Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:32][CH2:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[C:39](=[O:43])[N:38]([CH:44]1[CH2:49][CH2:48][C:47](=[O:50])[NH:46][C:45]1=[O:51])[C:37]2=[O:52].CCOC(C)=O>CN(C)C=O>[O:51]=[C:45]1[CH:44]([N:38]2[C:37](=[O:52])[C:36]3[C:40](=[CH:41][CH:42]=[C:34]([CH2:33][NH:32][C:10](=[O:12])[C:9]4[CH:8]=[CH:7][C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:14][CH:13]=4)[CH:35]=3)[C:39]2=[O:43])[CH2:49][CH2:48][C:47](=[O:50])[NH:46]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 43.4 %

Procedure:
A stirred mixture of 4-ethylsulfonylbenzoic acid (0.64 g, 3.00 mmol) and CDI (0.51 g, 3.15 mmol) in N,N-dimethylformamide (34 mL) was heated to 40° C. under nitrogen. After 2 h, 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione methane sulfonate (1.15 g, 3.00 mmol) was added and the mixture was heated at 40° C. for 2 h. The mixture was cooled to rt and EtOAc (150 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (3×100 mL) then concentrated in vacuo. The crude residue was purified by column chromatography (EtOAc/hexanes, gradient). The product fractions were combined and concentrated to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-ethanesulfonyl-benzamide as a white solid (0.63 g, 44% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.66 min (97.99%); mp: 182-184° C.; 1H NMR (DMSO-d6) δ 1.11 (t, J=7.4 Hz, 3H), 2.00-2.18 (m, 1H), 2.54-2.68 (m, 2H), 2.80-2.99 (m, 1H), 3.35 (q, J=7.4 Hz, 2H), 4.68 (d, J=5.7 Hz, 2H), 5.15 (dd, J=5.3, 12.8 Hz, 1H), 7.77-7.97 (m, 3H), 7.98-8.07 (m, 2H), 8.08-8.25 (m, 2H), 9.49 (t, J=5.8 Hz, 1H), 11.12 (s, 1H); 13C NMR (DMSO-d6) δ 7.06, 21.99, 30.93, 42.77, 49.02, 122.08, 123.58, 128.03, 128.32, 129.90, 131.63, 133.53, 138.50, 140.85, 147.11, 165.24, 166.96, 167.10, 169.82, 172.75; LCMS: MH=484; Anal Calcd for C23H21N3O7S+0.45H2O: C, 56.19; H, 4.49; N, 8.55. Found: C, 55.87; H, 4.47; N, 8.28.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[CH:20]=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[Br:23]Br>ClC(Cl)C>[Br:23][C:20]1[N:12]2[C:13]3[S:17][C:16]([CH2:18][CH3:19])=[CH:15][C:14]=3[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:9][CH2:10][C:11]2=[N:22][N:21]=1
Reactant: BrBr
Reactant: CCc1cc2c(s1)-n1cnnc1CN=C2c1ccccc1Cl
Solvent: CC(Cl)Cl
Product: CCc1cc2c(s1)-n1c(Br)nnc1CN=C2c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(2-Chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (10 g) was dissolved in dichloroethane (100 ml), and bromine (1.7 ml) was added under ice-cooling. The mixture was heated to room temperature, and allowed to stand overnight. The solvent was evaporated, and chloroform was added. The mixture was washed with an aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogencarbonate solution and brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (developing solvent:ethyl acetate-hexane) and crystallized from ethyl acetate to give 3.4 g of 9-bromo-4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine.
Reaction SMILES: O[C:2]([C:4](F)(F)F)=O.[Cl:8][C:9]1[S:21][C:12]2[NH:13][C:14](=[O:20])[C:15]([C:18]#[N:19])=[C:16]([OH:17])[C:11]=2[C:10]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2([OH:36])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:24][CH:23]=1.C(=O)C.CS(C)=O.CO>CC(O)=O>[Cl:8][C:9]1[S:21][C:12]2[NH:13][C:14](=[O:20])[C:15]([C:18]#[N:19])=[C:16]([OH:17])[C:11]=2[C:10]=1[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]2([OH:36])[CH2:35][CH2:34][N:33]([CH2:2][CH3:4])[CH2:32][CH2:31]2)=[CH:26][CH:27]=1
Reactant: N#Cc1c(O)c2c(-c3ccc(OCC4(O)CCNCC4)cc3)c(Cl)sc2[nH]c1=O
Reactant: O=C(O)C(F)(F)F
Agent: CC=O
Solvent: CO
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCN1CCC(O)(COc2ccc(-c3c(Cl)sc4[nH]c(=O)c(C#N)c(O)c34)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-chloro-4-hydroxy-3-{4-[(4-hydroxypiperidin-4-yl)methoxy]phenyl}-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile TFA salt (40 mg, 0.073 mmol), acetaldehyde (0.006 mL, 0.110 mmol), and MS-CNBH3 (88 mg, 0.110 mmol, 1.25 mmol/g loading) in a 1:1 mixture of DMSO/MeOH (1 mL) containing 2% v/v AcOH was shaken in a 1 dram vial at rt for 18 h. The mixture was then filtered and purified by RP-HPLC to give the title compound. MS (ESI) m/e 460 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.24 (t, J=7.29 Hz, 3H), 1.83 (m, 2H), 1.98 (m, 2H), 3.15 (m, 4H), 3.32 (d, J=7.29 Hz, 2H), 3.87 (s, 2H), 5.22 (s, 1H), 6.92 (d, J=8.82 Hz, 2H), 7.20 (d, J=8.82 Hz, 2H), 8.91 (s, 1H), 10.77 (s, 1H).
Reaction SMILES: [C:1](=O)([O:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:9]=1[Cl:16])[O:2]C(C)(C)C.C(Cl)([Cl:20])=O.ClC1C=C(Cl)C(Cl)=CC=1O.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:20][C:1]([O:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:9]=1[Cl:16])=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)OC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Agent: Oc1cc(Cl)c(Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: O=C(Cl)Oc1cc(Cl)c(Cl)cc1Cl

Procedure:
T-Butyl 2,4,5-trichlorophenyl carbonate is a known compound and one method for its preparation is described in an article by W. Broadbent, J. S. Morley and B. E. Stone in the Journal of the Chemical Society (C), 1967 pages 2632-2637. Briefly, in this method a solution of phosgene in toluene is treated with 2,4,5-trichlorophenol at -10° C, followed by addition of dimethylaniline at such a rate that the reaction temperature is maintained at 5°-10° C. The mixture is heated to 20°-24° C and maintained at this temperature for 12 hours. The mixture is cooled by addition of ice and the suspension filtered. From the organic layer in the filtrate, 2,4,5-trichlorophenyl chloroformate is isolated. A solution of the crude 2,4,5-trichlorophenyl chloroformate in methylene chloride is reacted with a solution of t-butanol and quinoline in methylene chloride. The reaction mixture is maintained at 20°-24° C for 12 hours. The mixture is cooled by addition of ice and the suspension is filtered. From the organic layer in the filtrate t-butyl 2,4,5-trichlorophenyl carbonate is isolated.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][C:7]=1[CH2:13][N:14]([CH:16]1[CH2:18][CH2:17]1)[CH3:15])([CH3:3])[CH3:2].C(N(CC)CC)C.O1CCCC1.[CH3:32][Si:33]([C:36]#[CH:37])([CH3:35])[CH3:34]>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH:1]([O:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][C:9]([C:37]#[C:36][Si:33]([CH3:35])([CH3:34])[CH3:32])=[CH:8][C:7]=1[CH2:13][N:14]([CH:16]1[CH2:18][CH2:17]1)[CH3:15])([CH3:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)OC(=O)c1ccc(Br)cc1CN(C)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)OC(=O)c1ccc(C#C[Si](C)(C)C)cc1CN(C)C1CC1

Procedure:
Following General Procedure D and using 4-bromo-2-[(cyclopropyl-methyl-amino)-methyl]-benzoic acid isopropyl ester (Intermediate 120, 1.23 g, 3.68 mmol), triethyl amine (10 mL), tetrahydrofuran (5 mL), copper(I)iodide (0.21 g, 1.1 mmol), trimethylsilyl acetylene (2.1 mL, 14.7 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.77 g, 1.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 7% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil (1.2 g, ˜100%).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[CH2:6][NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH:19](Br)[C:18]2=[O:24])[C:13]([I:25])=[C:12]([C:26]([NH:28][CH2:29][CH:30]([O:36][C:37](=[O:39])[CH3:38])[CH2:31][O:32][C:33](=[O:35])[CH3:34])=[O:27])[C:11]=1[I:40])=[O:9])(=[O:3])[CH3:2]>C(O)(=O)C.C(OCC)(=O)C.C([O-])(=O)C.[Ag+]>[C:1]([O:4][CH:19]1[CH2:20][CH2:21][CH2:22][N:17]([C:14]2[C:13]([I:25])=[C:12]([C:26]([NH:28][CH2:29][CH:30]([O:36][C:37](=[O:39])[CH3:38])[CH2:31][O:32][C:33](=[O:35])[CH3:34])=[O:27])[C:11]([I:40])=[C:10]([C:8]([NH:7][CH2:6][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:41][O:42][C:43](=[O:45])[CH3:44])=[O:9])[C:15]=2[I:16])[C:18]1=[O:24])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(N2CCCC(Br)C2=O)c1I)OC(C)=O
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OCC(CNC(=O)c1c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(N2CCCC(OC(C)=O)C2=O)c1I)OC(C)=O
Temperature: 25 °C

Procedure:
To a solution of N,N'-bis[2,3-bis[acetyloxy)propyl]-5-(3-bromo-2-oxo-1-piperidinyl)-2,4,6-triiodo-1,3-benzenedicarboxamide of example 8b (13.7 g, 13.3 mmol) in glacial acetic acid (400 ml), was added silver acetate (5.6 g, 33.5 mmol) and the mixture was refluxed for 21 hours. After cooling to room temperature, the mixture was filtered, and the filtrate concentrated in vacuo. The residue thus obtained, was redissolved in ethyl acetate (500 ml) and washed successively with water (50 ml), saturated aqueous sodium bicarbonate (3×50 ml) and saturated aqueous sodium chloride (50 ml). After drying over magnesium sulfate, the solvent was evaporated in vacuo and the crude product, that resulted, was purified by column chromatography over silica gel to obtain 5-[3-(acetyloxy)-2-oxo-1-piperidinyl]-N,N'-bis[2,3-bis(acetyloxy)propyl]-2,4,6-triiodo-1,3-benzenedicarboxamide as a white fluffy solid (10.3 g, 83% yield).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:11][S:12](O)(=[O:14])=[O:13]>ClCCl>[CH:9]1[C:10]2[CH2:1][CH2:2][CH2:3][CH2:4][C:5]=2[CH:6]=[CH:7][C:8]=1[S:12]([Cl:11])(=[O:14])=[O:13]
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc2c(c1)CCCC2
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc2c(c1)CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of commercially available 5,6,7,8-tetrahydronaphthalene (1.45 g; 11.3 mmol) in dichloromethane (22.7 mL) cooled to 0° C. was added chlorosulfonic acid (0.9 mL; 13.5 mmol) fast dropwise. The reaction mixture was stirred overnight warming to room temperature gradually. The reaction mixture was used in the next reaction directly without purification.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1([CH2:22][CH2:23][CH3:24])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][C:14]=3[CH3:21])C.[OH-].[Na+]>C1COCC1.CO>[C:19]([C:17]1[CH:16]=[CH:15][C:14]([CH3:21])=[C:13]2[C:18]=1[C:10]1[CH2:9][CH2:8][O:7][C:6]([CH2:22][CH2:23][CH3:24])([CH2:5][C:4]([OH:25])=[O:3])[C:11]=1[NH:12]2)#[N:20]
Reactant: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)ccc(C#N)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC1(CC(=O)O)OCCc2c1[nH]c1c(C)ccc(C#N)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a solution of 5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester (0.959 g, 2.82 mmol) in THF/MeOH (7 mL/15 mL) was added 1 N NaOH (5.64 mL, 5.64 mmol). The reaction mixture was stirred at ambient temperature overnight. Most of THF/MeOH was removed under reduced pressure and the resulting mixture was acidified with 1 N HCl. The mixture was extracted with EtOAc (3×30 mL). The combined organic phase was washed with brine (60 mL), dried over Na2SO4 and concentrated to provide 0.868 g (99%) of title compound as a white solid. 1H NMR (acetone-d6): 300 MHz δ 10.37 (bs, 1H), 7.35 (d, J=7.50 Hz, 1H), 7.03 (d, J=7.50 Hz, 1H), 4.05 (m, 2H), 3.08-2.91 (m, 4H), 2.54 (s, 3H), 2.09 (m, 2H), 1.45 (m, 1H), 1.03 (m, 1H), 0.84 (t, J=7.26 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:7][CH2:6][C@H:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4]1.C(O)C.CCCCCC>CCCCCC.C(O)C>[CH3:1][N:2]([CH3:19])[C@H:3]1[CH2:7][CH2:6][C@H:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4]1
Reactant: CN(C)C1CC[C@H](c2c[nH]c3ccc(C#N)cc23)C1
Solvent: CCCCCC
Solvent: CCO
Product: CN(C)[C@H]1CC[C@H](c2c[nH]c3ccc(C#N)cc23)C1
Reaction time: 0.33 h

Procedure:
The (3R)- and (3S)-diastereomers of (1S)-3-(3-dimethylaminocyclopentyl)-1H-indole-5-carbonitrile were resolved by chiral HPLC on a Chiral Technologies Chiralpak AD column (20μ, 50×500 mm) with a mobile phase of 10% ethanol in hexane-0.1% diethylamine at a flow rate of 75 mL/min. Analytical HPLC retention times refer to the following analytical chiral HPLC method: Chiralpak AD column, 4.6×250 mm with 10 μm packing. Solvents: 10% Ethanol/hexane (0.10% diethyl amine added in hexane as modifier). Flow: 1 mL/min for 20 min. UV detector at 280 nm. Loop volume: 20 μL. Injection load: 20 μL of a 1 mg/mL solution in ethanol.
Reaction SMILES: Cl.[C:2]([S:5][CH2:6][CH:7]=[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[O:11][CH:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]1)(=[NH:4])[NH2:3].NC(N)=S.CS(O)(=O)=O>C(O)(C(F)(F)F)=O>[Br:18][C:15]1[CH:16]=[C:17]2[C:8]3([CH2:7][CH2:6][S:5][C:2]([NH2:3])=[N:4]3)[CH2:9][CH:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:11][C:12]2=[CH:13][CH:14]=1
Reactant: N=C(N)SCC=C1CC(c2ccccc2)Oc2ccc(Br)cc21
Agent: CS(=O)(=O)O
Agent: Cl
Agent: NC(N)=S
Solvent: O=C(O)C(F)(F)F
Product: NC1=NC2(CCS1)CC(c1ccccc1)Oc1ccc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The above mixture of 2-(6-bromo-2-phenylchroman-4-ylidene)ethyl carbamimidothioate HCl salt and thiourea is dissolved in TFA (4 mL) containing MeSO3H (0.4 mL) and stirred at rt for 1 h. The solvent is removed under reduced pressure. The residue is dissolved in ethyl acetate and washed with sat NaHCO3. The separated aqueous phase is extracted with ethyl acetate once and the combined organic phases are washed with brine, and dried over Na2SO4, and filtered. The filtrate is concentrated to give crude 6-bromo-2-phenyl-5′,6′-dihydrospiro[chroman-4,4′-[1,3]thiazin]-2′-amine, which is used for next step without further purification.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:8]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][N:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:28]([N:31](CC)C(C)C)(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.CN.O1CCCC1>CN(C)C=O.O>[CH:1]1([CH2:6][CH:7]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:8]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH:31][CH3:28])=[O:17])=[CH:13][N:12]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)nc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
A solution of 6-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-nicotinic acid (prepared as in Example 46, 125 mg, 0.31 mmol), N,N-diisopropylethylamine (0.10 mL, 0.61 mmol), and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (142 mg, 0.32 mmol) in N,N-dimethylformamide (15 mL) at 25° C. was treated dropwise with a 2.0M solution of methylamine in tetrahydrofuran (0.16 mL, 0.32 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 6-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-N-methyl-nicotinamide (83 mg, 64%) as white solid: mp 229.1-231.7° C.; FAB-HRMS m/e calcd for C21H23Cl2N3O2 (M+H)+ 420.1245, found 420.1247.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:8]=3[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:10][CH:11]([CH2:12][CH3:13])[C:5]2=[N:4][N:3]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:25][C:24]([F:27])([F:26])[C:21]1[CH:22]=[CH:23][C:7]2[N:6]3[C:2]([N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[N:3][N:4]=[C:5]3[CH:11]([CH2:12][CH3:13])[N:10]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:8]=2[CH:20]=1
Reactant: CCC1N=C(c2ccccn2)c2cc(C(F)(F)F)ccc2-n2c(Br)nnc21
Reactant: C1CNCCN1
Product: CCC1N=C(c2ccccn2)c2cc(C(F)(F)F)ccc2-n2c1nnc2N1CCNCC1

Procedure:
In the manner given in Example 1, 1-bromo-8-(trifluoromethyl)-4-ethyl-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with excess of piperazine to give 8-(trifluoromethyl)-4-ethyl-1-piperazino-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH3:24])[C:18]([OH:23])=[C:19]([CH:22]=1)[CH:20]=O>>[Cl:14][C:15]1[CH:22]=[C:19]([CH3:20])[C:18]([OH:23])=[C:17]([CH:16]=1)[CH2:24][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: Cc1cc(Cl)cc(C=O)c1O
Product: Cc1cc(Cl)cc(CN2CCN(c3cc(=O)[nH]cn3)CC2)c1O

Procedure:
6-[4-(5-Chloro-2-hydroxy-3-methyl-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 5-chloro-2-hydroxy-3-methylbenzaldehyde (available from Alfa Aesar, Ward Hill, Mass., USA). 1H NMR (400 MHz, CDCl3) δ 2.19 (s, 3H), 2.58-2.63 (m, 4H), 3.48-3.67 (m, 6H), 5.40 (s, 1H), 6.80-6.81 (m, 1H), 7.03-7.04 (m, 1H), 7.85 (s, 1H), 10.60 (br s, 1H), 12.45 (br s, 1H). Mass spectrum (ES) MH+=335.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:29]=1[NH2:30].C[Al](C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:30][C:29]3[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:28]=3[F:27])=[O:21])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Reactant: Cc1ccc(N)c(F)c1
Agent: C[Al](C)C
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1ccc(C)cc1F
Yield: 38.4 %

Procedure:
The title compound was prepared according to the procedure described in Example-31, by using methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol), 2-fluoro-4-methyl aniline (0.050 g, 0.39 mmol) and trimethyl aluminium (2M solution in toluene) (0.5 mL) to afford 0.047 g of desired product. 1H NMR (DMSO-d6): δ 2.30 (s, 3H), 4.03 (s, 3H), 7.02 (d, J=8.1 Hz, 1H), 7.14 (d, J=11.7 Hz, 1H), 7.51 (t, 1H), 7.58 (d, 1H), 7.65-7.75 (m, 2H), 7.85 (s, 1H), 8.04-8.10 (m, 2H), 10.07 (br s, 1H), 12.65 (br s, 1H); MS (m/z): 469.16 [M−H]−.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][N:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29]([C:36](=[O:41])[C:37]([F:40])([F:39])[F:38])=[CH:28]3)=[CH:20][CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.C(Cl)Cl.Cl>CO>[NH2:7][C:8]([CH2:9][OH:10])([CH2:13][OH:12])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][N:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([C:36](=[O:41])[C:37]([F:38])([F:39])[F:40])=[CH:28]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(CCCn3cc(C(=O)C(F)(F)F)c4ccccc43)cc2)COC(C)(C)OC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: NC(CO)(CO)CCc1ccc(CCCn2cc(C(=O)C(F)(F)F)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of the product of Step E (0.15 g, 0.03 mmol) in a mixture of MeOH, CH2Cl2 and 30% HCl (1 ml, 3 ml, 15 drops respectively) was stirred at room temperature for 3 h. The solvent was distilled and co-distilled with iso-propanol (iPrOH), to give the product (0.01 g; 69%), as colourless solid. 1H-NMR (CDCl3) 1.89-1.92 (m, 2H); 2.12-2.22 (m, 2H); 2.53-2.61 (b, 4H); 3.65-3.75 (m, 4H); 4.13 (tr, 2H, J=7.02 Hz); 6.97 (d, 2H, J=7.71 Hz); 7.07 (d, 2H, J=7.8 Hz); 7.28-7.32 (m, 3H); 7.82 (s, 1H); 8.28-8.31 (m, 1H).
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].Cl.[NH2:17][OH:18].C(N(CC)CC)C>C(O)C>[OH:18][NH:17][C:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]1)=[NH:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C#N)CC1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=N)NO)CC1
Temperature: 25 °C
Yield: 100.7 %

Procedure:
To a solution of tert-butyl 4-cyanopiperazine-1-carboxylate (1.22 g, 5.77 mmol) in anhydrous ethanol (10 mL) were added hydroxylamine hydrochloride (420 mg, 6.04 mmol) and triethyl amine (843 L, 6.06 mmol). The reaction was heated to reflux for 45 min, after which TLC showed complete consumption of the starting material. The mixture was allowed to cool to room temperature overnight, and the resulting precipitate was removed by filtration. The filtrate was concentrated, yielding 1.42 g of a yellow gel that was used directly in the next step.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30](=[O:36])[NH:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)=[O:24])[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:17]=1)=[O:15])[C:10](O)=[O:11])(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][NH:85][CH2:84][C@H:83]1[CH3:88])=[O:81])[CH3:78]>CN(C=O)C>[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][N:85]([C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30](=[O:36])[NH:31][CH2:32][CH:33]3[CH2:35][CH2:34]3)=[O:24])[N:18]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:17]=2)=[O:15])[CH2:8][CH2:7][C:6]([OH:43])=[O:5])[CH2:84][C@H:83]1[CH3:88])=[O:81])[CH3:78]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCC2CC2)n(-c2ccccc2)n1)C(=O)O
Reactant: CCOC(=O)N1CCNC[C@H]1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NCC3CC3)n(-c3ccccc3)n2)C[C@H]1C
Reaction time: 16 h

Procedure:
To a solution of 100 mg (S)-2-({5-[2-((S)-2-(Cyclopropylmethyl-carbamoyl)-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester in 6 ml DMF were added 28 μl DIPEA, 64 mg HATU and 29 mg (R)-2-Methyl-piperazine-1-carboxylic acid ethyl ester. After stirring for 16 h the solution was concentrated, the residue dissolved in 1.5 ml dichloromethane and treated with 560 μl TFA. After stirring for 16 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 65 mg MS (ES+): m/e=696.