Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([NH:7][S:8]([CH2:11][C:12](O)=O)(=[O:10])=[O:9])=[CH:5][C:4]=1[N+:17]([O-:19])=[O:18].[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[C:23]=1C=O.C(N)C1C=CC=CC=1.C(OCC)(=O)C>C(O)(=O)C>[CH3:31][O:30][C:28]1[CH:27]=[C:26]([O:32][CH3:33])[CH:23]=[C:22]([O:21][CH3:20])[C:29]=1[CH:12]=[CH:11][S:8]([NH:7][C:6]1[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[C:4]([N+:17]([O-:19])=[O:18])[CH:5]=1)(=[O:10])=[O:9]
Reactant: COc1ccc(NS(=O)(=O)CC(=O)O)cc1[N+](=O)[O-]
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: NCc1ccccc1
Product: COc1cc(OC)c(C=CS(=O)(=O)Nc2ccc(OC)c([N+](=O)[O-])c2)c(OC)c1
Temperature: 25 °C
Yield: 48 %

Procedure:
A solution of 4-methoxy-3-nitroanilinesulfonylacetic acid (10 mmol) and 2,4,6-trimethoxy-benzaldehyde (10 mmol) in glacial acetic acid (15 mL) was stirred at room temperature for 10 min. A catalytic amount of benzylamine (300 microliters) was added to the solution. The solution was then refluxed for 8 h. The reaction mixture was then cooled to room temperature. To the cooled reaction mixture was added ethyl acetate. A solid precipitate formed and was separated by filtration. Additional of ethyl acetate (30 mL) was added and the resulting mixture was washed sequentially with saturated sodium bicarbonate, dilute HCL and brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated under vacuum. The solid residue obtained was recrystallized from 2-propanol. (m.p 177–179° C.; yield 48–52%).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10].[CH2:16]([CH:18]1[CH2:23][N:22]([C:24]2[C:25]([NH:43]CC3C=CC(OC)=CC=3)=[N:26][C:27]3[C:32]([CH:33]=2)=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=3)[CH2:21][CH2:20][O:19]1)[CH3:17].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(CCC)=CC(CCC)=CC=2CCC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)(C(F)(F)F)=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:43][C:25]1[C:24]([N:22]2[CH2:21][CH2:20][O:19][CH:18]([CH2:16][CH3:17])[CH2:23]2)=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:2]3[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=3[C:9]([N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[O:10])[CH:31]=2)[N:26]=1
Reactant: CCC1CN(c2cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3nc2NCc2ccc(OC)cc2)CCO1
Reactant: Cc1cccc(C(=O)N2CCCC2)c1Br
Agent: [Pd]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(CCC)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCC1CN(c2cc3cc(-c4c(C)cccc4C(=O)N4CCCC4)ccc3nc2N)CCO1
Temperature: 140 °C

Procedure:
A mixture of (2-bromo-3-methylphenyl)(pyrrolidin-1-yl)methanone (0.256 g, 0.953 mmol), 3-(2-ethylmorpholino)-N-(4-methoxybenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.16 g, 0.318 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-1-propyl-1,1′-biphenyl (0.030 g, 0.064 mmol), potassium phosphate, anhydrous (0.132 mL, 1.589 mmol), and Pd2(dba)3 (0.029 g, 0.032 mmol) was purged with N2 followed by the addition of degassed dioxane (2 mL) and degassed water (1.0 mL). The resulting mixture was heated in microwave at 140° C. for 12 min. The reaction went to completion and it was filtered, concentrated, and chromatographed on silica gel using 0-5% MeOH/DCM to afford a light yellow oil. To this product was added TFA (15 mL, 195 mmol) and heated at 70° C. for 18 h until the starting material was consumed. The mixture was concentrated and chromatographed on silica gel using 0-5% 2M NH3 in MeOH/DCM to afford a light yellow solid as (2-(2-amino-3-(2-ethylmorpholino)quinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone. MS (ESI, pos. ion) m/z: 445 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[C:20]([F:21])=[CH:19][CH:18]=[C:17]([O:22][CH2:23][CH3:24])[C:16]=2[F:25])=[CH:11][C:10]1=[O:26])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1>[CH2:23]([O:22][C:17]1[C:16]([F:25])=[C:15]([C:20]([F:21])=[CH:19][CH:18]=1)[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:27])=[O:2])[C:10](=[O:26])[CH:11]=1)[CH3:24]
Reactant: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)OC)C2)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1F
Temperature: 5 °C
Reaction time: 3 h
Yield: 105.6 %

Procedure:
To a solution containing (S)-2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (1.68 g, 0.004 mol) in tetrahydrofuran (60 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 18 mL, 0.009 mol). The mixture was stirred at 5° C. for 3 h, and the solvents evaporated. The residue was dissolved in water and washed with diethyl ether, and the diethyl ether layer discarded. The aqueous phase was acidified with dilute hydrochloric acid (pH <2), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford (S)-2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid, (1.56 g, 96%), as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br.Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)=[O:20]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:18]=1[C:19](=[O:20])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1
Reactant: O=C(CBr)c1ccncc1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Agent: Br
Product: CCOC(=O)n1c(C(=O)c2ccncc2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 4-(bromoacetyl)pyridine hydrobromide (A. Taurins and A. Blage, J. Heterocycl. Chem., 1970, 7, 1137-1141). 1H-NMR (CDCl3) δ: 8.75-8.73 (2H, m), 8.24 (1H, d, J=1.5 Hz), 7.57-7.54 (3H, m), 7.33 (1H, dd, J=1.8, 8.4 Hz), 6.04 (2H, br s), 3.82 (2H, q, J=7.0 Hz), 0.93 (3H, t, J=7.0 Hz)
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)[C:7]([NH:9][NH:10]C(OC(C)(C)C)=O)=[O:8]>C(OCC)(=O)C>[ClH:2].[Cl:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)[C:7]([NH:9][NH2:10])=[O:8]
Reactant: CC(C)(C)OC(=O)NNC(=O)C(CCCCl)c1cccc(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: NNC(=O)C(CCCCl)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4 N hydrochloric acid in ethyl acetate (12.1 mL) was added to tert-butyl N′-[5-chloro-2-(3-fluorophenyl)pentanoyl]hydrazinecarboxylate (711 mg), and the reaction solution was stirred at room temperature for two hours. The reaction solution was concentrated under reduced pressure to obtain a crude product of 5-chloro-2-(3-fluorophenyl)pentanoic acid hydrazide hydrochloride. A solution of ethyl (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate dihydrochloride (576 mg) and triethylamine (1.24 mL) in ethanol (10 mL) was added to a solution of the resulting crude product of 5-chloro-2-(3-fluorophenyl)pentanoic acid hydrazide hydrochloride and triethylamine (1 mL) in ethanol (10 mL), and the reaction solution was stirred at 80° C. in a nitrogen atmosphere for 23 hours. The reaction solution was cooled to room temperature and then the solvent was evaporated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the resulting residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=1:1→ethyl acetate→ethyl acetate:methanol=9:1) and further purified by silica gel column chromatography (elution solvent: ethyl acetate→ethyl acetate:methanol=9:1) to obtain 306 mg of a racemate of the title compound. The resulting racemate (152 mg) was separated by CHIRALPAK™ IA manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=1:1) to obtain a (+)-isomer of the title optically active compound with a retention time of 14 minutes (60 mg; >99% ee) and a (−)-isomer of the title optically active compound with a retention time of 15.5 minutes (61 mg; 92% ee).
Reaction SMILES: CC1C=CC(NC2C=C(C(O)=O)C(NC3C=CC(C)=CC=3)=CC=2C(O)=O)=CC=1.[C:29]1([NH:35][C:36]2[CH:44]=[C:43]([C:45](O)=[O:46])[C:42]([NH:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[CH:41][C:37]=2[C:38](O)=[O:39])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[CH:52]1[CH:53]=[C:54]2[C:45]([C:43]3[C:42]([NH:48][C:49]2=[CH:50][CH:51]=1)=[CH:41][C:37]1[C:38]([C:34]2[C:29]([NH:35][C:36]=1[CH:44]=3)=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:39])=[O:46]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Solvent: O
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12

Procedure:
A mixture of 85 parts of 2,5-di(4'-methylphenylamino)terephthalic acid and 15 parts of 2,5-diphenylaminoterephthalic acid is cyclized at 125° C. in 300 parts of monomethyl polyphosphate (P2O5 concentration: 81%). After hydrolysis of the ring closure melt in 1,200 parts of water at 20° C. in which 5 parts of (3'-dimethylaminopropyl) quinacridonebissulfonamide had been suspended, the crude quinacridone isolated was subjected to a solvent finish at 125° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1B(O)O)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C(O)C.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>[CH3:10][O:9][C:7]([C:5]1[S:6][C:2]([C:19]2[N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH:22]=[CH:21][CH:20]=2)=[CH:3][CH:4]=1)=[O:8]
Reactant: COC(=O)c1ccc(Br)s1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: COC(=O)c1ccc(-c2cccn2C(=O)OC(C)(C)C)s1
Temperature: 60 °C

Procedure:
A mixture of methyl 5-bromothiophene-2-carboxylate (4 g), 1-(tert-butoxycarbonyl)pyrrole-2-boronic acid (3.8 g), dichlorobis (triphenylphosphine)palladium(II) (1.2 g) and 2M sodium carbonate solution (18 mL) in DME/water/ethanol (7/3/2, 200 mL) was heated at 60° C. for 4 hours, cooled and partitioned between ethyl acetate and brine. The extract was washed with water and concentrated, and the concentrate was flash chromatographed on silica gel with 5-40% ethyl acetate in hexane.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C@H:22]([CH3:25])[CH2:23][OH:24])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][N:36]([C:39](=[O:41])[CH3:40])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1.C[Si](Cl)(C)C>C(O)CCC>[OH:24][CH2:23][C@H:22]([NH:21][C:4]1[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=[C:2]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([N:33]3[CH2:34][CH2:35][N:36]([C:39](=[O:41])[CH3:40])[CH2:37][CH2:38]3)=[CH:31][CH:32]=2)[N:3]=1)[CH3:25]
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N[C@H](C)CO)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(N[C@H](C)CO)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Temperature: 116 °C
Reaction time: 48 h
Yield: 8.4 %

Procedure:
A mixture of (R)-2-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)propan-1-ol (200 mg, 0.525 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (140 mg, 0.639 mmol) and trimethylsilyl chloride (0.130 mL, 1.03 mmol) in nBuOH (4 mL) was stirred at 116° C. for 48 h. It was concentrated in vacuo. The residue was purified by HPLC to give (R)-1-(4-(4-(4-(1-hydroxypropan-2-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (25 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:3]1.[C:22]([C:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1)#[CH:23]>CCCCCCC.C(Cl)Cl>[C:24]1([C:22]#[C:23][C:4]2[CH:5]=[C:6]([C:7]([F:8])([F:9])[F:10])[N:2]([CH3:1])[N:3]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1
Reactant: C#CC1=CCCCC1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(C(F)(F)F)n(C)n2)cc1
Solvent: ClCCl
Solvent: CCCCCCC
Product: Cn1nc(C#CC2=CCCCC2)cc1C(F)(F)F

Procedure:
This product was prepared from toluene-4-sulfonic acid 1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl ester and 1-ethynyl-cyclohexene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 7:3; yield (80 mg, 63%); 1H NMR δ (CDCl3): 6.63 (s, 1H), 6.27-6.29 (m, 1H), 3.96 (s, 3H), 2.14-2.22 (m, 4H), 1.73-1.58 (m, 4H); LCMS m/z: 254.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:6].[NH2:13][C:14]1[C:30]([Cl:31])=[CH:29][C:17]([C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][NH:24][CH2:23][C@H:22]2[O:27][CH3:28])=[O:19])=[C:16]([O:32][CH3:33])[CH:15]=1.C(N(CC)CC)C.[I-].[K+]>CN(C)C=O>[NH2:13][C:14]1[C:30]([Cl:31])=[CH:29][C:17]([C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][C:5](=[O:6])[C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)[CH2:23][C@H:22]2[O:27][CH3:28])=[O:19])=[C:16]([O:32][CH3:33])[CH:15]=1
Reactant: O=C(CCCCl)c1cccnc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCC(=O)c2cccnc2)C[C@H]1OC
Temperature: 70 °C
Yield: 20 %

Procedure:
A mixture of 3.47 parts of 4-chloro-1-(3-pyridinyl)-1-butanone, 4.5 parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide, 1.94 parts of N,N-diethylethanamine, 0.1 parts of potassium iodide and 67.5 parts of N,N-dimethylformamide was stirred and heated for 48 hours at 70° C. The reaction mixture was evaporated. The residue was washed with a sodium carbonate solution in water and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.36 parts (20%) of cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[4-oxo-4-(3-pyridinyl)butyl]-4-piperidinyl]benzamide; mp. 166.2° C. (compound 1).
Reaction SMILES: N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.I[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.[CH:24]([OH:27])([CH3:26])[CH3:25]>[Cu]I>[CH:24]([O:27][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)([CH3:26])[CH3:25]
Reactant: CC(C)O
Reactant: COc1ccc(I)cc1
Agent: [Cu]I
Agent: c1cnc2c(c1)ccc1cccnc12
Product: COc1ccc(OC(C)C)cc1
Temperature: 110 °C
Reaction time: 23 h
Yield: 83 %

Procedure:
A test tube was charged with CuI (20 mg, 0.10 mmol, 10 mol %), 1,10-phenanthroline (36 mg, 0.20 mmol, 20 mol %), CS2CO3 (456 mg, 1.4 mmol), 4-iodoanisole (234 mg, 1.0 mmol) and isopropanol (1.0 mL). The test tube was sealed and the reaction mixture was stirred at 110° C. for 23 h. The resulting suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with ethyl acetate. The filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (2×20 cm; hexane/ethyl acetate 20:1) provided 138 mg (83% yield) of the title compound as a colorless oil.
Reaction SMILES: I[CH3:2].[NH2:3][C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=[C:6]([SH:15])[N:5]=1>CN(C)C=O>[NH2:3][C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=[C:6]([S:15][CH3:2])[N:5]=1
Reactant: CI
Reactant: CCOC(=O)c1cnc(S)nc1N
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(SC)nc1N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Iodomethane (2.6 g, 18 mmol) was added to the hot solution (˜50° C.) of ethyl 4-amino-2-mercaptopyrimidine-5-carboxylate (3.0 g, 15 mmol) in N,N-dimethylformamide (150 mL) and stirred at room temperature for 20 min. Solvent was removed in vacuo and the solid residue was washed by water. After dried in vacuo, desired product was obtained as a white solid (3.1 g, 97%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:3]1[CH:18]=CC1C=CC=CC=1.I([O-])(=O)(=O)=[O:27].[Na+]>O1CCOCC1.[Os](=O)(=O)(=O)=O>[CH:18]([C:3]1[CH:2]([OH:1])[CH2:6][C:5](=[O:7])[C:4]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:27]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)CCCCCCC1=C(C=Cc2ccccc2)C(O)CC1=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)CCCCCCC1=C(C=O)C(O)CC1=O

Procedure:
The 2-formyl compounds useful in this invention are then conveniently prepared by cleaving the glycol structure of the corresponding 2-(α,β-dihydroxyphenethyl) substances. Methyl 3-hydroxy-5-oxo-2-(αβ-dihydroxyphenethyl)cyclopent-1-eneheptanoate in ethanol is contacted with aqueous sodium periodate, thus affording methyl 3-hydroxy-2-formyl-5-oxocyclopent-1-eneheptanoate. The 2-formyl compounds are alternatively produced from the corresponding 2-styryl derivatives by combining the hydroxylation and cleavage processes. Methyl 3-hydroxy-5-oxo-2-styrylcyclopent-1-eneheptanoate in aqueous dioxane is thus allowed to react with osmium tetroxide and sodium periodate to afford methyl 2-formyl-3-hydroxy-5-oxocyclopent-1-eneheptanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:37]#[N:38])=[C:6]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]([CH:18]([CH3:35])[C:19]([NH:21][C:22]3[CH:34]=[CH:33][C:25]([C:26]([O:28]C(C)(C)C)=[O:27])=[CH:24][CH:23]=3)=[O:20])[C:10](=[O:36])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:37]#[N:38])=[C:6]([C:8]2[C:13]([C:14]([F:17])([F:15])[F:16])=[CH:12][N:11]([CH:18]([CH3:35])[C:19]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:33][CH:34]=3)=[O:20])[C:10](=[O:36])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(C(F)(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)Nc1ccc(C(=O)O)cc1)n1cc(C(F)(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
251 mg (purity 79%, 0.36 mmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl]propanoyl}amino)benzoate (racemate) (Example 20.1E) were hydrolysed with TFA according to General Method 2. Yield: 35 mg (20% of theory)
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[N:25]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C.COCCOC>[Cl:1][C:2]1[C:3]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[N:25]=2)=[CH:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(I)c(Cl)cn2)CC1
Reactant: CC1(C)OB(c2cccc(F)n2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(-c3cccc(F)n3)c(Cl)cn2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
A mixture of tert-butyl 4-(5-chloro-4-iodopyridin-2-yl-amino)piperidine-1-carboxylate (468 mg, 1.069 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (429 mg, 1.925 mmol), PdCl2(dppf).CH2Cl2 adduct (87 mg, 0.107 mmol), DME (7.5 ml), and 2M sodium carbonate (2.406 ml, 4.81 mmol) reaction mixture was stirred at 100° C. for 2 hr. The reaction mixture was cooled to room temperature, mixed with 20 ml of ethyl acetate, filtered and concentrated to yield a crude material. The crude material was purified by silica gel chromatography using a 40 g column, eluting from 0%-40% ethyl acetate with hexane. The desired fractions were combined and concentrated to constant mass, giving 360 mg of the title compound as free base. LCMS (m/z): 407.2 (MH+), retention time=0.85 min.
Reaction SMILES: COC1C=C2C(=CC=1)CC(C1C=CC=CC=1N)C(C)(C)C2.Cl.[N:23]1([CH2:30][CH2:31][O:32][C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=O)=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.N1(CCOC2C=C[C:55]([CH2:56][NH:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=3[CH:64]3[C:73]([CH3:75])([CH3:74])[CH2:72][C:71]4[C:66](=[CH:67][CH:68]=[C:69]([O:76][CH3:77])[CH:70]=4)[CH2:65]3)=CC=2)CCCCCC1>>[N:23]1([CH2:30][CH2:31][O:32][C:33]2[CH:41]=[CH:40][C:36]([CH2:37][N:57]([CH2:56][CH3:55])[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=3[CH:64]3[C:73]([CH3:74])([CH3:75])[CH2:72][C:71]4[C:66](=[CH:67][CH:68]=[C:69]([O:76][CH3:77])[CH:70]=4)[CH2:65]3)=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc2c(c1)CC(C)(C)C(c1ccccc1NCc1ccc(OCCN3CCCCCC3)cc1)C2
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Agent: COc1ccc2c(c1)CC(C)(C)C(c1ccccc1N)C2
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)cc1)c1ccccc1C1Cc2ccc(OC)cc2CC1(C)C

Procedure:
Synthesized from 2-(6-methoxy-3,3-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl][2-(6-methoxy-3,3-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (434 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]ethyl[2-(6-methoxy-3,3-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (440 mg). This compound (438 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (370 mg).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:13])[N:5]=[C:4]([CH3:14])[N:3]=1.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:26][C:25](=[O:27])[CH:24]=[N:23]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.CCOCC>[CH3:14][C:4]1[N:5]=[C:6]([CH3:13])[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:2]([O:27][C:25]2[CH:24]=[N:23][N:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH3:15])[CH:26]=2)[N:3]=1
Reactant: COC(=O)Cc1c(C)nc(C)nc1Cl
Reactant: Cc1ccccc1N1CC(=O)C=N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1c(C)nc(C)nc1Oc1cnn(-c2ccccc2C)c1

Procedure:
A mixture of methyl (4-chloro-2,6-dimethyl-5-pyrimidinyl)-acetate (4.6 g, 21 mmol), 1-(2-methylphenyl)-1H-pyrazol-4-on (4.1 g, 23 mmol) and potassium carbonate (6.4 g, 46 mmol) in dimethylformamide (50 ml) is heated at +120° C. for 2 hours. Addition of water, extraction with ether and drying gives the intermediate methyl 2-[2,4-dimethyl-6-(1-(2-methylphenyl)-1H-pyrazol4-yloxy)-pyrimidin-5-yl]-acetate as an oil.