Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[CH2:10](I)[CH:11]=[CH2:12].O>CN1C(=O)N(C)CC1>[C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]([OH:8])[CH2:12][CH:11]=[CH2:10])=[CH:3][CH:2]=1
Reactant: C=CCI
Reactant: Cc1ccc(C=O)cc1
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: C=CCC(O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
5.90 ml (50 mmol) p-tolualdehyde was dissolved in 150 ml of DMI, and 5.5 ml (60 mmol, 1.2 eq.) allyl iodide and 10.34 g (66 mmol, 1.3 eq.) SnF2 were added. The reaction became warm to the touch and much precipitate formed as the reaction progressed. After stirring for 1 hour at room temperature, 200 ml of H2O was added, the mixture was extracted with Et2O (1×250 ml, 2 ×100 ml), the combined Et2O layers were washed with sat. NH4Cl (3×50 ml, to remove excess DMI), dried over MgSO4, and evaporated in vacuo to an oil. Flash chromatography (1:4 EtOAc:hexanes, Rf 0.56) yielded 7.5 g (93%) of product as a clear oil. 1H NMR (CDCl3): 7.25 and 7.15 (4H, phenyl), 5.8 and 5.15 (3H, vinyl), 4.65 (1H, CHOH), 2.5 (2H, CH2), 2.35 (2H, CH2), 2.35 (3H, CH3), and 2.15 (1H, OH) ppm.
Reaction SMILES: [C:1]([N:5]([CH3:29])[C:6]([C:8]1[N:12]2[CH2:13][CH2:14][C:15]3[C:20]([C:11]2=[C:10]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[CH:9]=1)=[CH:19][C:18]([NH2:21])=[C:17]([O:22][CH3:23])[CH:16]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:37][O:38][CH2:39][C:40](Cl)=[O:41]>ClCCl>[C:1]([N:5]([CH3:29])[C:6]([C:8]1[N:12]2[CH2:13][CH2:14][C:15]3[C:20]([C:11]2=[C:10]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[CH:9]=1)=[CH:19][C:18]([NH:21][C:40](=[O:41])[CH2:39][O:38][CH3:37])=[C:17]([O:22][CH3:23])[CH:16]=3)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cc2c(cc1N)-c1c(-c3cccs3)cc(C(=O)N(C)C(C)(C)C)n1CC2
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)Nc1cc2c(cc1OC)CCn1c(C(=O)N(C)C(C)(C)C)cc(-c3cccs3)c1-2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of the product of example 95 (30 mg), triethylamine (10.2 μl) and methoxyacetyl chloride (6.7 μl) was stirred at room temperature for 3 h. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (0→90% acetonitrile; system 1).
Reaction SMILES: [O:1]1CCN=[CH:2]1.[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11].[Li]C(CC)C.CN(C=O)C>C1COCC1>[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]2[C:8]=1[CH:2]([OH:1])[O:11][C:10]2=[O:12]
Reactant: O=C(O)c1cccc(F)c1
Reactant: C1=NCCO1
Agent: [Li]C(C)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1OC(O)c2c(F)cccc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a -78° C. solution of the oxazoline derivative (7.8 g, 40.4 mmol), prepared from 3-fluorobenzoic acid in tne usual manner, in THF (50 mL) was added over 15 min sec-BuLi (29 mL of 1.4 M solution). After 30 min, DMF (6.3 mL) was added, and the reaction mixture was stirred at -78° C. for 2 hr. Tne reaction was then quenched with water (10 mL), and the mixture was acidified witn HCl and allowed to stir for 12 hr. The layers were separated, the aqueous layer was extracted with EtOAc, and the combined organic layer was concentrated in vacuo. Tnis material was dissolved in 5% KOH (50 mL), and the base layer was washed with Et2O (2×100 mL) to remove neutrals. The resulting base layer was added to 0° C. solution of concentrated HCl (25 mL), and the resulting cold acidic solution was extracted with EtOAc (3×75 mL). Workup and drying gave a tacky yellow solid (4.4 g) which was recrystallized from CHCl3 to give the title compound (1.97 g, 30%), mp 97°-100° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][C:20]([CH3:31])([CH3:30])[CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH:28]=[O:29])[CH2:24][CH2:23]1)(=[O:17])[CH2:13][C:14]([CH3:16])=O.[NH2:32]/[C:33](/[CH3:39])=[CH:34]\[C:35]([O:37][CH3:38])=[O:36]>C(O)(C)C>[CH3:16][C:14]1[NH:32][C:33]([CH3:39])=[C:34]([C:35]([O:37][CH3:38])=[O:36])[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:13]=1[C:12]([O:18][CH2:19][C:20]([CH3:31])([CH3:30])[CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH:28]=[O:29])[CH2:24][CH2:23]1)=[O:17]
Reactant: CC(=O)CC(=O)OCC(C)(C)CN1CCN(C=O)CC1
Reactant: COC(=O)/C=C(/C)N
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)(C)CN2CCN(C=O)CC2)C1c1cccc([N+](=O)[O-])c1
Yield: 75.3 %

Procedure:
425 mg of m-nitrobenzaldehyde, 830 mg of 3-(4-formyl-1-piperazinyl)-2,2-dimethylpropyl acetoacetate, and 324 mg of methyl 3-aminocrotonate were dissolved in 6 ml of isopropanol, and the solution was subjected to heating reflux for 12 hours. Then, the solvent was concentrated under reduced pressure. The residue was purified by the chromatography method [30 g silica gel, eluted with ethyl acetate) to give 1090 mg of the subject compound (yield: 75%). The IR and NMR data of the compound thus obtained are as follows: ##STR15##
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:37])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:17][CH:16]2[C:34]([OH:36])=O)[CH:12]=[CH:13][CH:14]=1.[NH2:38][CH2:39][CH2:40][C@@H:41]([CH3:44])[CH2:42][OH:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:43][CH2:42][C@H:41]([CH3:44])[CH2:40][CH2:39][NH:38][C:34]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:37])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:31])([CH3:32])[CH3:33])[NH:17]1)=[O:36]
Reactant: C[C@@H](CO)CCN
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](CO)CCNC(=O)C1NC(CC(C)(C)C)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1F
Yield: 64.5 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.16 g, 0.29 mmol) was reacted with (R)-4-amino-2-methyl-1-butanol (TCI-US) (0.1 g, 1 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.3 g, 2 mmol) in CH2Cl2 (20 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-4-hydroxy-3-methyl-butyl)-amide as a white solid (0.1 g, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[Cl:21][C:22]1[N:27]=[N:26][C:25]([C:28](Cl)=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl.N1C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:16][CH2:17][N:18]([C:28]([C:25]3[N:26]=[N:27][C:22]([Cl:21])=[CH:23][CH:24]=3)=[O:29])[CH2:19][CH2:20]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(Cl)c1ccc(Cl)nn1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(Cl)nn1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a solution of 1-(6-chloronaphthalen-2-ylsulfonyl)-piperazine (0.450 g, 1.45 mmol) in methylene chloride (100 mL) and pyridine (0.154 mL) was added dropwise 6-chloropyridazine-3-carbonyl chloride (1.74 mmol). After the addition of the acid chloride, pyridine (0.154 mL) was added, and the reaction mixture was stirred overnight. The reaction mixture was diluted with chloroform (500 mL), washed with saturated sodium bicarbonate (200 mL), water (200 mL),and brine and dried over MgSO4. After filtration and evaporation of the solvent, trituration of the residue with ethyl acetate and filtration gave the product as a white powder (0.5 g, 76%)
Reaction SMILES: [Li].[O:2]([CH2:5][CH3:6])CC.IC.[CH3:9][CH:10]([N:12]1[CH2:17][CH2:16][C:15]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(C(O)=O)[CH2:14][CH2:13]1)[CH3:11]>O>[CH3:11][CH:10]([N:12]1[CH2:17][CH2:16][C:15]([C:5](=[O:2])[CH3:6])([NH:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:14][CH2:13]1)[CH3:9]
Reactant: CCOCC
Reactant: CC(C)N1CCC(Nc2ccccc2)(C(=O)O)CC1
Agent: [Li]
Solvent: O
Solvent: CI
Product: CC(=O)C1(Nc2ccccc2)CCN(C(C)C)CC1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 33.5 %

Procedure:
To a stirred mixture of 13.8 parts of lithium and 140 parts of 1,1'-oxybisethane is added dropwise a mixture of 156 parts of iodomethane and 140 parts of 1,1'-oxybisethane while nitrogen gas is introduced. After the addition is complete, there are added 420 parts of 1,1'-oxybisethane and stirring is continued at reflux temperature till all lithium has reacted (about 15 minutes). Then there are added portionwise 26.25 parts of 1-(1-methylethyl)-4-(phenylamino)-4-piperidinecarboxylic acid (exothermic reaction: reflux temperature is maintained) while nitrogen gas is still introduced. Upon completion, stirring at reflux is continued for 1.50 hours. After the nitrogen gas introduction is stopped, the reaction mixture is cooled to 5° C. and decomposed by pouring onto 600 parts of water. The organic phase is separated, washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume), saturated with ammonia, as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from petroleumether at 0° C. The product is filtered off and dried, yielding 8.7 parts (33.5%) of 1-[1-(1-methylethyl)-4-(phenylamino)-4-piperidinyl]ethanone; mp. 107.1° C.
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O)C([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=CC=2)(=O)=O)C=CC=CC=1.Br[C:29]1[C:30]([O:49][CH3:50])=[C:31]([C:36]([CH2:39][S:40]([N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)(=[O:42])=[O:41])=[CH:37][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33].O1C=CC(B(O)O)=C1>>[O:25]1[CH:26]=[CH:27][C:23]([C:29]2[C:30]([O:49][CH3:50])=[C:31]([C:36]([CH2:39][S:40]([N:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)(=[O:42])=[O:41])=[CH:37][CH:38]=2)[C:32]([O:34][CH3:35])=[O:33])=[CH:24]1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Reactant: COC(=O)c1c(CS(=O)(=O)N2CCCCC2)ccc(Br)c1OC
Agent: OB(O)c1ccoc1
Product: COC(=O)c1c(CS(=O)(=O)N2CCCCC2)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 3-bromo-2-methoxy-6-(piperidin-1-ylsulphonylmethyl)benzoate (Intermediate 147) and furan-3-boronic acid as a white solid.
Reaction SMILES: ClC1C=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][N:3]=1.[C:12]([N:19]1CCC(N)C[CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[CH3:26][CH2:27][N:28]([CH:32]([CH3:34])C)[CH:29]([CH3:31])C.O>CN1C(=O)CCC1>[F:11][C:8]([F:9])([F:10])[C:6]1[N:5]=[CH:4][N:3]=[C:32]([N:28]2[CH2:27][CH2:26][CH:20]([NH:19][C:12](=[O:13])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:31][CH2:29]2)[CH:34]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: FC(F)(F)c1cc(Cl)ncn1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(C(F)(F)F)ncn2)CC1
Yield: 92 %

Procedure:
To a mixture of 4-chloro-6-(trifluoromethyl)pyrimidine (0.82 g, 4.49 mmol) and Boc-4-aminopiperidine (1.17 g, 5.84 mmol) in NMP (5.7 mL) was added DIPEA (1.10 mL, 6.29 mmol) and after 30 minutes the mixture was poured into water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel, 70 g, 0 to 50% ethyl acetate in heptane) afforded the title compound (1.43 g, 92%) as a white solid. MS ISP (m/e): 347.2 [(M+H)+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].CCCCCC.C(OCC)(=O)C>C(OCC)(=O)C>[CH2:28]([O:27][C:25](=[O:26])[NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([F:18])[CH:11]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OCc2ccccc2)c(F)c1)OCc1ccccc1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A solution of 34.9 g 1-benzyloxy-2-fluoro-4-nitro-benzene (WO03064413) (MW: 247.28, 141 mmol) and 340 mg platine 5% on activated carbon in 350 ml ethyl acetate was stirred under hydrogen at rt and normal pressure. The reaction was monitored by HPLC and was complete after twenty hours. The catalyst was filtered over a glass fibre filter, and the filtrate evaporated under reduced pressure to dryness. The oily residue was dissolved in 500 ml acetone and treated with 250 ml of a saturated solution of sodium bicarbonate and 17.5 g of sodium bicarbonate (MW: 84.01, 208 mmol). The mixture was cooled to 5° C. and treated drop wise with 26.08 g of benzyl chloroformate (MW: 170.59, 152 mmol). The reaction was allowed to stirred at room temperature for two hours and monitored by TLC (hexane/ethyl acetate 3:1). The acetone was evaporated, the residue diluted with 500 ml water, and the solid filtered off. The crystals were washed with 500 ml water and dried. Yield: 48.05 g, 95.8%. MS: 352.5 (M+H)+, 350.8, (M−H)−. Method ESI+, ESI−.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([C:9]([N:11]2[CH2:14][CH:13]([NH2:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[CH2:32](Br)[CH2:33][CH2:34][CH3:35]>C(#N)C>[CH2:32]([NH:15][CH:13]1[CH2:14][N:11]([C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[C:3]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[O:10])[CH2:12]1)[CH2:33][CH2:34][CH3:35]
Reactant: NC1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reactant: CCCCBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCNC1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.1 %

Procedure:
To a solution of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine (0.09 M in acetonitrile, 500 mL, 0.045 mmol), prepared using procedures similar to those described in Example 2, was added triethylamine (20 μL, 0.135 mmol) and n-butylbromide (6.14 μL, 0.054 mmol) followed by additional acetonitrile (1.0 mL). The reaction mixture was stirred at room temperature for 16 h, at which time it was purified directly by reverse phase HPLC to afford the title compound (8.4 mg). 1H NMR (400 MHz, CDCl3): 8.50 (s, 1H), 7.39 (dd, 1H), 7.32 (dd, 1H), 7.13-7.09 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.57 (m, 1H), 4.35 (br s, 2H), 4.00 (br s, 1H), 3.87 (br s, 1H), 3.74-3.68 (m, 1H), 3.20 (br s, 3.5H), 2.56 (t, 2H), 2.03 (s, 2H), 1.50-1.42 (m, 2H), 1.39-1.29 (m, 2H), 0.91 (t, 3H). MS (EI) for C20H21F3IN3O: 504 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][N:39]([CH3:45])[C@@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1>>[CH3:38][N:39]([CH3:45])[C@@H:40]1[CH2:44][CH2:43][N:42]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:41]1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: CN(C)[C@@H]1CCNC1
Product: CN(C)[C@@H]1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)C1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and (R)—N,N-dimethylpyrrolidin-3-amine according to conditions described in general procedure C. Mp: 115-117° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.70-2.10 (m, 2 H), 2.13 (s, 6 H), 2.68-3.10 (m, 5 H), 3.25 (t, J=4.4 Hz, 4 H), 3.74 (t, J=4.8 Hz, 4 H), 6.15 (bd, 1 H), 7.04 (d, J=12.0 Hz, 1 H), 7.24 (d, J=8.4 Hz, 1 H), 7.40-7.61 (m, 5 H), 7.84 (d, J=8.0 Hz, 1 H), 7.98 (d, J=8.4 Hz, 1 H), 8.22 (d, J=5.5 Hz, 1 H), 10.45 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][C:18](=O)[C:19]2[S:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].Cl.[NH2:36][OH:37]>>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][C:18](=[N:36][OH:37])[C:19]2[S:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7]
Reactant: NO
Reactant: CC(C)(Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)O
Agent: Cl
Product: CC(C)(Oc1ccc(CCC(=NO)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)O

Procedure:
2-(2,3-Dichloro-4-(3-(hydroxyimino)-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoic acid is prepared from 2-(2,3-dichloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methyl propanoic acid and hydroxylamine hydrochloride according to general procedure I.
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH2:23])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[F:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([NH:31][CH2:32][C:33](O)=[O:34])=[O:30])=[CH:27][C:26]=1[C:38]([F:41])([F:40])[F:39]>>[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH:23][C:33](=[O:34])[CH2:32][NH:31][C:29](=[O:30])[C:28]2[CH:36]=[CH:37][C:25]([F:24])=[C:26]([C:38]([F:39])([F:41])[F:40])[CH:27]=2)[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(O)CNC(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: CCN=C=NCCCN(C)C
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=O)c2ccc(F)c(C(F)(F)F)c2)C1

Procedure:
The title compounds were prepared as white solids from the EDCI coupling of 3-amino-azetidine-1-carboxylic acid tert-butyl ester (BetaPharma) and (4-fluoro-3-trifluoromethyl-benzoylamino)-acetic acid (analog synthesis by the procedure described in Organic Synthesis XII, 40-2, 1932) using the procedure described in Step F of Example 1.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([C:14](=[O:17])[CH2:15][CH3:16])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33](Cl)=O>C1COCC1.CN(C=O)C.O>[CH3:16][C:15]1[C:14](=[O:17])[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:33]=1[C:29]1[O:28][CH:32]=[CH:31][N:30]=1
Reactant: CCC(=O)c1cccnc1Nc1ccccc1
Reactant: O=C(Cl)c1ncco1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ncco2)n(-c2ccccc2)c2ncccc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
A solution of 1-(2-phenylamino-pyridin-3-yl)-propan-1-one (2.0 g, 8.84 mmol) in THF (17.7 mL) at 25° C. was treated with sodium bis(trimethylsilyl)amide (1.0 M in THF) (22.1 mL, 22.1 mmol). The resulting red solution was then treated with a mixture of oxazole-2-carbonyl chloride (1.51 g, 11.5 mmol) in THF (8 mL) and 10 drops of DMF. The reaction was then stirred at 25° C. overnight. The reaction was diluted with water (50 mL) and was then extracted into ethyl acetate (3×50 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was absorbed onto silica and dried under high vacuum. Flash chromatography (25 g, 25%-75% ethyl acetate-hexanes) afforded 3-methyl-2-oxazol-2-yl-1-phenyl-1H-[1,8]naphthyridin-4-one (540 mg, 20.1%) as a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[CH3:20])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([O:12][CH2:11][C@H:10]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[CH3:20])[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(Br)ccc1[C@@H](CO)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Br)ccc1[C@H](COCc1ccccc1)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To 16F (0.6 g, 1.790 mmol) in CH2Cl2 (15 mL) was added triethylamine (0.299 mL, 2.148 mmol) and MsCl (0.167 mL, 2.148 mmol). The reaction was stirred at rt for 2 h. The solvent was removed and residue was redissolved in EtOAc. The solution was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (0-40% ETOAc/hexanes) to give 24A (0.74 g, 1.790 mmol, 100% yield) as an oil. 1H NMR (400 MHz, chloroform-d) δ ppm 7.28-7.40 (m, 7H) 7.13 (d, J=8.34 Hz, 1H) 4.39-4.59 (m, 4H) 3.69 (d, J=5.81 Hz, 2H) 3.52-3.62 (m, 1H) 2.85 (s, 3H) 2.33 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12]Cl)=[CH:8][N:7]=1)=[O:5])[CH3:2].[C-:14]#[N:15].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:14]#[N:15])=[CH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: [C-]#N
Reactant: CCOC(=O)c1ccc(CCl)cn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(CC#N)cn1

Procedure:
10.5 g (52.6 mmol) 5-(chloromethyl)pyridine-2-carboxylic acid ethyl ester [preparation according to H. Barth et al., Liebigs Ann. Chem. 1981, 2164-2179] are initially introduced into 75 ml anhydrous DMF and 2.58 g (52.6 mmol) sodium cyanide are added in portions at RT in the course of 3 h. The mixture is then introduced on to 500 ml saturated ammonium chloride solution and extracted with methylene chloride (four times with 100 ml each time). The combined organic phases are dried over sodium sulfate and concentrated and the residue is purified by chromatography over silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 1:4). 3.80 g (38% of th.) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[C:12](C)([C:18](OCC)=O)[C:13]([O:15]CC)=[O:14].S(=O)(=O)(O)O.O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[CH:12]([CH3:18])[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1c(F)cc([N+](=O)[O-])cc1F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC(C(=O)O)c1c(F)cc([N+](=O)[O-])cc1F
Yield: 85.1 %

Procedure:
A solution of compound (26b) (7.8 g, 24.9 mmol) in acetic acid (28 mL), and concentrated sulfuric acid (8.0 mL), and water (20 mL) were treated in the same manner as in (b) in Production Example 1 to give 4.9 g (85%) of compound (27b) as yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:25])[C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[CH:10]=2)[C:5]2[N:26]=[CH:27][CH:28]=[CH:29][C:4]=2[N:3]=1.[Br:30]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:30][CH2:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:25])[C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[CH:10]=2)[C:5]2[N:26]=[CH:27][CH:28]=[CH:29][C:4]=2[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2cccnc2n(-c2cccc(NC(=O)c3cc(Cl)cc(Cl)c3)c2)c1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(Nc1cccc(-n2c(=O)c(CBr)nc3cccnc32)c1)c1cc(Cl)cc(Cl)c1
Yield: 26.8 %

Procedure:
The mixture of 2-methyl-4-[3-(3,5-dichlorobenzoylamino) phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (4.4 g), N-bromosuccinimide (2.39 g) and benzoylperoxide in chloroform (40 ml) was refluxed for 3 hours. The mixture was washed with water and extracted by chloroform (80 ml), and evaporated. The crude product was purified by chromatography to obtain 2-bromomethyl-4-[3-(3,5-dichlorobenzoylamino)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (1.4 g).