Reactant: O=CO
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#CCCN(C=O)CC(=O)O
Temperature: 0 °C

Procedure:
A mixture of 21.0 g of N-(2-cyanoethyl)-glycine ethyl ester and 18.3 g of formic acid is refluxed for 2 h. After concentration of this mixture underreduced pressure, the residue is taken up in 50 ml of ethanol, and cooled to 0° C.; there is then added dropwise a solution of 25.5 g of potassium hydroxide and 40 ml of water in 80 ml of ethanol. After the reaction solution has warmed up to room temperature, the solvent is evaporated off, and the residue is acidified to pH 1 with conc. hydrochloric acid. The mixture is saturated with sodium chloride and subsequently extracted with ethyl acetate. The combined organic extracts are concentrated by evaporation to thus obtain N-(2-cyanoethyl)-N-formylglycine, m.p. 112°-114° C. (compound No. 1.1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH3:14])[CH3:13])[CH3:2].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][N:7]([C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH3:14])[CH3:13])[CH3:2]
Reactant: CCOC(=O)CCNC1CCCC1(C)C
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
A solution of 2.2 g (0.011 mole) of (rac)-3-(2,2-dimethyl-cyclopentylamino)-propanoic acid ethyl ester in 30 mL of water was added dropwise to a solution of 1.94 g (0.01 mole) of 2,4-dichloro-5-nitro-pyrimidine in 30 mL of ethyl ether. At 0 degrees, 2.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-92:8) gave 3.3 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(2,2-dimethyl-cyclopentyl)-amino]-propanoic acid ethyl ester (IV-59).