Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1.N1C=CC=CC=1.Cl>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[CH:12][C:13]([OH:15])=[O:14]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
10 g (70.4 mmol) of 3,4-di-fluoro-benzaldehyde, 14.65 g (2 eq.) of malonic acid, and 0.59 g (0.1 eq.) of piperidine were added to 16.7 g (3 eq.) of pyridine and stirred at room temperature for about 1 hour. After heating it to 80° C., the mixture was stirred for 12 hours. After the reaction, the resulting solution cooled down to room temperature and was slowly added with 1M HCl until it was titrated to about pH 4. The resulting powder was filtered and washed with water, and then dried in a vacuum oven. (Yield: 95%)
Reaction SMILES: C(O[C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:5][C:6]1[CH2:10][CH2:9][CH2:8][N:7]=1)C.F[B-](F)(F)F.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:11]1([C:4](=[N:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:5]=[C:6]2[CH2:10][CH2:9][CH2:8][NH:7]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=CC1=NCCC1)c1ccccc1
Agent: F[B-](F)(F)F
Product: C(=C1CCCN1)C(=Nc1ccccc1)c1ccccc1

Procedure:
By heating the solution of 9.1 g (0.03 mole) of 2-(2-ethoxy-2-phenyl-ethenyl)-1-pyrroline-tetrafluoroborate in 25 ml of aniline for one hour at 80° and processing analogously to Example 1, there is obtained crude 2-[2-phenyl-2-(phenyl-imino)-ethylidene]-pyrrolidine. An addition of 2.8 g of methanesulphonic acid is made to a solution of the crude base in ethyl acetate and the resulting crystals are filtered off. The product thus obtained is 2-[phenyl-2-(phenylimino)-ethylidene]-pyrrolidine-(1:1)-methanesulphonate, m.p. 193°-194° (decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2.[Cl:19][C:20]1[C:21]([O:31][CH3:32])=[CH:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25](Cl)=[O:26]>ClCCl.C(N(CC)CC)C>[Cl:19][C:20]1[C:21]([O:31][CH3:32])=[CH:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCc2c(N)cccc2C1
Reactant: COc1cc(OC)c(C(=O)Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)c(C(=O)Nc2cccc3c2CCN(C(=O)OC(C)(C)C)C3)cc1Cl
Yield: 72.7 %

Procedure:
To a solution of 5-amino-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline (1 g, 4 mmol) in dichloromethane (30 ml) and triethylamine (3 ml) was added 5-chloro-2,4-dimethoxybenzoyl chloride (1.03 g, 4.4 mmol). After stirring at room temperature for 2h the reaction mixture was diluted with dichloromethane (75 ml) and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, concentrated in vacuo and the residue recrystallised from ethyl acethate/petrol to afford the title compound as a colourless crystalline solid (1.3 g).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[C:7]1([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C1C=CC=CC=1>[Br:1][CH:2]([CH3:6])[C:3]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14]1)=[O:4]
Reactant: CC(Br)C(=O)Cl
Reactant: c1ccc(C2CNc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(Br)C(=O)N1CC(c2ccccc2)c2ccccc21
Yield: 96.6 %

Procedure:
A solution of 3.0 g of 2-bromopropionylchloride in 5 ml of benzene was added dropwise at 10° C. to a mixture of 3.0 g of 3-phenylindoline, 3.0 ml of triethylamine in 30 ml of dry benzene. The mixture was then washed with water, the benzene layer dried over sodium sulfate and the solvent removed in vacuo at room temperature to leave 4.9 g of the desired N-(2-bromopropionyl)-3-phenylindoline as a resin.
Reaction SMILES: [NH:1]([C:36]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37])[C@@H:2]([C:4]([NH:6][C@H:7]([C:18]([NH:20][C@H:21]([C:33]([OH:35])=[O:34])[CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])=[O:19])[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:5])[CH3:3].CN1CC[O:46]CC1.C(OC(Cl)=O)C(C)C.[NH2:57][C:58]1[CH:65]=[CH:64][C:61]([CH2:62][OH:63])=[CH:60][CH:59]=1>O1CCCC1>[NH:1]([C:36]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37])[C@@H:2]([C:4]([NH:6][C@H:7]([C:18]([NH:20][C@H:21]([C:33]([OH:35])=[O:34])[CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])=[O:19])[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:5])[CH3:3].[CH:60]1[C:61]([C:62]([OH:46])=[O:63])=[CH:64][CH:65]=[C:58]([NH2:57])[CH:59]=1
Reactant: Nc1ccc(CO)cc1
Reactant: CN1CCOCC1
Agent: C=CCOC(=O)NCCCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](C)NC(=O)OCC=C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)O)cc1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
A solution of 239 mg (0.419 mmol) Aloc-D-Ala-Trp-Lys(Aloc)-OH 28 was dissolved in dry tetrahydrofuran under an argon atmosphere and cooled to −40° C. N-methylmorpholine (48.3 μl, 1.05 equiv) and isobutylchloroformate (57.0 μl, 1.05 equiv) were added. The reaction mixture was stirred for 2 hours at a temperature below −30° C. A solution of 4-aminobenzyl alcohol (51.5 mg, 1.00 equiv) and N-methylmorpholine (50.6 μl, 1.1 equiv) in dry THF was added dropwise to the reaction mixture. After 2 hours tetrahydrofuran was evaporated and dichloromethane was added. The organic layer was washed with saturated sodium bicarbonate, a 0.5 N potassium bisulphate solution and brine, dried (Na2SO4) and evaporated to afford 265 mg (94%) of the desired product 29 as a cream coloured powder. 1H-NMR (300 MHz, CDCl3/CD3OD): δ 1.00–1.62 (m, 9H, CH3-Ala and 3 CH2-Lys), 2.90–3.70 (m, 4H, N—CH2-Lys and CH2-Trp), 4.48–4.92 (m, 7H, 2 Hα and 4 Aloc), 4.72 (s, 2H, CH2—OH), 5.00–5.50 (m, 5H, 4 Aloc and Hα), 5.35–6.05 (m, 2H, Aloc), 6.80–7.83 (m, 9H, aromatic) ppm; MS (FAB) m/e 677 (M+H)+, 699 (M+Na)+.
Reaction SMILES: [Si]([O:8][C@H:9]([CH3:42])[C@H:10]([C:22]1[O:26][C:25]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:29][CH:28]=2)=[N:24][N:23]=1)[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([Cl:20])[C:13]=1[CH3:21])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:20][C:14]1[C:13]([CH3:21])=[C:12]([NH:11][C@@H:10]([C:22]2[O:26][C:25]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:41])[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:29][CH:28]=3)=[N:24][N:23]=2)[C@H:9]([OH:8])[CH3:42])[CH:17]=[CH:16][C:15]=1[C:18]#[N:19]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(NC(=O)c4ccccc4)cc3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(NC(=O)c4ccccc4)cc3)o2)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: 13 °C
Yield: 90.7 %

Procedure:
To a pre-cooled (−55° C.) solution of N-(4-(5-((1R,2R)-2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-cyano-2-methylphenylamino)propyl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide (367 mg, 0.61 mmol) in THF (25 mL) was added TBAF (0.73 mL, 0.73 mmol, 1 M solution in THF) over 5 minutes. Upon complete addition the reaction mixture was allowed to warm to 13° C. over 3.5 h and quenched with sat. aq. NH4Cl (30 mL). The resulting mixture was partitioned between H2O (30 mL) and EtOAc (40 mL). The aqueous layer was extracted with EtOAc (30 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography over silica gel (20-60% EtOAc in hexanes) to provided the title compound as a colourless solid (270 mg, 91%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.83 (s 1H), 8.08-7.95 (m, 6H), 7.63-7.47 (m, 4H), 6.90 (d, J=8.6 Hz, 1H), 5.88 (d, J=8.8 Hz, 1H), 5.06 (dd, J=5.5, 8.8 Hz, 1H), 4.68 (br s, 1H), 4.53 (pentet, J=6.1 Hz, 1H), 2.37 (s, 3H), 1.43 (d, J=6.5 Hz, 3H).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([O:25][CH2:26][CH:27]5[CH2:31][CH2:30][CH2:29][N:28]5C(OCC5C=CC=CC=5)=O)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>CO.[OH-].[OH-].[Pd+2]>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([O:25][CH2:26][CH:27]5[CH2:31][CH2:30][CH2:29][NH:28]5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(OCC4CCCN4C(=O)OCc4ccccc4)ccc32)n1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](Nc1nccc(-n2cnc3cc(OCC4CCCN4)ccc32)n1)c1ccccc1
Reaction time: 15 h
Yield: 84.2 %

Procedure:
2-[(S)-1-Phenylethylamino]-4-[5-((N-benzyloxycarbonyl-pyrrolidin-2-yl)methoxy)benzimidazol-1-yl]pyrimidine (11 mg) was dissolved in methanol (1.0 mL) and catalytic Pd(OH)2 and trifluoroacetic acid were added and the resulting suspension was stirred under hydrogen atmosphere for 15 hours. Filtration and evaporation of solvent gave N-[(1S)-1-phenylethyl]-4-[5-(2-pyrrolidinylmethoxy)-1H-benzimidazol-1-yl]-2-pyrimidinamine (7.0 mg). Mass spectrum (ESI) 415.5 (M+1).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][CH2:4][CH2:5][CH3:6].[NH2-].[Na+].[CH3:10][O:11][CH2:12][C:13](OC)=[O:14].Cl>CCOCC>[CH3:10][O:11][CH2:12][C:13](=[O:14])[CH2:1][C:2](=[O:7])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(C)=O
Reactant: COCC(=O)OC
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Product: CCCCC(=O)CC(=O)COC
Reaction time: 0.2 h
Yield: 122.6 %

Procedure:
2-Hexanone (96.8 g) was added dropwise over 15 min under nitrogen to a stirred suspension of sodium amide (37.7 g) in dry ether (1 liter) at room temperature. The mixture was stirred for 12 min, a solution of methyl methoxyacetate (50.3 g) in dry ether (150 ml) was added dropwise over 20 min, and the mixture was heated under reflux for 2 h. The mixture was cooled, poured into ice and 2N hydrochloric acid (600 ml) and the aqueous layer extracted with ether (4×300 ml). The organic layers were washed with 8% sodium bicarbonate solution and brine, dried and evaporated to give an orange liquid (102 g). Purification by DFC, eluting with System A (5:95) gave a yellow liquid (36 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20](=S)[CH2:21][C:22](=O)[CH3:23])=[O:4].S(O)(O)(=O)=O.[CH2:31]([NH:39][NH2:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20]1[N:39]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:40]=[C:22]([CH3:23])[CH:21]=1)=[O:4]
Reactant: NNCCc1ccccc1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=S)CC(C)=O
Agent: O=S(=O)(O)O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1CCc1ccccc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 253c) was reacted with 2-phenethyl-hydrazine sulfate (CAS Reg. No. 56-51-4) to give the title compound as orange oil. MS (ESI): m/z=488.3 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([I:15])=[C:11]([F:16])[CH:10]=2)[CH2:4]1.C(N(CC)CC)C.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(Cl)Cl>[F:16][C:11]1[CH:10]=[C:9]([N:5]2[CH2:4][C@H:3]([CH2:2][NH:1][C:24](=[O:26])[CH3:25])[O:7][C:6]2=[O:8])[CH:14]=[CH:13][C:12]=1[I:15]
Reactant: CC(=O)OC(C)=O
Reactant: NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
A suspension of (5S)-5-aminomethyl-3-(3-fluoro-4-iodo-phenyl)-oxazolidin-2-one (1022, 16.0 g, 47.6 mmol) in CH2Cl2 (150 mL) was treated with triethylamine (TEA, 9.62 g, 13.2 mL, 95.2 mmol, 2.0 equiv) at 25° C., and the resulting reaction mixture was cooled down to 0-5° C. before being treated with acetic anhydride (Ac2O, 7.29 g, 6.75 mL, 71.4 mmol, 1.5 equiv) and 4-N,N-dimethylaminopyridine (DMAP, 58 mg, 0.5 mmol, 0.01 equiv) at 0-5° C. under N2. The resulting reaction mixture was subsequently stirred at 0-5° C. for 2 h. When TLC and HPLC showed that the reaction was complete, the reaction mixture was quenched with H2O (100 mL). The two layers were separated, and the aqueous layer was then extracted with CH2Cl2 (2×50 mL), and the combined organic extracts were washed with H2O (2×100 mL) and saturated NaCl aqueous solution (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the crude, (5S)-N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (1010, 17.36 g, 17.99 g theoretical, 96.5%) as white powders, which were found to be essentially pure and was directly used in the subsequent reactions without further purifications. For 1010: 1H NMR (300 MHz, DMSO-d6) δ 1.63 (s, 3H, NHCOCH3), 3.25 (t, 2H, J=5.4 Hz), 3.56 (dd, 1H, J=6.4, 9.2 Hz), 3.95 (t, 1H, J=9.1 Hz), 4.58 (m, 1H), 5.16 (t, 1H, J=5.7 Hz, OH), 7.02 (dd, 1H, J=2.4, 8.2 Hz), 7.38 (dd, 1H, J=2.4, 10.8 Hz), 7.66 (t, 1H, J=7.5, 8.4 Hz), 8.08 (t, 1H, J=5.8 Hz, NHCOCH3); C12H12FIN2O3, LCMS (EI) m/e 379 (M++H).
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[NH:20][C:19](=[O:21])[O:18][CH2:17][C:16]=2[CH:22]=1)(=O)C.C(O)(=O)C>O.CO>[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[NH:20][C:19](=[O:21])[O:18][CH2:17][C:16]=2[CH:22]=1
Reactant: CC(=O)OCCCCOc1ccc2c(c1)COC(=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: O=C1Nc2ccc(OCCCCO)cc2CO1
Temperature: 0 °C

Procedure:
A solution of 24 gm (0.6 mol) of sodium hydroxide in 100 ml of water is added dropwise to a solution of 150 gm (0.537 mol) of 6-(4-acetoxy-butoxy)-4H-3,1-benzoxazin-2-one in 500 ml of methanol, under stirring, at 10° to 15° C. After the mixture has been stirred for one hour at ambient temperature, first ice water and then 60 ml of glacial acetic acid are added. The product precipitated is subjected to suction filtration and recrystallized from water.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:33])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27]OS(C)(=O)=O)[O:24][CH2:23]2)[CH:17]([CH:34]([OH:36])[CH3:35])[C:16]3=[O:37])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[I-:38].[Na+]>CC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:33])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][I:38])[O:24][CH2:23]2)[CH:17]([CH:34]([OH:36])[CH3:35])[C:16]3=[O:37])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(COS(C)(=O)=O)C3)C(C)C12
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CI)C3)C(C)C12
Yield: 55.8 %

Procedure:
A mixture of 0.80 g of product from Example 57, 0.431 g of sodium iodide and 20 ml of acetone is heated at reflux temperature for 5 days. The reaction is concentrated in vacuo and the residue purified by chromatography (silica Gel: 80% ethyl acetate/hexane) to give 0.472 g of the desired product.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[NH:13][NH:12][C:11]2=[O:16])=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[CH2:18]([O:21][NH2:22])[C:19]#[CH:20].Cl.O1CCOCC1>C(O)C>[CH2:18]([O:21]/[N:22]=[C:1](/[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[NH:13][NH:12][C:11]2=[O:16])=[CH:6][CH:5]=1)\[CH3:2])[C:19]#[CH:20]
Reactant: CC(=O)c1ccc(-n2c(=O)[nH][nH]c2=O)cc1
Reactant: C#CCON
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: C#CCO/N=C(\C)c1ccc(-n2c(=O)[nH][nH]c2=O)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 7.4 %

Procedure:
To 4-(4-acetylphenyl)-1,2,4-triazolidine-3,5-dione (500 mg, 2.281 mmol) in ethanol (6.912 mL) was added O-(prop-2-ynyl)hydroxylamine hydrochloride (368 mg, 3.42 mmol) and HCl 4N in dioxane (1.711 mL, 6.84 mmol). The mixture was stirred at 50° C. for 2 hours and then concentrated in vacuo. Saturated sodium bicarbonate was added, extracted with ethyl acetate twice, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (60-100% ethyl acetate/heptane, and then 5% MeOH/ethyl acetate) giving (E)-4-(4-(1-(prop-2-ynyloxyimino)ethyl)phenyl)-1,2,4-triazolidine-3,5-dione (I-6a: 46 mg, 7%) as a white solid. LC-MS (M+1) 273.1, t=0.81 minute. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.23 (s, 3 H) 3.48 (t, J=2.40 Hz, 1 H) 4.80 (d, J=2.27 Hz, 2 H) 7.53 (d, J=8.59 Hz, 2 H) 7.76 (d, J=8.59 Hz, 2 H) 10.52 (s, 2 H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.CC(C)([O-])C.[Na+].Br[C:15]1[CH:22]=[C:21]([N:23]2[C:31]3[CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][C:27](=[O:34])[C:26]=3[C:25]([C:35]([F:38])([F:37])[F:36])=[N:24]2)[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH3:32][C:29]1([CH3:33])[CH2:30][C:31]2[N:23]([C:21]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([NH:1][CH:2]4[CH2:7][CH2:6][O:5][CH2:4][CH2:3]4)[CH:22]=3)[N:24]=[C:25]([C:35]([F:37])([F:38])[F:36])[C:26]=2[C:27](=[O:34])[CH2:28]1
Reactant: NC1CCOCC1
Reactant: CC1(C)CC(=O)c2c(C(F)(F)F)nn(-c3ccc(C#N)c(Br)c3)c2C1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)c2c(C(F)(F)F)nn(-c3ccc(C#N)c(NC4CCOCC4)c3)c2C1
Temperature: 120 °C
Yield: 147.5 %

Procedure:
4-Aminotetrahydropyran (245 mg, 2.42 mmol, 2.0 eq) and sodium tert-butoxide (233 mg, 2.42 mmol, 2.0 eq) were added to a stirred solution/suspension of 2-bromo-4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile (500 mg, 1.21 mmol, 1.0 eq), palladium (II) acetate (14 mg, 0.06 mmol, 0.05 eq), and DPPF (67 mg, 0.12 mmol, 0.10 eq) in 3.75 mL of toluene. The reaction vial was capped, and the reaction mixture was heated 20 minutes at 120° C. under microwave irradiation. The reaction mixture was diluted with water and ethyl acetate and combined. The layers were separated, and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified on a Biotage system (SiO2, hexanes-ethyl acetate) to afford 4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzonitrile (772 mg, 49%) as a tan solid: LC/MS (m/z): [M+H]+ 433.7. Further elution with ethyl acetate afforded 4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide (713 mg, 44%) as a yellow solid: LC/MS (m/z): [M+H]+ 451.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4].[Br:29][C:30]1[CH:31]=[C:32](I)[C:33]([NH2:36])=[N:34][CH:35]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCO.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>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:32]2[C:33]([NH2:36])=[N:34][CH:35]=[C:30]([Br:29])[CH:31]=2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4]
Reactant: Nc1ncc(Br)cc1I
Reactant: COC(=O)c1sc(B2OC(C)(C)C(C)(C)O2)cc1OC(C)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1sc(-c2cc(Br)cnc2N)cc1OC(C)c1ccccc1Cl
Yield: 79.4 %

Procedure:
3-[1-(2-Chloro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophene-2-carboxylic acid methyl ester (150 mg, 0.37 mmol, 1.1 Eq.), 5-Bromo-3-iodo-pyridin-2-ylamine (100 mg, 0.34 mmol, 1.0 Eq.) and Pd(PPh3)4 (39 mg, 0.04 mmol, 0.1 Eq.) were dissolved in toluene (1.6 mL) and EtOH (0.4 mL). 2M K2CO3 (0.5 mL, 1.0 mmol, 3.0 Eq) and the reaction heated under microwave conditions at 140° C. for 15 minutes. The reaction was partitioned between EtOAc (10 mL) and water (10 mL) and the aqueous phase extracted with EtOAc (3×10 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (40% EtOAc/petroleum Ether) to give the sub-title compound as an off-white solid (125 mg, 0.27 mmol, 80%); 1H NMR (400 MHz, CDCl3) δ 1.74 (3H, d), 3.92 (3H, s), 4.71 (2H, br s), 5.81 (1H, q), 6.81 (1H, s), 7.24-7.32 (2H, m), 7.38 (1H, dd), 7.54 (1H, d), 7.66 (1H, dd), 8.10 (1H, d)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]1(B(O)O)[CH2:24][CH2:23][CH2:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([C:20]3[CH2:24][CH2:23][CH2:22][CH:21]=3)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)C1=CCCC1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Cl)cc21
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(C3=CCCC3)cc21
Temperature: 90 °C
Yield: 56.5 %

Procedure:
A mixture of 6-chloro-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (340 mg, 1.2 mmol), cyclopenten-1-ylboronic acid (270 mg, 2.4 mmol), potassium carbonate (414 mg, 3.0 mmol) and dichlorobis(tri-o-tolyl-phosphine)palladium(II) (38 mg, 0.04 mmol) in 1,4-dioxane (6 mL) and water (1.5 mL) was degassed and heated in a reaction vial at 90° C. for 2 h. The reaction mixture was cooled, water (20 mL) was added and the product was extracted with EtOAc (2×20 mL). The combined organic layers were dried, filtered and the solvent evaporated. The crude material was purified by column chromatography (SiO2, petrol-EtOAc 0-60%) to afford the title compound (213 mg, 57%). MS: [M+H]+=315.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18])=[O:11].CI.[C:21](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:21][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18])=[O:11]
Reactant: Nc1ccccc1S(=O)c1nc2ccccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(S(=O)c2ccccc2N)nc2ccccc21
Yield: 86.8 %

Procedure:
2-(1H-Benzimidazol-2-yl sulphinyl)benzenamine (850 mg, 3.31 mmole) in dimethylformamide (16 ml) and methyl iodide (515 mg, 3.63 mmole) were stirred at room temperature for 6 hours in a stoppered flask in the presence of potassium carbonate (1.66 g, 12 mmole). The mixture was poured into water and extracted with ethyl acetate (3×). The combined extracts were washed with water (3×), dried (anhydrous sodium sulphate) and evaporated to give a pale grey solid which was triturated with ether to give the title compound as an off-white solid (0.78 g; 87%), mp 146°-8° (dec).