Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12])#[CH:2].CCN(CC)CC.Cl[C:23]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][N:26]=[C:25]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([CH:40]3[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)[N:24]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CCOC(C)=O.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.[Cu]I>[CH3:14][O:13][C:11](=[O:12])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=1[C:1]#[C:2][C:27]1[C:28]([C:29]([F:30])([F:31])[F:32])=[CH:23][N:24]=[C:25]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([CH:40]3[CH2:41][CH2:42][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:44][CH2:45]3)=[CH:36][CH:35]=2)[N:26]=1
Reactant: C#Cc1cc(C)ccc1CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C)cc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A solution of methyl 2-(2-ethynyl-4-methylphenyl)acetate (A86) (0.196 g, 71% pure) in DMF (3 mL) and Et3N (0.309 mL, 2.22 mmol) was added to a mixture of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (K5) (0.371 g, 0.812 mmol), PdCl2(PPh3)2 (0.078 g, 0.11 mmol), CuI (0.021 g, 0.11 mmol) and PPh3 (0.019 g, 0.074 mmol) in DMF (3 mL). The resulting mixture was heated under microwave irradiation at 120° C. for 15 minutes then diluted with EtOAc and passed through a plug of Celite, washing with EtOAc (50 mL). The filtrate was concentrated in vacuo and the residue purified by silica gel column chromatography (Biotage Isolera, 40 g cartridge, 0-35% EtOAc in petroleum benzine 40-60° C.) to give the title compound A87 as a yellow oil (133 mg, 30%); 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 7.74 (s, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.44 (s, 1H), 7.24-7.16 (m, 4H), 4.43-4.14 (m, 2H), 3.90 (s, 2H), 3.69 (s, 3H), 2.80 (t, J=11.7 Hz, 2H), 2.63 (tt, J=12.0, 3.3 Hz, 1H), 2.34 (s, 3H), 1.81 (d, J=12.7 Hz, 2H), 1.69-1.54 (m, 2H), 1.49 (s, 9H). LCMS-A: rt 7.057 min; m/z 609.3 [M+H]+.
Reaction SMILES: Cl.[N:2]1[C:11]2[NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O.Cl.Cl.[CH2:21]([O:23][C:24](=[O:38])[CH2:25][CH:26]([NH2:37])[C:27]1[CH:28]=[N:29][C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:22].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[N:2]1[C:11]2[NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:37][C@H:26]([C:27]1[CH:28]=[N:29][C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:38])=[O:18]
Reactant: CCOC(=O)CC(N)c1cnc2ccccc2c1
Reactant: O=C(O)CCCCc1ccc2c(n1)NCCC2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](NC(=O)CCCCc1ccc2c(n1)NCCC2)c1cnc2ccccc2c1
Reaction time: 8 h

Procedure:
A mixture of 1-6 (200 mg, 0.74 mmol), 5-7 (202 mg, 0.74 mmol), NMM (366 mL, 3.33 mmol), HOBT (130 mg, 0.96 mmol) and EDC (184 mg, 0.96 mmol) in 2 mL DMF was stirred overnight. After diluting with EtOAc (100 mL), the mixture was washed with sat. NaHCO3, water, and brine, dried (MgSO4), filtered and concentrated, and chromatographed on silica (10% EtOH/EtOAc) providing 5-8 as a colorless glass.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][C@H:19]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:24]=4[F:33])[C:18]3=[O:34])[CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH3:35][NH:36][CH3:37]>CN(C=O)C.C(#N)C.C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][C@H:19]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:24]=4[F:33])[C:18]3=[O:34])[CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([N:36]([CH3:37])[CH3:35])=[O:8]
Reactant: CNC
Reactant: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(c4ncc(C(=O)Cl)cc4Cl)CC3)C2=O)c(F)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cnc(N2CCC(N3CC[C@H](Nc4ccc(S(C)(=O)=O)cc4F)C3=O)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.3 %

Procedure:
To a solution of (S)-5-chloro-6-(4-(3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinoyl chloride (0.15 g, 0.28 mmol) in 5 mL of DMF/ACN/THF (1:1:1) was added dimethylamine (2 M solution in THF, 1.4 mL, 2.8 mmol) and the reaction was stirred at ambient temperature for 4 hours. The reaction was diluted with EtOAc (100 mL) and the organic layer was washed with water (20 mL) and brine (20 mL), and the organic layer was dried over MgSO4, and concentrated under vacuum. The material was triturated with isopropanol (about 6 mL) to give (S)-5-chloro-6-(4-(3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidin-1-yl)-N,N-dimethylnicotinamide (0.059 g, 0.11 mmol, 38% yield). Mass spectrum (apci) m/z=538.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[CH3:32][C:33]1[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([S:40]([NH2:43])(=[O:42])=[O:41])[N:34]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:43][S:40]([C:35]3[N:34]=[C:33]([CH3:32])[CH:38]=[C:37]([CH3:39])[N:36]=3)(=[O:41])=[O:42])=[O:24])=[CH:18][CH:19]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: Cc1cc(C)nc(S(N)(=O)=O)n1
Product: Cc1cc(C)nc(S(=O)(=O)NC(=O)NCCc2ccc(-n3nc(C)c(-c4ccccc4)c3C)cc2)n1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 4,6-dimethylpyrimidine-2-sulfonamide: 1H-NMR (CDCl3) δ 7.46-7.23 (10H, m), 6.82 (1H, br.s), 3.54-3.47 (2H, m), 2.89-2.84 (2H, m), 2.58 (6H, s), 2.33 (3H, s), 2.27 (3H, s).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[N:11]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[Cl:23])[N:10]=[CH:9][CH:8]=1)=[O:5])#[N:2].C(OC(=O)C)(=O)C.[N+:31]([O-])([OH:33])=[O:32]>C(O)(=O)C>[C:1]([CH2:3][C:4]([NH:6][C:7]1[N:11]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:20])([F:22])[F:21])=[CH:14][C:13]=2[Cl:23])[N:10]=[CH:9][C:8]=1[N+:31]([O-:33])=[O:32])=[O:5])#[N:2]
Reactant: O=[N+]([O-])O
Reactant: N#CCC(=O)Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: N#CCC(=O)Nc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 36 %

Procedure:
7.26 g (0.02 mol) of 5-cyanoacetylamino-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-pyrazole (Example 1) are taken in 70 ml of glacial acetic acid, and 2 ml of acetic anhydride and 2 ml of nitric acid are added dropwise in succession at about 10° C. A crystalline solid precipitates out of the initially clear solution after prolonged stirring. After filtration with suction, washing several times with diisopropyl ether and drying, 2.9 g (36% of theory) of 5-cyanoacetylamino-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-nitro-pyrazole of melting point 221°-223° C. are obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:4]=1[OH:20].CCCCC(C([O-])=O)CC.CCCCC(C([O-])=O)CC.[Sn+2].[C:42]([O:47][CH2:48][CH2:49][N:50]=[C:51]=[O:52])(=[O:46])[C:43]([CH3:45])=[CH2:44].COC1C=CC(O)=CC=1>C1COCC1.C(OCC)C>[C:42]([O:47][CH2:48][CH2:49][NH:50][C:51]([O:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:4]=1[OH:20])=[O:52])(=[O:46])[C:43]([CH3:45])=[CH2:44]
Reactant: COc1ccc(N=Nc2cc(C)cc(CO)c2O)cc1
Reactant: C=C(C)C(=O)OCCN=C=O
Agent: CCCCC(CC)C(=O)[O-]
Agent: COc1ccc(O)cc1
Agent: [Sn+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCNC(=O)OCc1cc(C)cc(N=Nc2ccc(OC)cc2)c1O
Temperature: 60 °C
Reaction time: 20 h

Procedure:
In a 500 ml 3-neck round bottom flask equipped with a magnetic stirrer and nitrogen inlet was dissolved 5.01 g (18.4 mmol) 2-(hydroxymethyl)-6-((4-methoxyphenyl)diazenyl)-4-methylphenol from Example 2 in 300 ml anhydrous THF. Stannous octoate (50 mg, Pfaltz & Bauer) was added followed by 2-isocyanatoethyl methacrylate (3.14 g, 20.2 mmol). MEHQ (100 mg) was added. The reaction mixture was stirred for 20 hr at 60° C. and then poured into 200 ml diethyl ether, and washed with 0.5 N HCl and water. The organic layer was dried with magnesium sulfate, filtered, and rotovapped to give the desired product which was recrystallized in ethanol to give 6.0 g (76%) of an orange solid. 1H NMR (CDCl3) delta: 13.22 (s, 1H, Ar—OH), 7.85 (m, 2H, Ar—H), 7.69 (s, 1H, Ar—H), 7.23 (s, 1H, Ar—HI), 7.03 (m, 2H, Ar—H), 6.09 (s, 1H, vinyl-H), 5.57 (s, 1H, vinyl-H), 5.24 (s, 2H, Ar—CH2), 5.02 (s, 1H, CONH), 4.24 (m, 2H, CH2OCO), 3.90 (s, 3H, Ar—OCH3), 3.53 (m, 2H, OCNHCH2), 2.38 (s, 3H, Ar—CH3), 1.92 (s, 3H, CH3—C═C).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:22]1[CH2:26][CH2:25][N:24]([CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)[CH2:23]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]CC)=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:38][OH:39].C[O-].[K+].Cl>CO>[OH:39][NH:38][C:17](=[O:19])/[CH:16]=[CH:15]/[C:12]1[CH:11]=[CH:10][C:9]([N:8]([C@@H:22]2[CH2:26][CH2:25][N:24]([CH:27]3[CH2:28][C:29]([CH3:36])([CH3:35])[NH:30][C:31]([CH3:34])([CH3:33])[CH2:32]3)[CH2:23]2)[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[N:14][CH:13]=1
Reactant: NO
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(C3CC(C)(C)NC(C)(C)C3)C2)nc1
Agent: C[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CC1(C)CC(N2CC[C@@H](N(C(=O)OC(C)(C)C)c3ccc(/C=C/C(=O)NO)cn3)C2)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.9 %

Procedure:
To a stirred solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(2,2,6,6-tetramethyl-4-piperidinyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (265 mg, 0.529 mmol) in methanol (5 mL) was added hydroxylamine hydrochloride (184 mg, 2.65 mmol) at ambient temperature. To this mixture was added 1N potassium methoxide in methanol (5.29 mL, 5.29 mmol) dropwise in an ice bath and the resulting mixture was stirred at ambient temperature for three hours. To the mixture was added 1N hydrogen chloride to neutralize the solution. The solvent was removed in vacuo and the residue was desalted using ion-exchange resin. The crude product was purified by preparative high-pressure liquid chromatography to afford tert-butyl (5-[(1E)-3-(hydroxyamino)-3-oxo-1-propen-1-yl]-2-pyridinyl)[(3R)-1-(2,2,6,6-tetramethyl-4-piperidinyl)-3-pyrrolidinyl]carbamate (103 mg) as a colorless wax.
Reaction SMILES: [CH3:1][O:2][CH:3]([N:5]1[CH:11]([CH3:12])[C:9](=[O:10])[NH:8][C:6]1=[O:7])[CH3:4].[Cl:13][C:14]([Cl:18])([Cl:17])[S:15]Cl.[OH-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(Cl)Cl>[CH3:1][O:2][CH:3]([N:5]1[CH:11]([CH3:12])[C:9](=[O:10])[N:8]([S:15][C:14]([Cl:18])([Cl:17])[Cl:13])[C:6]1=[O:7])[CH3:4]
Reactant: COC(C)N1C(=O)NC(=O)C1C
Reactant: ClSC(Cl)(Cl)Cl
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(C)N1C(=O)N(SC(Cl)(Cl)Cl)C(=O)C1C
Reaction time: 0.42 h
Yield: 87.7 %

Procedure:
A stirred mixture of 8.6 g (0.05 mole) 1-methoxyethyl-5-methylhydantoin (the product of Example 12), 10.2 g (0.055 mole) trichloromethylsulfenyl chloride and 1.0 g Aliquat® 336 in 100 ml methylene chloride was cooled in an ice bath. To that mixture a precooled sodium hydroxide solution (5.0 g of 50% sodium hydroxide diluted to 25 g) was added at once. After the addition, the temperature of the reaction mixture increased from 5° to 15° C. After 5 minutes the ice bath was removed; stirring was continued for about 25 minutes. The aqueous phase was separated. The organic phase was dried and stripped to give an oil. The oil was washed with hexane to give 14.1 g of a semi-solid. The semi-solid was taken up in 50 ml chloroform and applied to a column of 225 g silica gel; elution with 2% methanol in chloroform gave 10.1 g of the above-identified product as a viscous orange oil.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[S:4].Br.Br[CH:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=O.C(N(CC)CC)C>C(#N)C>[CH3:1][NH:2][C:3]1[S:4][C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:5]=1
Reactant: O=C(c1cccnc1)C(Br)c1ccccc1
Reactant: CNC(N)=S
Agent: Br
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNc1nc(-c2cccnc2)c(-c2ccccc2)s1
Yield: 83.6 %

Procedure:
To a solution of N-methylthiourea (484 mg) in acetonitrile (40 mL), was added 2-bromo-2-phenyl-1-(3-pyridyl)ethanone hydrobromide (2.0 g), and then triethylamine (0.8 mL) was added dropwise to the mixture with stirring. After addition, the resulting mixture was stirred at reflux for 3 h and the solvent was evaporated. An aqueous saturated solution of sodium hydrogen carbonate was added to the residue and extracted with ethyl acetate. The extracts were washed with water, dried and the solvent was evaporated. The crystalline residue was recrystallized from ethyl acetate-isopropyl ether to give the title compound (1.2 g, yield 80%).
Reaction SMILES: S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[C:16]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:20])[C@H:17]([CH3:19])O.N1C(C)=CC=CC=1C.[CH2:37]([O:40][NH2:41])[CH:38]=[CH2:39].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:22]([O:21][C:16](=[O:20])[C@@H:17]([CH3:19])[NH:41][O:40][CH2:37][CH:38]=[CH2:39])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[C@H](O)C(=O)OCc1ccccc1
Reactant: C=CCON
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=CCON[C@H](C)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A solution of triflic anhydride (10.86 g, 38.5 mmol) in dry CH2Cl2 (20 mL) was added dropwise to a solution of benzyl (S)-lactate (1a) (6.31 g, 35 mmol) in dry CH2Cl2 (100 mL) with cooling (−68˜−72° C.) and stirring. After 5˜7 min, a solution of 2,6-lutidine (4.31 g, 40.3 mmol) in dry CH2Cl2 (15 mL) was added dropwise at the same temperature and the reaction mixture was stirred for 30 min at −68˜−72° C. A solution of O-allylhydroxylamine (4.55 g, 77 mmol) in dry CH2Cl2 (15 mL) was added dropwise to the prepared solution of the alkylating reagent with cooling (−68˜−72° C.) and stirring. The reaction mixture was stirred for 15 min at ca. −72° C. and then was allowed to warm up to RT. After stirring for 15 h at RT, the reaction mixture was thoroughly shaken with sat. aqueous NaHCO3 (200 mL) and dried over MgSO4. After removal of the solvent, the residue was purified by dry flash chromatography (Silica Gel 60H for TLC, 10% EtOAc-hexanes) to afford 8.20 g (99.6%) of the product 2a as a pale yellowish oil. 1H NMR (100 MHz) in CDCl3+1 drop of D2O (J, Hz): δ 1.28 (3H, d, 3J=7.1, MeCH), 3.82 (1H, q, 3J=7.1, MeCH), 4.22 (2H, dt, 3J=5.7, 4J=1.2, OCH2CH═CH2), 5.16-5.37 (2H, m, CH═CH2), 5.23 (2H, CH2Ph), 5.76-6.15 (1H, m, 3J=5.7, 3Jcis=9.9, 3Jtrans=17.1, CH═CH2), 7.38 (5H, Ph). 13C (100 MHz) in CDCl3: δ 14.81, 59.09, 66.63, 75.22, 117.53, 128.06, 128.24, 128.56, 134.37, 135.84, 174.01. IR (film), cm−1: 3264, 1740, 1456, 1208, 1170. Anal. Calcd for C13H17NO3: C, 66.4; H, 7.3; N, 5.95. Found: C, 66.3; H, 7.4; N, 6.15%.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.Cl.[CH2:23]([NH2:25])[CH3:24]>CO.C(Cl)Cl>[CH2:23]([NH:25][CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:24]
Reactant: CCN
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCNCc1ccc2[nH]c(C(N)=O)c(Sc3ccccc3)c2c1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (80 mg, 0.27 mmol) with ethylamine hydrochloride (23.9 mg, 0.30 mmol) as described in General Procedure X to afford Iad (53.0 mg, 60.4%) as an ivory colored solid, tlc Rf=0.1 (10% MeOH/CH2Cl2−0.2% Et3N), m/z obs=326 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:42])[C:6]2=[N:7][CH:8]=[C:9](B3OC(C)(C)C(C)(C)O3)[CH:10]=[C:5]2[N:4]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=3)[N:23]=[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:37]([CH3:40])(=[O:39])=[O:38])[C:21]=2[CH3:41])[CH2:3]1.[NH2:43][C:44]1[N:49]=[C:48](Cl)[CH:47]=[CH:46][N:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[F:30][C:26]1[CH:25]=[C:24]2[C:29]([C:20]([N:4]3[C:5]4[C:6](=[N:7][CH:8]=[C:9]([C:46]5[CH:47]=[CH:48][N:49]=[C:44]([NH2:43])[N:45]=5)[CH:10]=4)[C:2]([CH3:1])([CH3:42])[CH2:3]3)=[C:21]([CH3:41])[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:37]([CH3:40])(=[O:38])=[O:39])=[N:23]2)=[CH:28][CH:27]=1
Reactant: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: Nc1nccc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(-c3ccnc(N)n3)cc21
Temperature: 120 °C

Procedure:
Prepared according to procedure P using 4-(3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline (131 mg, 0.22 mmol) (described herein), 2-amino-4-chloropyrimidine (28.9 mg, 0.22 mmol), bis(triphenylphosphine)palladium(ii) chloride (15.7 mg, 0.022 mmol), and sodium carbonate (70.9 mg, 0.67 mmol) in 1,4-dioxane (4.8 mL) and water (1.2 mL). The reaction mixture was heated in a microwave at 120° C. for 60 min. Purification afforded 4-(1-(7-fluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)-4-quinolinyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-2-pyrimidinamine as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.55 (1H, m), 8.11-8.35 (2H, m), 8.04 (1H, m), 7.64-7.91 (3H, m), 7.44-7.57 (1H, m), 7.20-7.44 (2H, m), 6.70-7.05 (1H, m), 4.9-5.35 (2H, m), 3.35-3.96 (2H, m), 2.97-3.22 (3H, m), 1.87-2.05 (3H, m), 1.44-1.73 (6H, m). Mass Spectrum (ESI) m/e=555 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[CH:6]1([CH2:5][CH:4]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([C:22]([F:25])([F:23])[F:24])[CH:13]=2)[C:3]([OH:26])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCCC1)c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCCCC2)C(=O)O)cc1C(F)(F)F
Temperature: 47.5 °C
Yield: 98.2 %

Procedure:
A solution of 3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid methyl ester (265 mg, 0.67 mmol) in ethanol (5 mL) was treated with a 1N aqueous sodium hydroxide solution (1.5 mL). The solution was heated at 45-50° C. for 5 h, at which time, thin layer chromatography analysis of the mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove ethanol, and the residue was diluted with water (20 mL) and extracted with diethyl ether (1×40 mL) to remove any neutral impurities. The aqueous layer was acidified with a 1N aqueous hydrochloric acid solution. The resulting acid was extracted into ethyl acetate (2×50 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid (249 mg, 97%) as a viscous oil: EI-HRMS m/e calcd for C17H21F3O4S (M+) 378.1113, found 378.1121.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N:3]=1.[CH:13]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])[CH3:14].[H-].[Na+]>O1CCOCC1>[CH:13]([O:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([O:25][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=2[O:8][CH3:9])[CH2:23][CH2:24]1)=[O:18])([CH3:15])[CH3:14]
Reactant: CC(C)OC(=O)N1CCC(O)CC1
Reactant: COc1c([N+](=O)[O-])ccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1c(OC2CCN(C(=O)OC(C)C)CC2)ccnc1Cl
Temperature: 100 °C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
To a solution of 2-chloro-3-methoxy-4-nitro-pyridine (102.3 mg, 0.543 mmol) and 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (110 mg, 0.587 mmol) in dioxane (3 mL), sodium hydride (60% dispersion, 32 mg, 0.8 mmol) were added. After stirring at 100° C. for 1 hour, mixture was purified by HPLC to give 4-(2-chloro-3-methoxy-pyridin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester as a white solid (42.0 mg, 24%). 1HNMR (CDCl3, 400 MHz) δ 8.16-8.15 (d, J=5.4 Hz, 1H), 6.92-6.90 (d, J=5.8 Hz), 4.97-4.91 (m, 1H), 4.72-4.68 (m, 1H), 3.91 (s, 3H), 3.75-3.68 (m, 2H), 3.75-3.68 (m, 2H), 3.55 (m, 2H), 2.02-1.85 (m, 4H), 1.27-1.26 (d, J=6.2 Hz, 6H). Exact mass calculated for C15H21ClN2O4 328.12. found 329.2 (MH+).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)([CH3:3])[CH3:2].Cl.[CH2:20]([C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:21].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CN1CCOCC1>CO.C(Cl)(Cl)Cl>[CH2:20]([C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH2:30][CH2:31][N:32]([C:14]([C:13]2[CH:12]=[CH:11][C:10]([N:5]3[C@H:4]([CH:1]([CH3:2])[CH3:3])[CH2:8][O:7][C:6]3=[O:9])=[CH:18][CH:17]=2)=[O:16])[CH2:33][CH2:34]1)[CH3:21]
Reactant: CCc1cc(C)ccc1N1CCNCC1
Reactant: CC(C)[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: CCc1cc(C)ccc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.4 %

Procedure:
To a mixture of (R)-4-(4-isopropyl-2-oxooxazolidin-3-yl)benzoic acid (482 mg) described in Preparation Example 18, 1-(2-ethyl-4-methylphenyl)piperazine hydrochloride (499 mg), which is the intermediate described in Preparation Example 15, and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (829 mg) were added chloroform (3 mL), methanol (3 mL) and N-methylmorpholine (220 μL), and the mixture was stirred at room temperature overnight. After evaporation of the solvent, the residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (88 mg).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1>>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: COc1ccc(C2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)cc1
Yield: 72 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 4-bromoanisole, the hydrochloride salt of the title compound was formed in 72% yield as a white solid, mp 228°-231° C. elemental