Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[C:4]([O:11][CH3:12])(=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].Cl>C(OCC)(=O)C.CS(C)=O>[F:20][C:18]1[CH:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]([CH:5]([C:4]([O:11][CH3:12])=[O:10])[C:6]([O:8][CH3:9])=[O:7])[CH:19]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 76.9 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel and having an inner volume of 100 ml were charged 3.40 g (62.9 mmol) of sodium methoxide and 20 ml of dimethyl sulfoxide under argon atmosphere, and then, while stirring at room temperature, 8.31 g (62.3 mmol) of dimethyl malonate with a purity of 99% was gradually added dropwise to the mixture over 5 minutes. After cooling the mixture to 20° C., 5.10 g (31.4 mmol) of 2,4-di-fluoronitrobenzene was gradually added dropwise to the mixture over 5 minutes, and the temperature of the mixture was raised to 80° C. and the mixture was reacted for one hour. After completion of the reaction, the mixture was cooled to room temperature, and then, 100 ml of ethyl acetate was added to the mixture, and 5.25 ml (31.4 mmol) of 6 mol/l hydrochloric acid was gradually added dropwise to the mixture while stirring. Then, the organic layer was separated, and washed successively with 30 ml of water and 30 ml of a saturated saline solution in this order, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting concentrate was purified by silica gel column chromatography (filler: Daisogel 1002W, eluent: hexane:ethyl acetate=9:1 (volume ratio)) to obtain 6.55 g of dimethyl 2-(5-fluoro-2-nitrophenyl)malonate (isolation yield: 75%) as a white crystal with a purity of 97.2% (areal percentage by high performance liquid chromatography).
Reaction SMILES: [C:1]1([CH3:27])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][C:18]([C:19]4[CH:20]=[C:21]([CH2:25]O)[CH:22]=[CH:23][CH:24]=4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Li+].[OH-].[ClH:30]>C1COCC1.O>[Cl:30][CH2:25][C:21]1[CH:20]=[C:19]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:27])=[CH:2][CH:3]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cccc(CO)c4)ccnc32)cc1
Reactant: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cccc(CCl)c4)ccnc32)cc1
Reaction time: 4 h

Procedure:
To a stirred solution of compound G″ in THF, water was added LiOH (3.68 g, 0.087 mol) at rt and stirred for 4 h at same temperature. The reaction mixture was concentrated to obtain residue which was diluted with water (50 ml), acidified with 2N aq. HCl solution, adjusted to pH=5-6, the precipitated solid was filtered, washed with water and dried (traces water were removed by co-evaporating with toluene) to obtain compound H″. The compound H″ was washed with diethyl ether to obtain desired purity.
Reaction SMILES: C(NC(C)C)(C)C.[CH3:8][S@@:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:10].C([O:26][C:27](=O)[C@@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[C:33](=[O:49])[C@@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:39](=[O:48])[CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)C1C=CC=CC=1>C1COCC1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([S@:9]([CH2:8][C:27]([C@@H:28]2[CH2:32][CH2:31][CH2:30][N:29]2[C:33](=[O:49])[C@@H:34]2[CH2:38][CH2:37][CH2:36][N:35]2[C:39](=[O:48])[CH2:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[O:26])=[O:10])=[CH:12][CH:13]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CCc1ccccc1
Reactant: COc1ccc([S@](C)=O)cc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc([S@@](=O)CC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)CCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
To diisopropylamine (0.13 ml) in THF (8 ml) was dropwise added 1.62M n-butyllithium-hexane solution (1.2 ml) at -78° C., followed by stirring at 0° C. for 0.5 hour. The reaction mixture was cooled to -30° C., dropwise added with (S)-(-)-4methoxyphenyl methyl sulfoxide (157 mg) in THF (8 ml), and stirred at 0° C. for 0.5 hour. The reaction mixture was cooled to -78° C., added with N-(3-phenylpropionyl)-L-prolyl-L-proline benzyl ester (400 mg) in THF (8 ml) quickly, and stirred for 0.5 hour. The reaction mixture was treated as in Example 13-A) and the residue obtained was purified by medium pressure liquid chromatography (silica gel, eluate; chloroform:methanol=99:1) to give 195 mg of the title compound (See Table 5).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[F:8][C:9]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[CH3:26][N:27]([CH3:31])[C:28](Cl)=[O:29]>O.C(Cl)(Cl)Cl>[CH3:26][N:27]([C:28]([N:15]1[CH2:16][CH2:17][CH:12]([O:11][C:10]2[C:18]([F:25])=[C:19]([F:24])[C:20]([F:23])=[C:21]([F:22])[C:9]=2[F:8])[CH2:13][CH2:14]1)=[O:29])[CH3:31]
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Reactant: CN(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(C)C(=O)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71.1 %

Procedure:
To a stirring solution of 10 g of potassium carbonate in 50 ml of water was added 4.42 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine hydrochloride in 50 ml of chloroform, followed by a solution of 3.23 g of dimethylcarbamoyl chloride in 20 ml of chloroform which was added, dropwise, over a period of 20 minutes. After stirring for 20 hours at room temperature, the layers were separated; the organic layer was washed with water followed by a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Filtration, followed by evaporation of the filtrate afforded an oil. The oil was purified by means of high pressure liquid chromatography (silica gel; elution with 5% methanol/dichloromethane) to afford 3.50 g (69.0%) of 1-[(N,N-dimethylamino)carbonyl]-4-(2,3,4,5,6-pentafluorophenoxy)piperidine as an oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](/[C:8](=[N:11]\[S@@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])/[CH2:9][F:10])[C:5]([F:18])=[C:4]([Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:3]=1.C1COCC1.[Cl-].[C:32]([O:36][C:37](=[O:40])[CH2:38][Zn+])([CH3:35])([CH3:34])[CH3:33]>C([O-])(O)=O.[Na+].O>[Br:1][C:2]1[N:7]=[C:6]([C@:8]([NH:11][S@@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])([CH2:9][F:10])[CH2:38][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:40])[C:5]([F:18])=[C:4]([Si:19]([CH2:20][CH3:21])([CH2:22][CH3:23])[CH2:24][CH3:25])[CH:3]=1
Reactant: CC[Si](CC)(CC)c1cc(Br)nc(/C(CF)=N\[S@](=O)C(C)(C)C)c1F
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC[Si](CC)(CC)c1cc(Br)nc([C@](CF)(CC(=O)OC(C)(C)C)N[S@](=O)C(C)(C)C)c1F
Temperature: 0 °C

Procedure:
To a 1000 mL 3-neck round-bottomed flask equipped with an addition funnel and internal temperature probe was added (R,E)-N-(1-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide (43.3 g, 95 mmol) and THF (400 mL). The mixture was cooled to 0° C. and 2-tert-butoxy-2-oxoethylzinc chloride (Rieke Metals; 458 mL, 229 mmol, 0.5 M in diethyl ether) was added dropwise over 1 h keeping the internal temperature under 3° C. After the addition the ice bath was allowed to melt and warm to rt overnight. The reaction mixture was diluted with sat NaHCO3 (200 mL) and water (200 mL) and extracted with EtOAc (3×200 mL). The combined extracts were washed with brine, dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (Gradient: 0.0 to 25% EtOAc/hexane, 1500 g RediSep column) afforded:
Reaction SMILES: C(C1[CH:4]=[C:5]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:30])[NH:22][C:23]([CH3:29])=[CH:24][C:25]=2[CH2:26][CH2:27][CH3:28])=[O:17])[C:6]2[C:7]([CH3:15])=[CH:8][N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1)#N.[OH-].[K+].C(O)C.CC[O:38][C:39]([CH3:41])=[O:40]>>[CH3:15][C:7]1[C:6]2[C:10](=[CH:11][C:41]([C:39]([OH:38])=[O:40])=[CH:4][C:5]=2[C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:30])[NH:22][C:23]([CH3:29])=[CH:24][C:25]=2[CH2:26][CH2:27][CH3:28])=[O:17])[N:9]([CH:12]([CH3:13])[CH3:14])[CH:8]=1
Reactant: CCOC(C)=O
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(C#N)cc2c1c(C)cn2C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(C(=O)O)cc2c1c(C)cn2C(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 64.9 %

Procedure:
To a 5 ml microwave vial was added, 6-cyano-3-methyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indole-4-carboxamide (100 mg, 0.247 mmol), KOH (41.6 mg, 0.742 mmol) was ground and added followed by Ethanol (8 mL) the reaction was microwaved at 145° C. for 22 hr. The reaction was poured onto acidic Ice water (20 mL) and was stirred for 20 min. EtOAc was added and the mix was stirred an additional 10 min. The layers were separated and the majority of the product was in the EtOAc which was evaporated. The residue was dissolved in MeOH (1 mL) and material was crashed out with ice and was filtered to give product 3-methyl-1-(1-methylethyl)-4-({[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]amino}carbonyl)-1H-indole-6-carboxylic acid (70 mg, 0.160 mmol, 64.9% yield) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.49 (br. s., 1H) 8.18 (s, 1H) 8.10 (s, 1H) 7.53 (d, J=7.58 Hz, 2H) 5.90 (s, 1H) 4.76-4.90 (m, 1H) 4.36 (d, J=4.80 Hz, 2H) 2.55 (br. s., 1H) 2.18 (s, 3H) 2.13 (s, 3H) 1.52-1.61 (m, 2H) 1.44 (d, J=6.57 Hz, 6H) 0.94 (t, J=7.33 Hz, 3H) MS (ES) [M+H]+ 423.8
Reaction SMILES: C(OCCOC)(=O)CC(C)=O.[CH3:12][C:13]1([CH3:21])[O:18][C:17](=[O:19])[CH:16]=[C:15]([CH3:20])O1.[NH3:22].C(OC(C)C)(=O)CC(C)=O>CC(O)C.COCCO>[NH2:22]/[C:15](/[CH3:20])=[CH:16]\[C:17]([O:18][CH:13]([CH3:21])[CH3:12])=[O:19]
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: N
Agent: CC(=O)CC(=O)OC(C)C
Agent: COCCOC(=O)CC(C)=O
Solvent: COCCO
Solvent: CC(C)O
Product: C/C(N)=C/C(=O)OC(C)C

Procedure:
The ester, 2-methoxyethyl acetoacetate (51), was prepared by the reaction of 2-methoxyethanol with 2,2,6-trimethyl-4H-1,3-dioxin-4-one (53) (eq. 28). (Hyatt, J. A. J. Org. Chem. 1984, 49, 5102. Hyatt, J. A.; Feldman, P. L.; Clemens, R. J. Ibid. 1984, 49, 5105. Kato, T.; Sato, M.; Kanuma, N. Chem. Pharm. Bull. 1982, 30, 1315). The enamine, 1-methylethyl 3-aminocrotonate (52) was prepared by the reaction of ammonia with 1-methylethyl acetoacetate (54) (eq. 29) (Iwanami, J. et al. Chem. Pharm. Bull. 27, 1426 (1979)) which was obtained by the reaction of 2-propanol with 53 (eq. 30) as shown in Schemes IIa, IIb and IIc. ##STR13##
Reaction SMILES: [OH-].[Na+].CO.[Cl:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][CH2:17][CH2:18][C:19]1([C:33]([O:35]CC)=[O:34])[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][S:27][C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[CH2:21][CH2:20]1)=[CH:13][C:12]([O:38][CH3:39])=[C:11]([O:40][CH3:41])[CH:10]=2>O1CCOCC1>[Cl:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][CH2:17][CH2:18][C:19]1([C:33]([OH:35])=[O:34])[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][S:27][C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[CH2:21][CH2:20]1)=[CH:13][C:12]([O:38][CH3:39])=[C:11]([O:40][CH3:41])[CH:10]=2
Reactant: CCOC(=O)C1(CCCc2c(Cl)cnc3cc(OC)c(OC)cc23)CCN(CCSc2cccs2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc2ncc(Cl)c(CCCC3(C(=O)O)CCN(CCSc4cccs4)CC3)c2cc1OC
Temperature: 20 °C
Yield: 73.7 %

Procedure:
26 cm3 of aqueous 5N sodium hydroxide and 20 cm3 of methanol were added to a solution of 1.47 g of ethyl 4-[3-(3-chloro-6,7-dimethoxyquinolin-4-yl)propyl]-1-[2-(thiophen-2-ylthio)ethyl]piperidine-4-carboxylate in 20 cm3 of dioxane, with stirring and at a temperature in the region of 20° C., and the mixture was then maintained at a temperature of about 70° C. for 21 hours. The reaction mixture was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under a pressure of 50 kPa of argon, on a column of silica gel (particle size 40-63μ; mass 60 g), eluting with a mixture of dichloromethane/methanol/aqueous ammonia (12/3/0.5 by volume). Fractions 11 to 25 were combined and then concentrated to dryness under the above conditions. 1.03 g of 4-[3-(3-chloro-6,7-dimethoxy-quinolin-4-yl)propyl]-1-[2-(thiophen-2-ylthio)ethyl]-piperidine-4-carboxylic acid was obtained in the form of a white solid melting at 214° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].CCCCCCC.C1COCC1.[Cl:21][C:22]1[CH:27]=[C:26]([O:28][C:29]2[CH:41]=[CH:40][C:39]([C:42]3[CH:43]=[N:44][CH:45]=[N:46][CH:47]=3)=[CH:38][C:30]=2[C:31](N(CC)CC)=[O:32])[CH:25]=[CH:24][N:23]=1>C1COCC1>[Cl:21][C:22]1[C:27]2[C:31](=[O:32])[C:30]3[CH:38]=[C:39]([C:42]4[CH:47]=[N:46][CH:45]=[N:44][CH:43]=4)[CH:40]=[CH:41][C:29]=3[O:28][C:26]=2[CH:25]=[CH:24][N:23]=1
Reactant: CCN(CC)C(=O)c1cc(-c2cncnc2)ccc1Oc1ccnc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: O=c1c2cc(-c3cncnc3)ccc2oc2ccnc(Cl)c12
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
Lithium diisopropylamide, 1.8 M in heptane/THF (5.80 mL, 10.45 mmol) was added dropwise to a −78° C. solution of 2-(2-chloropyridin-4-yloxy)-N,N-diethyl-5-(pyrimidin-5-yl)benzamide (1.000 g, 2.61 mmol) in THF (20.0 mL). The reaction mixture was stirred at −78° C. for 2.5 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and the mixture was partitioned between EtOAc and water. The aqueous phase was separated and extracted with DCM. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford an orange solid. This material was purified via column chromatography on silica gel (RediSep 40 g column, eluting with 100% EtOAc) to afford 1-chloro-8-(pyrimidin-5-yl)-10H-chromeno[3,2-c]pyridin-10-one as an off-white solid. MS m/z=310.0 [M+H]+. Calcd for C16H8ClN3O2: 309.7.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:36][CH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][O:39]1)(=O)=O>CN(C=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:36][CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Reactant: CS(=O)(=O)OCCC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)c2nc(OC)n(CCC3CCCCO3)c2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
A mixture of N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt (200 mg) and potassium carbonate (236 mg) in dry DMF (2 mL) were heated at 60° C. with stirring for 1 h. 2-(Tetrahydro-2H-pyran-2-yl)ethyl methanesulfonate (142 mg) was added and the reaction was continued for 3 h at 60° C. The mixture was quenched with water and extracted with EtOAc (×3). The combined organics were washed with water and brine, dried using a hydrophobic frit and evaporated to give crude material (250 mg). The material was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluent (20-60%) and the appropriate fractions combined and evaporated to remove acetonitrile. The remaining aqueous mixture was made basic with saturated sodium hydrogen carbonate, extracted three times with dichloromethane and the combined extracts dried by passing through a phase separation cartridge then evaporated to give 75 mg of material which was recrystallised from ether/light petrol yielding the title compound as a solid, 54 mg.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:3].[NH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][N:28]1[C:36]2[C:35]([CH3:37])=[C:34]([CH3:38])[N:33]=[C:32]([NH2:39])[C:31]=2[N:30]=[C:29]1[CH3:40]>>[NH2:39][C:32]1[C:31]2[N:30]=[C:29]([CH3:40])[N:28]([CH2:27][CH2:26][O:25][CH2:24][CH2:23][NH:22][S:18]([C:15]3[CH:16]=[CH:17][C:12]([N:11]=[N:10][C:7]4[CH:8]=[CH:9][C:4]([N:2]([CH3:3])[CH3:1])=[CH:5][CH:6]=4)=[CH:13][CH:14]=3)(=[O:20])=[O:19])[C:36]=2[C:35]([CH3:37])=[C:34]([CH3:38])[N:33]=1
Reactant: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)Cl)cc2)cc1
Reactant: Cc1nc(N)c2nc(C)n(CCOCCN)c2c1C
Product: Cc1nc(N)c2nc(C)n(CCOCCNS(=O)(=O)c3ccc(N=Nc4ccc(N(C)C)cc4)cc3)c2c1C

Procedure:
Using the method of Examples 34-50, 4-dimethylaminoazobenzene-4′-sulfonyl chloride was reacted with 1-[2-(2-aminoethoxy)ethyl]-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The product was purified using Method A. The observed accurate mass was 551.2551.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][CH:27]=2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=1)[C:22]1[CH:23]=[N:24][C:25]([C:28]([F:30])([F:31])[F:29])=[N:26][CH:27]=1)=[O:6]
Reactant: O=C(O)c1cccc(F)c1Cl
Reactant: NCC(c1ccc(F)cc1)c1cnc(C(F)(F)F)nc1
Product: O=C(NCC(c1ccc(F)cc1)c1cnc(C(F)(F)F)nc1)c1cccc(F)c1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-3-fluorobenzoic acid and 2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=442.1, tR (minutes, Method F)=3.24. [α]D20=12.8 (c=6.8 mg/mL,CHCl3)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].CCN(CC)CC.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([S:11]([C:3]2[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=2[Cl:1])[C:6]([OH:8])=[O:7])(=[O:13])=[O:12])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc(C(=O)O)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of 4-chloro-3-(chlorosulfonyl)benzoic acid (200 mg, 0.784 mmol) and Et3N (130 μl, 0.938 mmol) in CH2Cl2 (5 ml) was added 1-(t-butoxycarbonyl)piperazine (161 mg, 0.864 mmol) at 0° C. This mixture was stirred at room temperature overnight, and then diluted with CH2Cl2, washed with 10% citric acid solution. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was suspended in Et2O, and the precipitate was collected by filtration to give crude 3-{[4-(tert-butoxycarbonyl)-1-piperazinyl]sulfonyl}-4-chlorobenzoic acid (200 mg, 63.0%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=O)[CH2:11][C:12]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])=O)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[CH2:29]([NH:31][NH2:32])[CH3:30].CCN(CC)CC>CCO>[CH2:29]([N:31]1[C:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:11][C:12]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])=[N:32]1)[CH3:30]
Reactant: N#Cc1cccc(C(=O)CC(=O)CCc2ccc(F)cc2)c1
Reactant: CCNN
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCn1nc(-c2cccc(C#N)c2)cc1CCc1ccc(F)cc1
Yield: 25.9 %

Procedure:
A mixture of 3-[5-(4-fluorophenyl)-3-oxo-pentanoyl]-benzonitrile (1.0 g, 3.39 mmol), ethyl hydrazine oxalate (763 mg, 5.08 mmol) and Et3N (709 □L, 5.08 mmol) in EtOH (50 mL) was heated at reflux for 3 hours. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (100 mL) and H2O (50 mL). The organics were separated, washed with brine (50 mL), concentrated under reduced pressure, and the residue purified by column chromatography on silica eluting with 40% EtOAc/iso-hexanes to yield first 3-{1-ethyl-5-[2-(4-fluorophenyl)-ethyl]-1H-pyrazol-3-yl}-benzonitrile (280 mg, 26%) (by-product) and then 3-{1-ethyl-3-[2-(4-fluorophenyl)-ethyl]-1H-pyrazol-5-yl}-benzonitrile (380 mg, 35%).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][NH:9][C:10]([C:12]2([NH2:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.Cl[C:22]1[C:23]2[CH:30]=[CH:29][NH:28][C:24]=2[N:25]=[CH:26][N:27]=1.C(N(CC)CC)C>C(O)CCC>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C:12]2([NH2:18])[CH2:13][CH2:14][N:15]([C:22]3[C:23]4[CH:30]=[CH:29][NH:28][C:24]=4[N:25]=[CH:26][N:27]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:19][CH:20]=1
Reactant: NC1(C(=O)NCc2ccc(Cl)cc2)CCNCC1
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: NC1(C(=O)NCc2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
A degassed mixture of 4-amino-piperidine-4-carboxylic acid 4-chloro-benzylamide dihydrochloride (48 mg, 0.13 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (21 mg, 0.12 mmol), triethylamine (126 uL, 0.9 mmol) and n-butanol (1.2 mL) was stirred at 100° C. for 18 h. The solvents were removed by evaporation and the crude mixture was first purified on a SCX-II acid resin, eluting with methanol then 2M ammonia/methanol, and then by preparative TLC, eluting with 10% methanol in dichloromethane, to give 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic acid 4-chloro-benzylamide (37 mg, 0.096 mmol, 80%). LC-MS (LCT2) m/z 385 [M+H+], R, 2.84 min.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[I:12].[OH-].[Li+]>O1CCOCC1.O>[NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[I:12]
Reactant: COC(=O)c1ccc(N)c(I)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(C(=O)O)cc1I
Yield: 98.6 %

Procedure:
A solution of 3.00 g (10.8 mmol) of methyl 4-amino-3-iodobenzoate and 1.30 g (54.1 mmol) of lithium hydroxide in 150 ml of a dioxane/water mixture (1:1) was stirred at room temperature for 6 h. The dioxane was distilled off in vacuo, and the remaining aqueous phase was adjusted to pH 5 with 1 M hydrochloric acid. The precipitate was filtered off with suction and washed with water. 2.80 g (98%) of the title compound were obtained as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH:16]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)=[O:17].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[CH:16]([C:18]1[CH:23]=[C:22]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=2)[CH:21]=[CH:20][CH:19]=1)=[O:17]
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(CNS(C)(=O)=O)c1ccc(-c2cccc(C=O)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a degassed solution of 1.5 g (5.1 mmol) of material from Example 1, 1.2 g (8.1 mmol) of 3-formylbenzeneboronic acid and 1.1 g (8.1 mmol) of potassium carbonate in 30 mL of toluene was added 0.3 g (0.3 mmol) of tetrakis-(triphenylphosphine)palladium(0). The mixture was heated to 100° C. for 16 hours whereupon 5 mL of water was added and heating continued for 1 hour. The mixture was then cooled to ambient temperature and 10 mL of water was added. The organic portion was separated and the aqueous portion was extracted twice with ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography on 50 g silica gel (40% ethyl acetate/hexane) afforded 0.7 g (41%) of the title compound.