Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C@H:10]1[C@H:26]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:25]([CH2:35][O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:24][C@H:11]1OC(=O)C1C=CC([N+]([O-])=O)=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([NH:47][C:48]1[N:56]=[C:55]2[C:51]([NH:52][CH:53]=[N:54]2)=[C:50]([NH:57]C(=O)C)[N:49]=1)(=O)C>C(Cl)Cl.C(Cl)CCl>[NH2:47][C:48]1[N:56]=[C:55]2[C:51]([N:52]=[CH:53][N:54]2[C@@H:11]2[O:24][C@H:25]([CH2:35][O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@@H:26]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@@H:10]2[O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[C:50]([NH2:57])[N:49]=1
Reactant: CC(=O)Nc1nc(NC(C)=O)c2[nH]cnc2n1
Reactant: O=C(O[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: Nc1nc(N)c2ncn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1

Procedure:
Dry HCl gas was bubbled into a solution of 2,3,5-tri-O-benzyl-1-O-p-nitrobenzoyl-β-D-arabinofuranose (17 g, 30 mmol) in CH2Cl2 (187 ml) at -10°-0° for 21/2 hr. The precipitated p-nitrobenzoic acid was removed by filtration and washed with CH2Cl2. The CH2Cl2 solution was evaporated in vacuo. The residue, dissolved in 500 ml of ethylene chloride, was added to a mixture of 2.6-diacetamidopurine (7.03 g, 30 mmol) and molecular sieve (Linde 4A, 75 g) in 500 ml of ethylene chloride. This mixture was refluxed until all the chlorosugar was consumed (TLC) (8-11 days). The mixture was then stirred with Celite and filtered. The solid was washed with CHCl3, and the combined filtrates were evaporated to dryness in vacuo. The residue was dissolved in benzene and filtered (to remove unreacted 2,6-diacetamidopurine). The filtrate was again evaporated to dryness in vacuo and the residue dissolved in 100 ml of 1 N methanolic NaOMe. After a 3-hr reflux period, the solution was chilled, neutralized with acetic acid, and refrigerated overnight. The solid that precipitated was removed by filtration, washed with MeOH, and dried in vacuo; yield 5.6 g (34%); mp 159°-161°; TLC homogenous.
Reaction SMILES: [CH3:1][S:2][C:3](=[N:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[CH:30]=[CH2:31]>CC(C)=O>[CH2:31]([N:4]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[C:3](=[N:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[S:2][CH3:1])[CH:30]=[CH2:29]
Reactant: CSC(=Nc1ccccc1)NN1C(=O)c2ccccc2C1=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN(C(=Nc1ccccc1)SC)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To 50 ml of dry acetone, 4.0 g (0.013 m) of the product of Example 2, 2.2 g (0.016 m) of powdered anhydrous potassium carbonate, and 1.4 ml (0.016 m) of allyl bromide was added in succession and the mixture stirred overnight at room temperature. The mixture was poured into 300 ml of ice water with stirring. The aqueous layer was decanted and the residue suspended in fresh ice cold water, stirred and filtered to give a yellow semisolid product. This was purified by stirring in hexane to give a yellow powder 1.8 g (39%), m.p. 78°-81°.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2OS(C(F)(F)F)(=O)=O.[C:21]([C:23]1([OH:33])[CH2:32][CH2:31][C:26]2([O:30][CH2:29][CH2:28][O:27]2)[CH2:25][CH2:24]1)#[CH:22]>CN(C=O)C.C(N(CC)CC)C.O.CCOCC.[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>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C:22]#[C:21][C:23]1([OH:33])[CH2:32][CH2:31][C:26]2([O:27][CH2:28][CH2:29][O:30]2)[CH2:25][CH2:24]1
Reactant: COc1ccc2nccc(OS(=O)(=O)C(F)(F)F)c2n1
Reactant: C#CC1(O)CCC2(CC1)OCCO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1ccc2nccc(C#CC3(O)CCC4(CC3)OCCO4)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A degassed solution of trifluoromethanesulphonic acid 6-methoxy-[1,5]naphthyridin-4-yl ester (986 mg, 3.2 mmol) (WO 03 010138) and 8-ethynyl-1,4-dioxa-spiro[4.5]decan-8-ol (638 mg, 3.5 mmol) (prepared according to J. Chem. Soc. Perk. Trans. 1, 2000, 3382) in DMF (3 ml) was added dropwise to a likewise degassed suspension of copper(I) iodide (50 mg) and PdCl2(PPh3)2 (100 mg) in DMF (2 ml) and triethylamine (3 ml). The reaction mixture was stirred at room temperature for 30 minutes and diluted with water and ether, and the organic phase was washed with water, saturated ammonium chloride solution and saturated sodium chloride solution, dried over MgSO4 and concentrated. The crude product was purified by chromatography on silica gel (hex/EtOAc 1:1, EtOAc).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH2:28]>C(O)C>[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH:28][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1
Reactant: CN(C)CCN
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Solvent: CCO
Product: CCCOc1ccccc1-c1nc2nc(NCCN(C)C)ncc2c(=O)[nH]1

Procedure:
In a similar manner to Example 38, reaction of 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.49 g) and N,N-dimethylethylenediamine (1.24 g) in ethanol (20 ml) yielded the title compound, 0.46 g. m.p. 181-2° C. (recrystallized for methanol).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([CH3:19])[O:7][C@H:6]1[O:20][CH2:21][CH2:22][NH:23]C(=O)OCC1C=CC=CC=1)(=[O:3])[CH3:2]>O.[Pd]>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([CH3:19])[O:7][C@H:6]1[O:20][CH2:21][CH2:22][NH2:23])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@H](OCCNC(=O)OCc2ccccc2)O[C@@H](C)[C@H]1OC(C)=O
Agent: [Pd]
Solvent: O
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@H](OCCN)O[C@@H](C)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl {2-[(2,3,4-tri-O-acetyl-α-L-fucopyranosyl)oxy]ethyl}carbamate (1.0 g, 2.139 mmol) in water (10 mL) was added Pd/C (68 mg, 0.642 mmol). The resulting suspension was degassed and stirred under a balloon of H2 at rt. After 1 hr, the reaction mixture was filtered through a Celite pad and the filtrate was lyophilized to yield the title compound. UPLC Method B: m/e=334.1563 [M+1]; Rt=1.43 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][C:12]1=[O:17])[C:5]([OH:7])=O.[Cl:18][C:19]1[CH:35]=[CH:34][C:22]2[NH:23][C:24]([CH:26]([NH2:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:18][C:19]1[CH:35]=[CH:34][C:22]2[NH:23][C:24]([CH:26]([NH:33][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C:12]4=[O:17])=[C:2]([CH3:1])[CH:3]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:25][C:21]=2[CH:20]=1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1=O
Reactant: NC(c1ccccc1)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC(c2ccccc2)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCOCC1=O

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid, 1-(5-chloro-1H-benzimidazol-2-yl)-1-phenyl-methylamine, TBTU and DIPEA in THF.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([Br:12])=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.N([O-])=O.[Na+].[H+].[B-](F)(F)(F)[F:19]>>[Br:12][C:5]1[CH:4]=[CH:3][C:2]([F:19])=[C:11]2[C:6]=1[CH:7]=[CH:8][N:9]=[CH:10]2
Reactant: F[B-](F)(F)F
Reactant: Nc1ccc(Br)c2ccncc12
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Product: Fc1ccc(Br)c2ccncc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 8-amino-5-bromoisoquinoline in 48% HBF4 (30 mL) at 0° C. was slowly added an aqueous (10 mL) solution of NaNO2 (172 mg, 2.5 mmol). The reaction mixture was stirred at 0° C. for 1 h and was then concentrated under reduced pressure to give a dark residue. The dark residue was heated to 150° C. for 16 h. The resulting dark oil was cooled to 23° C., quenched with ammonium hydroxide and extracted with DCM. The organic solution was concentrated and the resulting dark solid was recrystallized from EtOAc/Hexanes. The desired product (100 mg) was in the mother liquor while the by-product was filtered away as a solid. LCMS showed an m/z of 228.0/226.0 with a retention time of 1.318 min, method [1].
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:41][C@H:42]([OH:52])[C@@H:43]([NH2:51])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][CH:34]=2)=[CH:31][N:30]=[CH:29]1>CN(C=O)C>[S:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:41][C@H:42]([OH:52])[C@@H:43]([NH:51][C:11](=[O:13])[C@H:6]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][CH:34]=2)=[CH:31][N:30]=[CH:29]1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2cncs2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2cncs2)cc1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, 1.36 g (7.2 mmol) of N-methoxycarbonyl-(L)-iso-leucine, 2.59 g (13.5 mmol) of EDC and 1.22 g (9 mmol) of HOBT are dissolved in 20 ml of DMF. After 30 min, 3.79 ml (27 mmol) of TEA are added and a solution of 2.11 g (4.5 mmol) of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-amino-6phenyl-2-azahexane (Example 2b) in 40 ml of DMF are added dropwise. After 3 hours, the reaction mixture is worked up analogously to Example 2c to form the title compound: m.p: 163-166° C.; Anal. (C33H45N5O6S (0.14 H2O) calc. C 61.71, H 7.11, N 10.90, S 4.99, H2O 0.39: found C 61.61, H 7.10, N 10.79, S 4.76, H2O 0.4; HPLC20-100 : tRet =16.0; FAB MS (M+H)+ =640.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=1)=[C:11]2[CH2:25][CH2:26][NH2:27])([CH3:7])[CH3:6])[CH3:2].[CH3:29][S:30]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42][CH:43]=O)=[CH:36][CH:35]=1)(=[O:32])=[O:31]>>[CH2:1]([O:3][C:4](=[O:28])[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:18]=[C:19]([CH3:24])[CH:20]=[C:21]([CH3:23])[CH:22]=1)=[C:11]2[CH2:25][CH2:26][NH:27][CH2:43][CH2:42][CH2:41][CH2:40][C:37]1[CH:38]=[CH:39][C:34]([NH:33][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:35][CH:36]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN)c2c1
Reactant: CS(=O)(=O)Nc1ccc(CCCC=O)cc1
Product: CCOC(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3ccc(NS(C)(=O)=O)cc3)c2c1
Yield: 43 %

Procedure:
The reductive amination reaction of 2-[3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid ethyl ester and 4-[4-(methanesulfonamido)phenyl]butyraldehyde was carried out according to the procedure of Example 14.1 Step B to give the titled compound in 43% yield as a stiff foam; virtually homogenous by TLC in 92.5:7.5 CH2Cl2 --MeOH. 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (PB-NH3 /CI): m/e=604 (M+H).
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=1)=[N:5]2.[H-].[Na+].[CH2:22](Br)[C:23]#[CH:24]>CN(C)C=O>[CH2:24]([N:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:6]2[CH:7]=[CH:8][C:9]3[N:4]([CH:3]=[N:2][N:1]=3)[N:5]=2)[CH:11]=1)[C:17](=[O:19])[CH3:18])[C:23]#[CH:22]
Reactant: CC(=O)Nc1cccc(-c2ccc3nncn3n2)c1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN(C(C)=O)c1cccc(-c2ccc3nncn3n2)c1

Procedure:
A mixture of 3.0 g of N-[3-(1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide, 0.6 g of sodium hydride (50% in oil), 250 ml of dimethylformamide and 1.38 ml of propargyl bromide was reacted as described in Example 5, giving 1.77 g of the desired product as orange crystals, mp 195°-198° C.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)[CH:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)C.C(OC(=O)C1C=CC(NC2N=C(C3C=NC=CC=3)C=CN=2)=CC=1)C>>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[C:16]1[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:24])=[O:3])=[CH:10][CH:9]=2)[N:17]=1
Reactant: CCOC(=O)c1ccc(Nc2nccc(-c3cnccn3)n2)cc1
Agent: CCOC(=O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Product: O=C(O)c1ccc(Nc2nccc(-c3cnccn3)n2)cc1

Procedure:
4-(4-pyrazin-2-yl-pyrimidin-2-ylamino)-benzoic acid ethyl ester prepared in Preparation 12 was used instead of 4-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzoic acid ethyl ester according to the similar procedure to Preparation 19 to give the titled compound as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([NH:15][C:16](=[O:29])[N:17]([CH3:28])[C:18]2=[O:27])=[N:13]1.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([N:15]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])[C:16](=[O:29])[N:17]([CH3:28])[C:18]2=[O:27])=[N:13]1
Reactant: Cc1ccccc1CBr
Reactant: Cn1ccnc1-c1c2c(=O)n(C)c(=O)[nH]c2nn1Cc1c[nH]c2ccc(Cl)cc12
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccccc1Cn1c(=O)n(C)c(=O)c2c(-c3nccn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 2-[(5-chloro-1H-indol-3-yl)methyl]-5-methyl-3-(1-methyl-1H-imidazol-2-yl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione and 1-(bromomethyl)-2-methylbenzene using DBU as a base in DMF at 80° C., Mass: 514.11 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7](=O)[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][OH:34])[CH2:28][CH2:27]1.C([O-])([O-])=O.[Cs+].[Cs+].C(Cl)(Cl)Cl.CO>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:11][C:9]1[CH:10]=[C:2]([O:34][CH2:33][CH2:32][N:29]2[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]2)[CH:3]=[C:4]2[C:8]=1[CH2:7][N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: CN1CCN(CCO)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1cc(OCCN2CCN(C)CC2)cc2c1CN(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 100 °C
Reaction time: 24 h
Yield: 18.5 %

Procedure:
A mixture of 5-bromo-7-methyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.120 g, 0.3 mmol), 2-(4-methyl-piperazin-1yl)-ethanol (0.074 mL, 0.6 mmol), Pd(OAc)2 (0.002 g, 0.006 mmol), and Cs2CO3 (0.195 g, 0.6 mmol) in toluene (3 mL) was stirred at 100° C. for 24 h. Workup and silica gel column chromatography using 5:1 CHCl3-MeOH afforded 7-methyl-5-[2-(4-methyl-piperazin-1-yl)-ethoxy]-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-lone (0.025 g, 18%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.49 (bs, 8H), 2.75 (s, 3H), 2.83 (t, 2H), 4.16 (m, 5H), 4.73 (s, 2H), 6.70 (d, 2H), 7.13-7.37 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]2[S:6][C:7]([C:9]([NH:11][C@H:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]([OH:15])=[O:14])=[O:10])=[CH:8][C:4]=2[CH:3]=1.C(OC(=O)[C@H](CC1C=CC=CC=1)N)(C)(C)C>>[F:1][C:2]1[CH:24]=[CH:23][C:5]2[S:6][C:7]([C:9]([NH:11][C@@H:12]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:13]([OH:15])=[O:14])=[O:10])=[CH:8][C:4]=2[CH:3]=1
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1cc2cc(F)ccc2s1
Agent: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1cc2cc(F)ccc2s1

Procedure:
Following the 10a synthetic method, using B1 (110.65 mg, 0.5 mmol) instead of A1 gave 10b as a white powder; (163.96 mg, 95.5%). [α]D25: +21.8 (c=0.35, CHCl3); 1H-NMR (300 MHz, CDCl3): δ 7.97 (s, 1H), 7.74-7.69 (m, 1H), 7.60 (s, 1H), 7.39-7.16 (m, 7H), 6.86 (d, J=7.5 Hz, 1H), 5.09-5.07 (m, 1H), 3.39-3.22 (m, 2H); 13C NMR (300 MHz, CDCl3): δ 175.03, 162.49, 162.17, 159.27, 139.84, 139.51, 136.42, 135.52, 129.37, 128.76, 127.36, 125.57, 124.05, 115.93, 110.45, 53.87, 37.31; HRMS (ESI): calcd for: C18H14FNO3S [M−H]−=342.0606, obsd [M−H]−=342.0596.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][CH:9]([CH3:41])[CH2:10][C:11]1([C:38]([CH3:40])=[CH2:39])[CH2:16][CH:15]([CH2:17][O:18]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:14][C:12]1=[O:13]>C(Cl)Cl>[CH3:8][CH:9]([CH3:41])[CH2:10][C:11]1([C:38]([CH3:40])=[CH2:39])[CH2:16][CH:15]([CH2:17][OH:18])[O:14][C:12]1=[O:13]
Reactant: C=C(C)C1(CC(C)C)CC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)OC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)C1(CC(C)C)CC(CO)OC1=O
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 70 %

Procedure:
TFA (15.0 mL) is added to a solution of [S-(R*,R*)]-α-(2-methylpropyl)-α-(propen-2-yl)-γ-trityloxymethyl-γ-butyrolactone (2.09 g, 4.60 mmol) and CH2Cl2 (30.0 mL) at 0° C. The solution is stirred for 75 minutes at 0° C. and is concentrated. Aqueous workup (CH2Cl2, MgSO4) and purification by flash chromatography (1:1 hexane:EtOAc) provides 684 mg (70%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1.[ClH:24]>CCOC(C)=O>[ClH:24].[F:23][C:2]([F:1])([F:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2C(F)(F)F)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccccc1C1CCNCC1

Procedure:
The title compound was prepared according to the procedure described in Example 1 (Step e) from tert-butyl 4-[2-(trifluoromethyl)phenyl]piperidine carboxylate (Step b) (1.64 g, 5 mmol) and satd HCl in EtOAc (50 m[). The title compound was obtained as a white solid (1.32 g). MS (ESI, pos. ion) m/z: 230 (M+1); MS (ESI, neg. ion) m/z: 228 (M−1). Calc'd for C12H15CF3N: 265.70.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:15](=[O:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[C:18](OC(=O)C)(=[O:20])[CH3:19].C(N(CC)CC)C.O>ClCCl>[C:18]([O:1][CH2:2][C:3]1[C:8]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[N:7][CH:6]=[C:5]([C:15](=[O:17])[CH3:16])[CH:4]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1cnc(OCC(F)(F)F)c(CO)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCc1cc(C(C)=O)cnc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 85.8 %

Procedure:
A mixture of 1-(5-(hydroxymethyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.16 g, 0.64 mmol, Step-6), acetic anhydride (0.18 mL, 1.91 mmol) and triethylamine (0.44 mL, 3.19) in dichloromethane (4 mL) is stirred at room temperature for 3 days. The reaction mixture is poured into water, extracted with ethyl acetate and dried over sodium sulfate and concentrated in vacuo to give 0.16 g (86% yield) of the title compound as colorless oil. This material is used for the next reaction (Step-8) without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[C:4]([OH:11])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.[C:16](=O)([O-])[O-].[Cs+].[Cs+].IC.O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:16])[C:3]=1[C:12]([F:13])([F:14])[F:15]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1O
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CI
Product: COc1c([N+](=O)[O-])ccc(Cl)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-chloro-6-nitro-2-(trifluoromethyl)phenol (1.00 g, 4.14 mmol), cesium carbonate (4.05 g, 12.4 mmol), and iodomethane (465 μL, 7.45 mmol) in DMF (20 mL) was allowed to stir at rt overnight. The reaction mixture was diluted with EtOAc and poured into water. The mixture was extracted 3 times with EtOAc and the organic solution was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, EtOAc in hexanes) provided the title compound. 1H NMR (300 MHz, CDCl3) δ: 7.90 (d, 1H), 7.40 (d, 1H), and 3.97 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].[C:24]([N:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH2:36][CH2:35][CH:34]2[C:37]([O-])=[O:38])[CH2:29][CH2:28]1)(=[O:26])[CH3:25].[Li+]>>[C:24]([N:27]1[CH2:28][CH2:29][CH:30]([N:33]2[CH2:36][CH2:35][CH:34]2[C:37]([N:14]2[CH2:15][C@H:11]([S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:10])=[O:9])[CH2:12][C@H:13]2[C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])=[O:38])[CH2:31][CH2:32]1)(=[O:26])[CH3:25]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: CC(=O)N1CCC(N2CCC2C(=O)[O-])CC1
Agent: [Li+]
Product: CC(=O)N1CCC(N2CCC2C(=O)N2C[C@H](S(=O)(=O)c3ccccc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)CC1

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H and lithium 1-(1-acetylpiperidin-4-yl)azetidine-2-carboxylate 20F carried out according to the general procedure L yielded (2S,4R)-1-(1-(1-acetylpiperidin-4-yl)azetidine-2-carbonyl)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 1:1 epimers as an off-white solid (93%). MS ISP (m/e): 526.3 (100) [(M+H)]]+.
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](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[CH2:23]([N:26]1[C:30](=[O:31])[C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[S:27]1(=[O:37])=[O:36])[C:24]#[CH:25]>>[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]([C:25]#[C:24][CH2:23][N:26]3[C:30](=[O:31])[C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[S:27]3(=[O:37])=[O:36])[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: C#CCN1C(=O)c2ccccc2S1(=O)=O
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Product: Cc1nnc2n1-c1sc(C#CCN3C(=O)c4ccccc4S3(=O)=O)cc1C(c1ccccc1Cl)=NC2

Procedure:
The title compound was prepared by reacting 4-(2-chlorophenyl)2-iodo-9-methyl-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazepine with 2-(2-propynyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide [ref. R. Granger and J. Giroux, French patent No. 1,273,867 February 1962] as described in Example 37. It was isolated by chromatography and crystallized from ethyl acetate to give colorless crystals with m.p. 232°-234° C.