Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.Br[CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:26][CH2:27][N:28]4[C:29](=[O:38])[C:30]5[C:31](=[CH:34][CH:35]=[CH:36][CH:37]=5)[C:32]4=[O:33])[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Temperature: 80 °C
Yield: 67.5 %

Procedure:
A solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (290 mg, 0.81 mmol), prepared as described in Example 1, N-(2-bromoethyl)phthalimide (215 mg, 0.84 mmol) and K2CO3 (337 mg, 2.44 mmol) in DMF (3 ml), was heated at 80° C. for 2.5 hours. After this time, the reaction mixture was cooled to RT and diluted with ethyl acetate. The resultant solution was then washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified using silica gel column chromatography using an automated system eluting with a 1:1 mixture of ethyl acetate:hexane to give the title compound, 2-(2-(7,8-bis(4-chlorophenyl)-3-oxo-[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl)ethyl)isoindoline-1,3-dione as a yellow solid (290 mg, 68%). MS M+H=530.
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:22]([CH2:24][NH:25][C:26](=[O:33])[C@@H:27]([OH:32])[CH2:28][CH:29]([CH3:31])[CH3:30])#[N:23].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>ClCCCl>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([CH:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:32][C@@H:27]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:26]([NH:25][CH2:24][C:22]#[N:23])=[O:33])=[N:13][CH:14]=1
Reactant: CC(C)C[C@H](O)C(=O)NCC#N
Reactant: N=C(OC(c1ccccc1)c1ccc(Br)cn1)C(Cl)(Cl)Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCCl
Product: CC(C)C[C@H](OC(c1ccccc1)c1ccc(Br)cn1)C(=O)NCC#N

Procedure:
To a solution of (5-bromopyridin-2-yl)(phenyl)methyl 2,2,2-trichloroethanimidoate from example 53 step 2 (2 g, 4.9 mmol) in 1,2-dichloroethane (50 mL) was added (2S)-N-(cyanomethyl)-2-hydroxy-4-methylpentanamide (830 mg, 4.9 mmol, 1 eg) and camphor sulfonic acid (114 mg, 0.49 mmol, 0.10 eg). The suspension was heated to reflux for 18 hours, then concentrated to dryness. Residue was chromatographed with 25% EtOAc/hexane to yield the title compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].N1C=CC=CC=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[CH:26][CH:25]=[CH:24]3)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: Nc1ccc2ncccc2c1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1ccc(S(=O)(=O)Nc2ccc3ncccc3c2)cc1
Reaction time: 0.08 h
Yield: 92.7 %

Procedure:
To a solution of 4n-propylbenzenesulphonyl chloride (159 mg, 0.728 mmol) in dichloromethane (4 mL) was added pyridine (140 μL, 1.74 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-aminoquinoline (100 mg, 0.694 mmol) was added. The resulting mixture was stirred for 2 h at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a white solid (210 mg, 93%), single spot at Rf 0.71 (ethyl acetate). mp 180.1-180.7° C., HPLC purity 99+% (tR 2.37 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 8.83 (1H, dd, J=4.2, 1.7 Hz), 8.05 (1H, d, J=8.4 Hz), 7.97 (1H, d, J=9.2 Hz), 7.70 (2H, d, J=8.2 Hz), 7.57 (1H, d, J=2.5 Hz), 7.40-7.34 (2H, m), 7.22 (2H, m), 6.85 (1H, s, N—H, 2.57 (2H, t, J=7.2 Hz), 1.57 (2H, sextet, J=7.2 Hz), 0.87 (3H, t, J=7.3 Hz). LCMS: 325.23 (M−). FAB-MS (MH+, C18H18N2O2S): calcd 327.1167, found 327.1167.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C@H:6]2[O:12][C:13]1[CH:26]=[CH:25][C:16]2[C@H:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:18][O:19][C:15]=2[CH:14]=1.Br[C:28]1[C:41]([CH3:42])=[CH:40][C:31]([C:32]([NH:34][CH2:35][C:36]([OH:39])([CH3:38])[CH3:37])=[O:33])=[CH:30][C:29]=1[CH3:43]>>[CH3:24][O:23][C:21](=[O:22])[CH2:20][C@H:17]1[C:16]2[CH:25]=[CH:26][C:13]([O:12][C@H:6]3[C:7]4[C:3](=[C:2]([C:28]5[C:41]([CH3:42])=[CH:40][C:31]([C:32](=[O:33])[NH:34][CH2:35][C:36]([OH:39])([CH3:38])[CH3:37])=[CH:30][C:29]=5[CH3:43])[CH:10]=[CH:9][C:8]=4[F:11])[CH2:4][CH2:5]3)=[CH:14][C:15]=2[O:19][CH2:18]1
Reactant: Cc1cc(C(=O)NCC(C)(C)O)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(C(=O)NCC(C)(C)O)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared following a procedure analogous to that described in Step 5 in the preparation of Intermediate 1, starting from 4-bromo-N-(2-hydroxy-2-methyl-propyl)-3,5-dimethyl-benzamide.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[Cl:18][C:19]1[CH:20]=[C:21]([C:25]([NH:27][CH:28]2[CH2:33][CH:32]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=3)[CH2:31][N:30]([C:44]([N:46]3[CH2:55][CH2:54][C:49]4(OCC[O:50]4)[CH2:48][CH2:47]3)=[O:45])[CH2:29]2)=[O:26])[CH:22]=[CH:23][CH:24]=1>CC(C)=O.O>[Cl:18][C:19]1[CH:20]=[C:21]([C:25]([NH:27][CH:28]2[CH2:33][CH:32]([C:34]3[CH:35]=[CH:36][C:37]([C:40]([F:42])([F:41])[F:43])=[CH:38][CH:39]=3)[CH2:31][N:30]([C:44]([N:46]3[CH2:47][CH2:48][C:49](=[O:50])[CH2:54][CH2:55]3)=[O:45])[CH2:29]2)=[O:26])[CH:22]=[CH:23][CH:24]=1
Reactant: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC3(CC2)OCCO3)C1)c1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCN(C(=O)N2CC(NC(=O)c3cccc(Cl)c3)CC(c3ccc(C(F)(F)F)cc3)C2)CC1

Procedure:
54.6 mg of pyridinium p-toluenesulphonate (0.217 mmol) were added to a solution of the acetal from Example 64A (400 mg, 0.725 mmol) in 15 ml of acetone/water (10:1) and the mixture was stirred under reflux for 3 d, with another 54.6 mg of pyridinium p-toluenesulphonate (0.217 mmol) being added after 24 h and 48 h. The solvent was then removed under reduced pressure, the residue was taken up in water and the mixture was extracted with dichloromethane. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 363 mg (92% of theory)
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl.C(=O)([O-])O.[Na+]>[CH3:15][S:16]([O:1][CH2:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC1(CO)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(C#N)CC1
Reaction time: 1 h
Yield: 88.5 %

Procedure:
A stirred mixture of 1-(hydroxymethyl)cyclopropanecarbonitrile (24.30 mmol, 2.36 g) in dichloromethane (30 mL) was treated with triethylamine (48.6 mmol, 6.83 mL, 4.92 g) and portionwise with methanesulfonyl chloride (31.6 mmol, 2.445 mL, 3.62 g) keeping the reaction mixture at 0° C. The solution was allowed to stir for 1 hour then diluted with saturated sodium hydrogencarbonate and extracted with 10% methanol/dichloromethane (×3). The organic layers were combined and concentrated under reduced pressure to give the intermediate (1-cyanocyclopropyl)methyl methanesulfonate (3.77 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:6]=2[NH:5][N:4]=1.Br[CH2:15][C:16]([NH:18][C:19]1[S:23][C:22]2[CH2:24][CH2:25][CH2:26][CH2:27][C:21]=2[C:20]=1[C:28]([NH2:30])=[O:29])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:13][C:2]([F:1])([F:12])[C:3]1[C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:6]=2[N:5]([CH2:15][C:16]([NH:18][C:19]2[S:23][C:22]3[CH2:24][CH2:25][CH2:26][CH2:27][C:21]=3[C:20]=2[C:28]([NH2:30])=[O:29])=[O:17])[N:4]=1
Reactant: FC(F)(F)c1n[nH]c2ccncc12
Reactant: NC(=O)c1c(NC(=O)CBr)sc2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1c(NC(=O)Cn2nc(C(F)(F)F)c3cnccc32)sc2c1CCCC2
Temperature: 60 °C
Yield: 4.7 %

Procedure:
A mixture of 3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine (20 mg, 0.107 mmol), 2-(2-bromoacetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (33.9 mg, 0.107 mmol) and potassium carbonate (29.5 mg, 0.214 mmol) in DMF (0.5 mL) was heated to 60° C. and this temperature maintained for 2 h. The reaction mixture was allowed to cool to RT, and purified by preparative reverse phase HPLC to give a white solid (2.1 mg, 5 μmol, 4.6%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.Br[C:10]1[C:11](=[O:18])[N:12]([CH3:17])[CH:13]=[C:14]([Br:16])[CH:15]=1>>[Br:16][C:14]1[CH:15]=[C:10]([NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[N:7]=2)[C:11](=[O:18])[N:12]([CH3:17])[CH:13]=1
Reactant: Cc1nccc(N)n1
Reactant: Cn1cc(Br)cc(Br)c1=O
Product: Cc1nccc(Nc2cc(Br)cn(C)c2=O)n1
Yield: 42.6 %

Procedure:
Following the procedures described in Example 196, reaction of 2-methylpyrimidin-4-amine (2.0 g, 18.3 mmol) and 3,5-dibromo-1-methylpyridin-2(1H)-one (9.6 g, 36 mmol) afforded 213a as a yellow solid (2.3 g, 43.4%). MS: [M+H]+ 295. 1H NMR (500 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.78 (s, 1H), 8.26 (d, J=4.5 Hz, 1H), 7.68 (s, 1H), 7.18 (d, J=4.5 Hz, 1H), 3.59 (s, 3H), 2.52 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH:30][C:31]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[S:33][C:32]=1[C:40](O)=[O:41]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:40]([C:32]4[S:33][C:34]([C:36]([F:39])([F:37])[F:38])=[CH:35][C:31]=4[OH:30])=[O:41])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: O=C(O)c1sc(C(F)(F)F)cc1O
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2sc(C(F)(F)F)cc2O)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 3-hydroxy-5-(trifluoromethyl)thiophene-2-carboxylic acid (32 mg, 0.15 mmol).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[C:37]1(=O)[CH2:41][CH2:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>>[CH:37]1([NH:1][CH2:2][C:3]2[N:11]=[C:10]3[C:6]([N:7]=[CH:8][N:9]3[C@H:12]3[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]3)=[C:5]([NH:22][CH2:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:4]=2)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: O=C1CCCC1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC4CCCC4)nc32)[C@H](O)[C@@H]1O
Yield: 40.9 %

Procedure:
The title compound was prepared by a similar method to example 6 from (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (110 mg, 0.22 mmol), cyclopentanone (18 mg, 0.21 mmol), sodium triacetoxyborohydride (70 mg, 0.33 mmol) and acetic acid (0.14 ml, 0.25 mmol) to afford the title compound as a solid (48 mg). MS: 559 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21](OCC(OC)=O)=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:42]([S:49][CH2:50][CH2:51][NH2:52])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH2:42]([S:49][CH2:50][CH2:51][NH:52][C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:6]([O:5][CH3:1])=[O:7])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: NCCSCc1ccccc1
Agent: Cl
Product: COC(=O)c1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)NCCSCc2ccccc2)cc1C(=O)O
Yield: 25.1 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (100 mg, 0.18 mmol) and 2-(benzylsulfanyl)-1-ethanamine hydrochloride (44 mg, 0.22 mmol) according to Method C with HPLC purification to give the title compound (15 mg). 1H-NMR (400 MHz, CD3OD) d 7.76 (s, 1H), 6.97 (d, J=8.6 Hz, 1H), 4.77 (s, 2H), 4.51 (m, 1H), 4.24 (dd, J=5.1 Hz, J=9.3 Hz, 1H), 3.71 (s, 2H), 3.19 (m, 1H), 2.74 (m, 1H), 2.41 (m, 2H), 1.35 (s, 9H); HRMS m/z 679.2542 (calc. of monoisotopic mass for C34H41N3O9S gives 679.2564).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[I:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][CH:10]=1>C(O)(=O)C>[I:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:14][C:5](=[O:7])[CH3:6])=[CH:11][CH:10]=1
Reactant: NCc1ccc(I)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)NCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.34 mL (3.5 mmol) acetic anhydride are added to 750 mg (3.22 mmol) 4-iodo-benzylamine in 15 ml acetic acid and the mixture is stirred at rt for 4 h. After that time, the solvent is evaporated and the residue partitionated between TBME and water. The organic layer is separated, washed with water (1×) and saturated NaHCO3 solution (2×). The organic layer is dried over sodium sulphate and the solvent is evaporated to yield the desired product.
Reaction SMILES: [CH:1]([N:4](CC)[CH:5](C)C)(C)C.[C:10]([O:14][C:15]([NH:17][C@@H:18]([CH:22]([CH3:24])[CH3:23])[C:19](O)=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].Cl.CN(C)CCCN=C=NCC.CNC>C1COCC1.C(Cl)Cl>[CH3:1][N:4]([CH3:5])[C:19]([C@@H:18]([NH:17][C:15](=[O:16])[O:14][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:22]([CH3:24])[CH3:23])=[O:20]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
N,N-Diisopropylethylamine (1.0 mL, 5.74 mmol) was added to a mixture of (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (0.217 g, 1.0 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.211 g, 1.1 mmol) and dimethylamine in THF (2M, 1.0 mL) in methylene chloride (10 mL). The mixture was stirred overnight at RT. The mixture was washed with water, saturated NaHCO3 solution, brine, dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on silica gel to give the desired product (131 mg, 53.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[S:16][CH:17]=3)[C:10](Cl)=[N:9]2)=[CH:5][CH:4]=1.[C-:28]#[N:29].[K+]>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[S:16][CH:17]=3)[C:10]([C:28]#[N:29])=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2cc(-c3csc(Nc4ccccn4)n3)c(Cl)n2)cc1
Reactant: [C-]#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(Cn2cc(-c3csc(Nc4ccccn4)n3)c(C#N)n2)cc1
Yield: 68 %

Procedure:
According to Scheme 13 Step 1: A solution of N-(4-(1-(4-methoxybenzyl)-3-chloro-1H-pyrazol-4-yl)thiazol-2-yl)pyridin-2-amine (75 μmol, 30 mg), KCN (75 μmol, 4.9 mg), Pd(PPh3)4 (7.5 μmol, 8.7 mg) and CuI (75 μmol, 14.4 mg) in acetonitrile (2 mL) was microwaved at 180° C. for 50 minutes under nitrogen. After evaporation of the solvent, the crude residue was dissolved in AcOEt. The organic phase was washed with a saturated aqueous solution of Na2CO3, was dried over MgSO4, was filtered and was concentrated to yield 1-(4-methoxybenzyl)-4-(2-(pyridin-2-ylamino)thiazol-4-yl)-1H-pyrazole-3-carbonitrile (51 μmol, 20 mg, 68%).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH2:14][C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[C:19]1([C:25]2([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:33]3[CH:29]([CH2:30][NH:31][CH2:32]3)[S:28](=[O:35])(=[O:34])[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[C:36]1([C:25]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:33]3[CH:29]([CH2:30][N:31]([C:15](=[O:16])[CH2:14][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:32]3)[S:28](=[O:34])(=[O:35])[CH2:27][CH2:26]2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=S1(=O)CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)N1CC2C(C1)S(=O)(=O)CCC2(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.35 cm3 of triethylamine and a solution of 0.17 cm3 of phenylacetyl chloride in 5 cm3 of dichloromethane are added to a suspension, cooled to 0° C., of 0.46 g of (4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1,1-dioxide hydrochloride in 10 cm3 of dichloromethane. After stirring for 1 hour at 0° C. and then 1 hour at 20° C., the reaction mixture is diluted with 10 cm3 of dichloromethane, washed twice with 30 cm3 of distilled water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is crystallized from 30 cm3 of ethyl ether, the crystals are drained and dried. 0.50 g of (4aRS,7aRS)-4,4-diphenyl-6-phenylacetylperhydrothiopyrano[2,3-c]pyrrole 1,1-dioxide is obtained in the form of white crystals.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][S:26][CH2:27][CH2:28][OH:29])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][S:26][CH2:27][CH2:28][O:29][C:31](=[O:33])[CH3:32])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCCCCSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCCSCCCCCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 87 %

Procedure:
Following a procedure similar to that described in Example 67(c), but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-6-(2-hydroxyethylthio)hexanamide [prepared as described in step (b) above] and acetic anhydride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in an 87% yield.
Reaction SMILES: CI.[Br:3][C:4]1[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=2[CH:23]=1.[C:29]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:3][C:4]1[C:5]([N:24]([CH3:29])[S:25]([CH3:28])(=[O:26])=[O:27])=[CH:6][C:7]2[O:11][C:10]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=2[CH:23]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(Br)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Reaction time: 8 h
Yield: 93.5 %

Procedure:
CH3I (31.6 g, 223 mmol) was added to a mixture of 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (32 g, 74 mmol), K2CO3 (25.6 g, 186 mmol) and KI (246 mg, 1.5 mmol) in DMF (150 mL) under N2 protection. The mixture was stirred at 80˜90° C. overnight. After concentrated in vacuo, the resulting residue was washed with water (200 mL) and EtOAc (200 mL) to provide the product of 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (31.5 g, 94%). 1H-NMR (CDCl3, 400 MHz) δ 8.16 (s, 1H), 7.88˜7.92 (m, 2H), 7.70 (s, 1H), 7.18˜7.23 (m, 2H), 5.78 (br s, 1H), 3.34 (s, 3H), 3.09 (s, 3H), 3.00 (d, J=4.8 Hz, 3H). MS (M+H)+: 455/457.
Reaction SMILES: [CH3:1][C:2]1([C:15](OCC)=[O:16])[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[Li+].[BH4-].Cl>C1COCC1>[OH:16][CH2:15][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1
Reactant: CCOC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(CO)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a cold (−20° C.) solution of 1-tert-butyl 3-ethyl 3-methyl-1,3-piperidinedicarboxylate (2.3 g, 8.48 mmol) in dry THF was added LiBH4 (2M in THF, 10.6 mmol), and the stirring was continued overnight. The reaction mixture was allowed to warm to room temperature. The reaction mixture was cooled by ice water and acidified (pH 5-6) with aqueous 1N HCl. The mixture was concentrated under reduced pressure, then extracted with ethyl acetate. The organic phase was separated, dried over MgSO4, filtered, and evaporated. The crude product was purified by column chromatography on silica gel (hexane:ethyl acetate, 4:1-3:1) to give tertbutyl 3-(hydroxymethyl)-3-methyl-1-piperidinecarboxylate as a colorless oil form (1.5 g, yield; 78%).
Reaction SMILES: F[C:2]1[C:3]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[NH:18]1[CH2:20][CH2:19]1>O1CCOCC1>[N:18]1([C:2]2[C:3]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=2)[C:7]([NH2:9])=[O:8])[CH2:20][CH2:19]1
Reactant: C1CN1
Reactant: CS(=O)(=O)c1cc([N+](=O)[O-])c(C(N)=O)cc1F
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cc([N+](=O)[O-])c(C(N)=O)cc1N1CC1
Yield: 76.1 %

Procedure:
A stirred suspension of 5-fluoro-4-(methysulfonyl)-2-nitrobenzamide (Atwell et al., Anti-Cancer Drug Design, 1996, 11, 553-567) (262 mg, 1.00 mmol) in dry dioxane (15 mL) was treated with aziridine (207 μL, 4.00 mmol) at 35° C. for 1 h. The solvent was then removed under reduced pressure, and the residue was shaken with water and recrystallized from MeOH to give 12 (217 mg, 76%) mp 222-224° C., 1H NMR [(CD3)2SO]δ68.39 (s, 1H, H-3), 8.14 & 7 86 (2xbr s, 2H, CONH2), 7.33 (s, 1H, H-6), 3 41 (s, 3H, CH3), 2.57 (s, 4H, aziridine-H). Anal. Calcd for C10H11N3O5S: C, 42.10,H, 3.89, N, 14.73. Found. C, 45.25;H, 3.71; N, 14 98%.