Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][C@@H:8]([CH2:17]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].[N-:30]=[N+:31]=[N-:32].[Na+].CS(C)=O>CCOC(C)=O>[C:1]([O:5][C:6](=[O:29])[CH2:7][C@@H:8]([CH2:17][N:30]=[N+:31]=[N-:32])[CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCC[C@@H](C)C[C@H](COS(=O)(=O)c1ccc(C)cc1)CC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCC[C@@H](C)C[C@H](CN=[N+]=[N-])CC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 88.7 %

Procedure:
Compound 159 (3.01 g, 7.05 mmol), sodium azide (1.26 g, 19.40 mmol) and DMSO (12 mL) were combined and heated to 60° C. for 3 hours. EtOAc (100 mL) was added to the reaction and filtered. The solids were washed with EtOAc (20 mL), and the filtrated evaporated. The crude material was chromatographed on silica eluting with 5% EtOAc/hexanes to give 160 as an oil (1.86 g, 89%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])=[CH:5][CH:4]=1)#[CH:2].Br[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([CH:38]=1)[C:26]([N:28]=[S@@:29]([CH3:37])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>>[F:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([F:18])[C:11]=1[C:10]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:21]2[CH:22]=[N:23][CH:24]=[C:25]([CH:38]=2)[C:26]([N:28]=[S@@:29]([CH3:37])(=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[CH:8][CH:7]=1)=[O:19]
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reactant: C#Cc1ccc(NC(=O)c2c(F)cccc2F)cc1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccc(NC(=O)c3c(F)cccc3F)cc2)c1)c1ccccc1
Yield: 74.3 %

Procedure:
In a manner similar to that described in Example 449, N-(4-ethynyl-phenyl)-2,6-difluoro-benzamide (0.114 g, 0.443 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (100 mg, 0.295 mmol) were reacted to give the title compound as a solid (113 mg, 74%)
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][CH2:6]1)=[O:4].[CH3:19]I.[H-].[Na+].Cl>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH3:19])[CH2:9][CH2:10]1)=[O:4]
Reactant: CI
Reactant: COC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1

Procedure:
16.2 g (62.95 mmol) of trans-4-tert-butoxy carbonylamino-cyclohexanecarboxylic acid methyl ester and 5.87 mL (94.43 mmol, 1.5 eq) of methyl iodide in 100 ml DMF were treated under stirring and ice-cooling with 3.57 g (81.84 mmol, 1.3 eq) of NaH (55% in oil). The solution was stirred at RT for 20 h and then treated under ice-cooling with 1M HCl. The reaction mixture was dissolved in ether and washed 4 times with water. The ether-phases were concentrated under reduced pressure to yield 17.5 g (quantitative) of trans-4-(tert-butoxycarbonyl-methyl-amino)-cyclohexanecarboxylic acid methyl ester, MS: 201 (M−OC4H9).
Reaction SMILES: O[CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)[C:3]1[S:18][C:6]2[N:7]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:8](=[O:13])[N:9]([CH3:12])[C:10](=[O:11])[C:5]=2[CH:4]=1.C([SiH](CC)CC)C.[OH-].[Na+]>FC(F)(F)C(O)=O>[F:25][C:21]1[CH:20]=[C:19]([CH2:2][C:3]2[S:18][C:6]3[N:7]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:8](=[O:13])[N:9]([CH3:12])[C:10](=[O:11])[C:5]=3[CH:4]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cc(C(O)c3cccc(F)c3)sc21
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cc(Cc3cccc(F)c3)sc21
Reaction time: 16 h
Yield: 9 %

Procedure:
To a solution of 6-(1-hydroxy-(3-fluorophenyl)methyl)-3-methyl-1-(2-methypropyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione (Example 51) (957 mg) in trifluoroacetic acid (7 ml) was added triethylsilane (4 ml) and the reaction was allowed to stir for 16 h. The mixture was then poured onto 10% sodium hydroxide and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate arid then concentrated in vacuo to a viscous oil. The oil was purified by normal phase HPLC to give the title compound (82 mg).
Reaction SMILES: [C:1]([C:3]1[CH:48]=[CH:47][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([CH:10]([C:18]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4S(C3C=CC(C)=CC=3)(=O)=O)[NH:11]C(=O)C(F)(F)F)=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(C)=CC(C)=C4C=3C=CN4S(C3C=CC(C)=CC=3)(=O)=O)NC(=O)C(F)(F)F)N(COCC[Si](C)(C)C)C=2C=1)#N>>[NH2:11][CH:10]([C:18]1[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[C:23]2[C:19]=1[CH:20]=[CH:21][NH:22]2)[C:8]1[NH:7][C:6]2[CH:47]=[CH:48][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[N:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(NC(=O)C(F)(F)F)c4nc5cc(C#N)ccc5n4COCC[Si](C)(C)C)c(C)cc(C)c32)cc1
Agent: Cc1ccc(S(=O)(=O)n2ccc3c(C(NC(=O)C(F)(F)F)c4nc5ccc(C#N)cc5n4COCC[Si](C)(C)C)c(C)cc(C)c32)cc1
Product: Cc1cc(C)c2[nH]ccc2c1C(N)c1nc2cc(C#N)ccc2[nH]1

Procedure:
The title compound was synthesized from a mixture of (±)-N-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(5,7-dimethyl-1-tosyl-1H-indol-4-yl)methyl)-2,2,2-trifluoroacetamide and (±)-N-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(5,7-dimethyl-1-tosyl-1H-indol-4-yl)methyl)-2,2,2-trifluoroacetamide as described in Example 64-B and 64-C. 1H NMR (400 MHz, DMSO-d6) δ ppm. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.88 (s, 1H) 7.93 (s, 1H) 7.59 (d, J=8.08 Hz, 1H) 7.48 (app dd, J=8.34, 1.26 Hz, 1H) 7.11 (t, J=2.78 Hz, 1H) 6.73 (s, 1H) 6.19 (s, 1H) 5.77 (s, 1H) 2.43 (s, 3H) 2.39 (s, 3H). HRMS calcd. for C19H17N5 (M+H)+ 316.1557. found 316.1563.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[N:14][C:15]([NH:18][C:19]3[N:20]=[CH:21][C:22]4[CH:27]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[N:25]([CH:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[C:23]=4[N:24]=3)=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)[CH3:5].[Li+].[OH-]>C1COCC1.O>[CH:33]1([N:25]2[C:23]3[N:24]=[C:19]([NH:18][C:15]4[N:14]=[CH:13][C:12]([N:9]5[CH2:8][CH2:7][N:6]([CH:4]([CH3:5])[C:3]([OH:38])=[O:2])[CH2:11][CH2:10]5)=[CH:17][CH:16]=4)[N:20]=[CH:21][C:22]=3[CH:27]=[C:26]2[C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: COC(=O)C(C)N1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)O)N1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.5 %

Procedure:
To a solution of 2-{4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazin-1-yl}-propionic acid methyl ester (250 mg, 0.48 mmol) in 10 mL of THF is added a solution of LiOH (19 mg, 48 mmol) in 10 mL of H2O. After 18 h stirring at room temperature, the resulting mixture is concentrated and diluted with H2O and adjusted to pH=6 with 1 N HCl. Ished with dichloromethane then solids precipitated and collected to give 2-{4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazin-1-yl}-propionic acid (225 mg, 94%). MS(ESI) m/z 507.3 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:49])[NH:7][CH:8]([C:21](=[O:48])[N:22]([CH:34]([C:36]1[NH:37][CH:38]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43](Br)[CH:42]=2)[N:40]=1)[CH3:35])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1)[CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17](=[O:19])[NH2:18])=[CH:12][C:11]=1[CH3:20])([CH3:4])([CH3:3])[CH3:2].[C:50]([O-])([O-:52])=[O:51].[K+].[K+]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[Fe+2]>[C:1]([O:5][C:6]([NH:7][CH:8]([CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17](=[O:19])[NH2:18])=[CH:12][C:11]=1[CH3:20])[C:21]([N:22]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1)[CH:34]([C:36]1[NH:37][CH:38]=[C:39]([C:41]2[CH:42]=[C:43]([CH:44]=[CH:45][CH:46]=2)[C:50]([OH:52])=[O:51])[N:40]=1)[CH3:35])=[O:48])=[O:49])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN(C(=O)C(Cc2c(C)cc(C(N)=O)cc2C)NC(=O)OC(C)(C)C)C(C)c2nc(-c3cccc(Br)c3)c[nH]2)cc1OC
Reactant: O=C([O-])[O-]
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COc1ccc(CN(C(=O)C(Cc2c(C)cc(C(N)=O)cc2C)NC(=O)OC(C)(C)C)C(C)c2nc(-c3cccc(C(=O)O)c3)c[nH]2)cc1OC
Temperature: 100 °C
Yield: 87 %

Procedure:
To a solution of [1-[{1-[4-(3-bromo-phenyl)-1H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-carbamoyl]-2-(4-carbamoyl-2,6-dimethyl-phenyl)-ethyl]-carbamic acid tert-butyl ester (290 mg; 0.40 mmol) in DMF (5 mL) was added K2CO3 (262 mg; 1.9 mmol) and the resulting mixture was degassed with Argon for 5 min. At this time, Pd(OAc)2 (8.9 mg; 0.04 mmol) and 1,1-bis(diphenylphosphino)ferrocene (46 mg; 0.083 mmol) were added. Carbon monoxide was then bubbled through the resulting mixture for 10 min at room temperature, the reaction was capped, and warmed to 100° C. for 6 h. After cooling to room temperature the mixture was partitioned between EtOAc and water, filtered through Celite, and then separated. The aqueous phase was then washed with a second portion of EtOAc. The aqueous phase was then acidified to pH 5 with 2N citric acid and the resulting aqueous solution extracted with EtOAc (4×). These latter EtOAc extracts were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield the crude product (HPLC: 87% at 254 nm).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28].C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:3]=[CH:4][C:5]([C:8](=[C:16]3[CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][C:20]([CH3:23])([CH3:22])[CH2:21]3)[C:9]3[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=3)=[CH:6][CH:7]=2)=[CH:32][CH:31]=1)(=[O:29])=[O:28]
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)C1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
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: [Na+]
Solvent: COCCOC
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)CC(C)(C)C1
Temperature: 25 °C
Yield: 45.3 %

Procedure:
To a round-bottomed flask were added 4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14) (85% pure—contains 15% 3,3,5,5-tetramethylcyclohexanone) (0.117 g, 0.25 mmoL), 4-(methanesulphonyl)benzeneboronic acid (0.165 g, 0.82 mmoL), tetrakis(triphenylphosphine)palladium (0) (0.026 g, 0.023 mmoL), 2 M Na2CO3 (3 mL), and ethylene glycol dimethyl ether (8 mL). The stirred reaction mixture was heated at reflux under a nitrogen atmosphere for 3.5 h. The oil bath was removed and the reaction mixture was allowed to cool at RT. The reaction mixture was transferred to a separatory funnel and partitioned between H2O and EtOAc. The organic phase was separated and the aqueous phase was extracted with EtOAc. The organic extracts were combined, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo to give a brown oil. The crude product was purified by flash chromatography on silica gel using a hexanes:EtOAc gradient (100:0 to 75:25) to give 0.063 g (53%) of compound 163 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 0.89 (s, 12 H), 1.26 (s, 2 H), 1.93 (s, 4 H), 3.23 (s, 3 H), 6.67 (d, J=8.5 Hz, 2 H), 6.95 (d, J=8.4 Hz, 2 H), 7.25 (d, J=8.2 Hz, 2 H), 7.67 (d, J=8.3 Hz, 2 H), 7.91 (d, J=8.6 Hz, 2 H), 7.95 (d, J=8.6 Hz, 2 H), 9.29 (s, 1 H). HRMS (ESI) Calcd for C30H33O3S: 473.2150 (M−H)−. Found: 473.2168.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][C:25]#[N:26].O>CN(C)C=O.C1(C)C=CC=CC=1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:22][CH2:23][CH2:24][C:25]#[N:26])[C:9]2=[O:17])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Nc2ccccc2C1(O)c1cccc(Cl)c1
Reactant: N#CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: N#CCCCN1C(=O)C(O)(c2cccc(Cl)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(m-Chlorophenyl)-3-hydroxy-2-indolinone (31.2g) in dry dimethylformamide (120 ml.) was added dropwise with stirring under nitrogen to a suspension of sodium hydride (5.2g of a 60% dispersion in oil) in dry dimethylformamide (120ml.) while keeping the temperature at 10°C. The reaction was then left stirring at room temperature for 1 hour. 4-Bromobutyronitrile (18.6g.) in dry toluene (120 ml.) was added dropwise and the mixture stirred for 36 hours. The reaction mixture was poured into water and extracted with toluene. The organic extracts were dried over magnesium sulphate and evaporated to an oil which afforded 21.3 g. colourless crystals, m.p. 124°-126°C, from ethanol.
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[O:16][CH3:17].COC(C)(C)C>CS(C)=O>[C:12]([C:10]1[CH:9]=[CH:8][C:7]([O:16][CH3:17])=[C:6]([CH2:5][C:1]#[N:2])[CH:11]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: COc1ccc(C(C)(C)C)cc1CBr
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Product: COc1ccc(C(C)(C)C)cc1CC#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.9 %

Procedure:
Potassium cyanide (2.96 g) was added to a solution of 2-bromomethyl-4-tert-butyl-1-methoxybenzene (7.78 g) in dimethyl sulfoxide (50 mL), and the mixture was stirred at room temperature for 16 hours. Ice and tert-butyl methyl ether were added to the reaction solution, and the organic layer was separated. The aqueous layer was reextracted with tert-butyl methyl ether. The combined organic layers were sequentially washed with water (twice) and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane→ethyl acetate:heptane=1:49). The target fraction was concentrated. The resulting residue was triturated with hexane to obtain 1.90 g of the title compound. The trituration mother liquor was concentrated. Then, the resulting residue was triturated with hexane to obtain 0.47 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[C:18](=[O:26])[N:19]([CH3:25])[CH:20]=[C:21]([O:23][CH3:24])[N:22]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:24][O:23][C:21]1[N:22]=[C:17]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[C:18](=[O:26])[N:19]([CH3:25])[CH:20]=1
Reactant: COc1cn(C)c(=O)c(O)n1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cn(C)c(=O)c(OS(=O)(=O)C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
62 g of trifluoromethanesulfonic acid anhydride are added dropwise to a suspension of 31.2 g of 3-hydroxy-5-methoxy-1-methylpyrazin-2-one, 15.8 g of pyridine and 500 ml of methylene chloride at 20°-25° C. The solution formed is stirred at 20°-25° C. for a further 2 hours, and 200 ml of ice-water are then added. The organic phase is separated off, washed with 10% sodium bicarbonate solution and water, dried over sodium sulfate and evaporated to give 39.5 g of 5-methoxy-1-methyl-3-trifluoromethylsulfonyloxy-pyrazin-2-one of melting point 107°-108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:20])[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:20])[CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2cc(F)cc(Cl)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1(c2cc(F)cc(Cl)c2)CNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
A mixture of tert-butyl 3-(3-chloro-5-fluorophenyl)-3-hydroxyazetidine-1-carboxylate (1.25 g, 4.14 mmol) and trifluoroacetic acid (3 ml) in dichloromethane (50 ml) was stirred at ambient temperature for 1 h. The solvent was evaporated and the crude product was purified on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1) to give the title compound (0.74 g). MS m/z (rel. intensity, 70 eV) 201 (M+, 1), 172 (47), 157 (53), 130 (76), 109 (bp).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13](O)=[O:14])[CH:5]=[CH:6][CH:7]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([NH2:37])[CH:32]=1>>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:37][C:13]([C:12]2[S:11][C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)=[N:9][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[O:14])[CH:34]=[CH:35][CH:36]=1
Reactant: COc1cccc(N)c1
Reactant: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(=O)O)s3)c2cc1OC
Product: COc1cccc(NC(=O)c2sc(-n3cnc4cc(OC)c(OC)cc43)nc2-c2cccc(Cl)c2)c1
Yield: 86.6 %

Procedure:
In a similar manner as described for Example 53, 4-(3-Chloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (41 mg, 0.1 mmol) and 3-anisidine (12.3 mg, 0.1 mmol, Aldrich) gave 4-(3-Chloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (3-methoxy-phenyl)-amide (45.1 mg, 86.6%) as a white solid. MS m/z 521 (M+1).
Reaction SMILES: Cl[CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11].[Al+3].[Cl-].[Cl-].[Cl-].[CH3:16][N:17]1[C:21]([NH2:22])=[CH:20][CH:19]=[N:18]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[NH2:22][C:21]1[N:17]([CH3:16])[N:18]=[CH:19][C:20]=1[CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11]
Reactant: CCCC1CC(=O)N(CCl)C1
Reactant: Cn1nccc1N
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCCC1CC(=O)N(Cc2cnn(C)c2N)C1
Temperature: 65 °C
Yield: 15.8 %

Procedure:
In a 25 ml, three-necked flask fitted with a magnetic stirrer, under inert atmosphere, 1-(chloromethyl)-4-propylpyrrolidin-2-one x63 (0.136 g, 0.77 mmol) is added dropwise to a suspension of AlCl3 (0.033 g, 0.25 mmol) in TCE at 0° C. In another 25 ml, three-necked flask fitted with a magnetic stirrer and reflux condenser under inert atmosphere, 1-methyl-1H-pyrazol-5-amine x64 (0.05 g, 0.51 mmol) is dissolved in TCE (10 ml) and the mixture is heated at 65° C. At this temperature, the solution containing compound x63 and AlCl3 is added dropwise and the mixture is heated at 80° C. for 16 h. Water and CH2Cl2 are added, the pH is brought up to 8 with sodium bicarbonate and the aqueous phase is extracted with CH2Cl2. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated. The crude product is purified by preparative chromatography on silicagel, then by preparative chromatography on reverse phase to afford 19 mg of 1-[(5-amino-1-methyl-1H-pyrazol-4-yl)methyl]-4-propylpyrrolidin-2-one 170.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[NH:6]2.[C:13](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[N:6]2[CH3:13]
Reactant: O=C([O-])[O-]
Reactant: O=C1Nc2cccc(Br)c2C1=O
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C(=O)c2c(Br)cccc21
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
To a stirred solution of 4-bromoisatin (90.4 g, 400 mmol) in N,N-dimethylformamide (400 mL) was added cesium carbonate (196.0 g, 600 mol) at ambient temperature. The reaction mixture was stirred for 30 min, iodomethane (37.4 mL, 600 mmol) was added and the mixture was stirred at ambient temperature for 18 h. The solid was removed by filtration, the filtrate was concentrated in vacuo, and the residue was triturated in water and washed with diethyl ether to afford 4-bromo-1-methyl-1H-indole-2,3-dione (82.0 g, 85%): 1H NMR (300 MHz, DMSO-d6) δ 7.95-7.89 (m, 1H), 7.68-7.64 (m, 1H), 7.53-7.49 (m, 1H), 3.50 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]([N:9]([CH2:31][CH3:32])[C:10]1[N:30]=[C:13]2[CH:14]=[CH:15][C:16]([NH:18][C:19]([C:21]3[N:25]([CH3:26])[N:24]=[CH:23][C:22]=3[C:27](O)=[O:28])=[O:20])=[CH:17][N:12]2[N:11]=1)[CH3:8]>>[CH2:31]([N:9]([CH2:7][CH3:8])[C:10]1[N:30]=[C:13]2[CH:14]=[CH:15][C:16]([NH:18][C:19]([C:21]3[N:25]([CH3:26])[N:24]=[CH:23][C:22]=3[C:27]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:28])=[O:20])=[CH:17][N:12]2[N:11]=1)[CH3:32]
Reactant: CCN(CC)c1nc2ccc(NC(=O)c3c(C(=O)O)cnn3C)cn2n1
Reactant: C1COCCN1
Product: CCN(CC)c1nc2ccc(NC(=O)c3c(C(=O)N4CCOCC4)cnn3C)cn2n1

Procedure:
Using morpholine and 5-(2-diethylamino-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. White solid (65 mg, 94%). MS: m/z=357 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1([C:15]2[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=2)[CH:8]2[CH:4]1[CH2:5][N:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7]2)[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[CH2:1]([C:3]1([C:15]2[CH:16]=[C:17]([NH:21][S:23]([CH3:22])(=[O:25])=[O:24])[CH:18]=[CH:19][CH:20]=2)[CH:8]2[CH:4]1[CH2:5][N:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7]2)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCN1CC2C(C1)C2(CC)c1cccc(N)c1
Solvent: c1ccncc1
Product: CCCCCCN1CC2C(C1)C2(CC)c1cccc(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.7 %

Procedure:
To a solution of 3-(6-ethyl-3-hexyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation 20, 500 mg, 1.56 mmol) in pyridine (5 ml) at 0° C. under nitrogen was added dropwise over 5 minutes methanesulfonylchloride (0.20 ml, 0.30 g, 2.6 mmol). The mixture was allowed to warm to room temperature and was stirred for 18 hours. The mixture was concentrated in vacuo and the residue was purified by silica (25 g) column chromatography eluting with 50:50:1 ethyl acetate:hexane:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (180 mg, 33%).
Reaction SMILES: C([NH:4][CH2:5][CH:6]1[O:11][CH:10]([CH3:12])[CH2:9][N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[CH2:7]1)(=O)C.[OH-].[Na+]>Cl>[NH2:4][CH2:5][CH:6]1[O:11][CH:10]([CH3:12])[CH2:9][N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[CH2:7]1
Reactant: CC(=O)NCC1CN(Cc2ccccc2Cl)CC(C)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1CN(Cc2ccccc2Cl)CC(CN)O1
Reaction time: 2 h
Yield: 85.4 %

Procedure:
A solution of 2-acetylaminomethyl-4-(2-chlorobenzyl)-6-methylmorpholine (3.0 g) in 10% hydrochloric acid (60 ml) is refluxed with stirring for 2 hours. The reaction mixture is basified with aqueous sodium hydroxide solution and extracted with chloroform. The organic layer is washed successively with water and saturated aqueous sodium choride solution, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to give the title compound (2.2 g) as an oil.