Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]([OH:23])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1[C:48]2[N:49]=[CH:50][CH:51]=[CH:52][C:47]=2[N:46]=N1.FC(F)(F)C(O)=O.N[C@H]1C[C@H](C#N)C1>CN(C=O)C.CC#N>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]([NH:46][C@H:47]1[CH2:48][C@H:51]([C:50]#[N:49])[CH2:52]1)=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1nnc2ccc3c(cc(C(=O)O)n3Cc3ccccc3)n12
Agent: F[P-](F)(F)(F)(F)F
Agent: N#C[C@H]1C[C@H](N)C1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1nnc2ccc3c(cc(C(=O)N[C@H]4C[C@H](C#N)C4)n3Cc3ccccc3)n12
Reaction time: 0.01 h

Procedure:
To a solution of 6-benzyl-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid (0.045 g, 0.15 mmol, from Step 3) in DMF (1 mL) was added N,N-diisopropylethylamine (0.15 mL, 0.86 mmol, Aldrich) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.125 g, 0.329 mmol, Aldrich). After about 30 seconds, trans-3-aminocyclobutanecarbonitrile trifluoroacetate (0.060 g, 0.28 mmol, from Step 4) in DMF (2 mL) was added and the reaction was stirred overnight. The reaction was diluted with MeCN and filtered, then purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (35 mg, 62%).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[C@@H:3]([C:14]([O:16]C)=[O:15])[NH:4][C:5]([N:7]([CH3:13])[CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[O:6].[OH-].[Li+]>O1CCCC1>[CH3:1][C:2]([CH3:19])([CH3:18])[C@@H:3]([C:14]([OH:16])=[O:15])[NH:4][C:5]([N:7]([CH3:13])[CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[O:6]
Reactant: C=CCCCN(C)C(=O)N[C@H](C(=O)OC)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCCCN(C)C(=O)N[C@H](C(=O)O)C(C)(C)C
Yield: 100 %

Procedure:
A solution of methyl 3-methyl-N-{[methyl(pent-4-enyl)amino]carbonyl}-L-valinate (3.00 g, 11.2 mmol), lithium hydroxide (1M, 56.0 mL, 56.0 mmol) in tetrahydrofuran (40 mL) was heated to 50° C. for 1 h. Contents of the reaction flask were cooled and evaporated to remove tetrahydrofuran. The remaining mixture was poured into 5% potassium bisulfate and extracted with methylene chloride (3×10 mL). The combined organic extracts were dried with anhydrous sodium sulfate, filtered and evaporated to give the title compound as a colorless oil, 2.87 g (100% yield). LRMS (ESI) m/z 257 [(M+H)+; calcd for C13H25N2O3: 257].
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[N:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[CH:29]1([NH:32][C:33](=[O:50])[C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:35]=2)[CH2:31][CH2:30]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:29]1([NH:32][C:33](=[O:50])[C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[C:36]([C:2]3[CH:10]=[C:9]4[C:5]([C:6]([S:19]([C:22]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=5)(=[O:21])=[O:20])=[N:7][N:8]4[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:16])[CH3:17])=[CH:4][CH:3]=3)[CH:35]=2)[CH2:30][CH2:31]1
Reactant: C[Si](C)(C)CCOCn1nc(S(=O)(=O)c2ccc(F)cc2)c2ccc(Br)cc21
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(S(=O)(=O)c3ccc(F)cc3)nn(COCC[Si](C)(C)C)c2c1
Yield: 69.8 %

Procedure:
A mixture of 6-bromo-3-[(4-fluorophenyl)sulfonyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-indazole (Intermediate 70) (0.06 g) N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 5) (0.04 g) aqueous sodium carbonate (1M, 0.66 ml) and tetrakis(triphenylphosphine)palladium(0) (0.015 g) in 1,2-dimethoxyethane (4 ml) was stirred at reflux under nitrogen for 18 h. The mixture was concentrated under vacuum and the residue was purified on a Varian Bond-Elut SPE cartridge, eluting with cyclohexane:ethyl acetate (100:0 to 50:50) to give the title compound (0.05 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([O:21]C4C(F)=C(F)C(F)=C(F)C=4F)(=O)=[O:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][N:9]=2)=[C:4]([O:33][CH3:34])[CH:3]=1.[S:35]1[CH:39]=[N:38][N:37]=[C:36]1[NH2:40].ClC1C=C(C2C3C(=CC(S(OC4C(F)=C(F)C(F)=C(F)C=4F)(=O)=O)=CC=3)N=CN=2)C(OC)=CC=1C1C=CC=C(F)C=1.S1C(N)=NC=N1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:40][C:36]4[S:35][CH:39]=[N:38][N:37]=4)(=[O:21])=[O:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][N:9]=2)=[C:4]([O:33][CH3:34])[CH:3]=1
Reactant: COc1cc(Cl)ccc1-c1ncnc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Nc1nncs1
Agent: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1ncnc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: Nc1ncns1
Product: COc1cc(Cl)ccc1-c1ncnc2cc(S(=O)(=O)Nc3nncs3)ccc12

Procedure:
The title compound was prepared in an analogous manner to that of EXAMPLE 521, except that perfluorophenyl 4-(4-chloro-2-methoxyphenyl)quinazoline-7-sulfonate and 1,3,4-thiadiazol-2-amine were used instead of perfluorophenyl 4-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)quinazoline-7-sulfonate and 1,2,4-thiadiazol-5-amine to afford 4-(4-chloro-2-methoxyphenyl)-N-(1,3,4-thiadiazol-2-yl)quinazoline-7-sulfonamide as a yellow solid. (ESI) 434.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]1)[CH3:2].Cl[C:18]1[N:23]=[CH:22][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][N:19]=1.CCN(CC)CC>CS(C)=O.O>[CH2:1]([O:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:18]2[N:19]=[CH:20][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][N:23]=2)[CH2:8]1)[CH3:2]
Reactant: CCOc1ccccc1O[C@@H]1CCCNC1
Reactant: CCOC(=O)c1cnc(Cl)nc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(N2CCC[C@@H](Oc3ccccc3OCC)C2)nc1
Temperature: 100 °C
Yield: 94.4 %

Procedure:
To a solution of (R)-3-(2-ethoxyphenoxy)piperidine (45 g, 204 mmol) and ethyl 2-chloropyrimidine-5-carboxylate (41.7 g, 224 mmol) in DMSO (300 mL) was added Et3N (40 mL, 305 mmol) at 20-25° C. The reaction mixture was heated to 100° C. for 2 hours, then was cooled to 20-25° C., diluted with H2O (300 mL) and extracted with EtOAc (3 times with 300 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to obtain ethyl (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylate (71.5 g). MS (ES+) 372.3 (M+H).
Reaction SMILES: [OH-:1].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]#[N:29])=[C:26]([C:30]([OH:33])([CH3:32])[CH3:31])[N:25]=[C:24]2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(O)C>[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]([NH2:29])=[O:1])=[C:26]([C:30]([OH:33])([CH3:32])[CH3:31])[N:25]=[C:24]2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: [OH-]
Reactant: CCCCc1nc(C(C)(C)O)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(C(C)(C)O)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
10 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 232 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carbonitrile [prepared as described in Example 10(a)] in 10 ml of ethanol, and the resulting mixture was heated under reflux for 3 hours. At the end of this time, the reaction mixture was worked up in a similar manner to that described in Example 45(c), to afford 185 mg of the title compound as an amorphous solid.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[F:55][C:56]1[CH:61]=[CH:60][C:59]([C@H:62]([NH:64][C:65]([C@H:67]2[CH2:72][CH2:71][C@H:70]([NH:73][S:74]([C:77]3[CH:82]=[CH:81][C:80]([C:83](=[O:85])[CH3:84])=[CH:79][CH:78]=3)(=[O:76])=[O:75])[CH2:69][CH2:68]2)=[O:66])[CH3:63])=[CH:58][CH:57]=1>C(Cl)Cl.CO>[F:55][C:56]1[CH:61]=[CH:60][C:59]([C@H:62]([NH:64][C:65]([C@H:67]2[CH2:68][CH2:69][C@H:70]([NH:73][S:74]([C:77]3[CH:78]=[CH:79][C:80]([C:83](=[O:85])[CH2:84][Br:1])=[CH:81][CH:82]=3)(=[O:75])=[O:76])[CH2:71][CH2:72]2)=[O:66])[CH3:63])=[CH:58][CH:57]=1
Reactant: [Br-]
Reactant: CC(=O)c1ccc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)N[C@H](C)c3ccc(F)cc3)CC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: C[C@@H](NC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(C(=O)CBr)cc2)CC1)c1ccc(F)cc1
Reaction time: 28 h

Procedure:
Tetrabutylammonium-tribromide (216 mg, 0.447 mmol) was added to solution of trans-4-(4-acetyl-benzenesulfonylamino)-cyclohexanecarboxylic acid [(R)-1-(4-fluoro-phenyl)-ethyl]-amide (Example 104, 194 mg, 0.434 mmol) in DCM/MeOH (2/1, 1.45 ml) at room temperature. The reaction was stirred 16-40 hours, then concentrated and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate and concentrated to crude product which was chromatographed on a Biotage 40S column using ethyl acetate/heptane as the eluent to give the title compound (122 mg, 0.232 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][CH2:12][OH:13])=[CH:5][C:4]=1[CH3:14]>[Pd].CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=[CH:5][C:4]=1[CH3:14]
Reactant: COc1ccc(C#CCCO)cc1C
Agent: [Pd]
Solvent: CO
Product: COc1ccc(CCCCO)cc1C
Yield: 55.6 %

Procedure:
This compound was prepared in a manner analogous to that of Step E of Example 1, by the hydrogenation of 1.4 grams (0.0074 mole) of 4-(4-methoxy-3-methylphenyl)but-3-yn-1-ol in the presence of 0.05 gram (catalyst) of 10% palladium on carbon in 150 mL of methanol. The reaction product was purified by column chromatography on silica gel using mixtures of hexane and ethyl acetate as an eluant. The appropriate fractions of eluate were combined and concentrated under reduced pressure, yielding 0.8 gram of subject compound. The NMR spectrum was consistent with the proposed structure. This reaction was repeated on a larger scale.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[CH3:54][C:55]([CH3:58])([O-])[CH3:56].[K+].[Cl-].[NH4+]>C(O)(C)(C)C.C(N(CC)CC)C.ClCCl>[C:55]([O:23][C:22]([C:21]1[N:20]=[C:19]([C:25]([F:27])([F:28])[F:26])[N:16]2[CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:29][C:30]3[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=3[F:38])[CH2:14][C:15]=12)=[O:24])([CH3:58])([CH3:56])[CH3:54]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)OC(C)(C)C)c2C1)Cc1cc(F)c(F)cc1F
Yield: 33.6 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.3 g, 0.54 mmol), 10 mL of dichloromethane and 5 mL of tert-butanol were added into a 100 mL reaction flask, followed by addition of 0.3 mL of triethylamine and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.277 g, 1.09 mmol) under stirring. After stirring at room temperature for 2 hours, 10 mL of tert-butanol and potassium tert-butoxide (0.24 g, 2.16 mmol) were added to the solution. The reaction mixture was stirred at room temperature for another 2 hours and monitored by thin layer chromatography until the disappearance of the starting materials. 10 mL of saturated ammonium chloride was added to the reaction mixture and white precipitates were formed. The precipitates were filtered through a pad of 100-200 mesh silica gel and 50 mL of water was added to the filtrate. Then the filtrate was extracted with ethyl acetate (25 mL×5). The combined organic phase was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-7-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid tert-butyl ester 36a (0.11 g, yield 33.6%) as a white solid.
Reaction SMILES: [N+:1](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])=[N-:2].[CH3:13][O:14][C:15]([C:17]#[C:18][C:19]([O:21][CH3:22])=[O:20])=[O:16]>C1C=CC=CC=1>[O:12]=[C:4]1[N:1]2[N:2]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:17]([C:15]([O:14][CH3:13])=[O:16])=[C:3]2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5]1
Reactant: [N-]=[N+]=C1C(=O)Nc2ccccc21
Reactant: COC(=O)C#CC(=O)OC
Solvent: c1ccccc1
Product: COC(=O)c1nn2c(=O)[nH]c3ccccc3c2c1C(=O)OC
Reaction time: 6 h

Procedure:
A solution of 4.8 g (0.03 mole) of 3-diazooxindole in 150 ml of warm (45°) benzene is treated with 5.10 g (0.036 mole) of dimethylacetylene dicarboxylate. After stirring for 6 hours at 45°, an additional 0.426 g (0.003 mole) of ester is added and reaction continued overnight.
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=2)[C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=2)[C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2sc3cccnc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)sc2cccnc12
Reaction time: 8 h
Yield: 63.6 %

Procedure:
To a mixture of methyl 4-{[cyclohexyl(3-methylthieno[3,2-b]pyridin-2-yl)methyl]amino}benzoate (1.31 g) synthesized above, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (10 mL), and the mixture was stirred overnight with heating under reflux. 1N Aqueous sodium hydroxide solution (5 mL) was additionally added, and the mixture was further stirred with heating under reflux for 7 hr, and concentrated under reduced pressure. The residue was dissolved in water (20 mL), and 1N hydrochloric acid (15 mL) was added at 0° C. The resulting precipitate was collected by filtration, and the obtained brown solid was dissolved in ethyl acetate. The solution was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title object compound (804 mg, 64%) as a brown solid.
Reaction SMILES: [CH:1]1([C:4]2[C:13]([C:14]3[NH:23][C:17]4[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:16]=4[N:15]=3)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:24])[CH:5]=2)[CH2:3][CH2:2]1.[CH:25]1(C2C(C=O)=CC(C(OC)=O)=C(C)C=2)CCC1.C1(C2C(C=O)=CC(C(OC)=O)=C(C)C=2)CC1>>[CH:1]1([C:4]2[C:13]([C:14]3[NH:23][C:17]4[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:16]=4[N:15]=3)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:24])[CH:5]=2)[CH2:3][CH2:25][CH2:2]1
Reactant: COC(=O)c1cc(C=O)c(C2CCC2)cc1C
Reactant: COC(=O)c1cc(-c2nc3c([nH]2)CN(C)CC3)c(C2CC2)cc1C
Agent: COC(=O)c1cc(C=O)c(C2CC2)cc1C
Product: COC(=O)c1cc(-c2nc3c([nH]2)CN(C)CC3)c(C2CCC2)cc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 87.4, except methyl 4-cyclobutyl-5-formyl-2-methylbenzoate (compound 82.5) was used in place of methyl 4-cyclopropyl-5-formyl-2-methylbenzoate (compound 87.1).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1>[CH2:10]([N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCBr
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCN1CCCC1=O
Yield: 31 %

Procedure:
Following example 1, on refluxing 13 g of 50% oil dispersion of sodium hydride (6.5 g NaH, 0.27 M), 20.35 g (0.239 M) of azacyclopentan-2-one and 47.28 g (0.264M) of 1-bromoheptane in dry toluene for 21 hours was obtained 13.6 g (31%) of colorless oil; boiling point 115°-120°/0.6 mm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][NH:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([C:23]2[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=2)[CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:36]([CH:38]1[O:40][CH2:39]1)Cl>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][NH:14][C:15]1[CH:16]=[C:17]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:36][CH:38]3[CH2:39][O:40]3)[CH:24]=2)[N:18]=[C:19]([O:21][CH3:22])[N:20]=1
Reactant: ClCC1CO1
Reactant: COc1nc(NCCc2ccc(C(F)(F)F)cc2F)cc(-c2cccc(O)c2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(NCCc2ccc(C(F)(F)F)cc2F)cc(-c2cccc(OCC3CO3)c2)n1
Reaction time: 4 h
Yield: 50.8 %

Procedure:
To a suspension of 3-{6-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenol (280 mg, 0.68 mmol), and Cs2CO3 (0.44 g, 1.36 mmol) in DMF (2 mL) is added epichlorohydrin (80 μL, 1.02 mmol) at room temperature. After 4 h at 20° C., the mixture is diluted with water (10 mL), and extracted with EtOAc (2×10 mL). The extracts are washed with water (2×20 mL), dried (MgSO4), filtered, and concentrated. The residue is chromatographed on SiO2 eluting with 50% EtOAc in heptane to afford [2-(2-fluoro-4-trifluoromethyl-phenyl)-ethyl]-[2-methoxy-6-(3-oxiranylmethoxy-phenyl)-pyrimidin-4-yl]-amine [0.16 g, Example 66]. LCMS: RT=2.62 minutes; MS: 464 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](Br)=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[C:18]([C:5]2[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][C:6]=2[C:8]([F:11])([F:10])[F:9])[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2cccc(Cl)c2)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A mixture of 5-amino-2-bromobenzotrifluoride (Dakwood Products, Inc.) (500 mg, 2.1 mMol), 3-chlorophenylboronic acid (970 mg, 6.2 mMol, 3 equiv) (Aldrich), Pd(PPh3)4 (70 mg, 0.018 mMol, 0.03 equiv), Na2CO3 (2 M solution in H2O, 5 mL, 10 mMol, 4.76 equiv), and toluene (14 mL) is stirred at reflux for 1 h. The reaction mixture is allowed to cool to rt and filtered through a pad of celite, washing the filter cake with CH2Cl2 and H2O. The layers are separated and the aqueous phase is extracted with CH2Cl2 (2×60 mL). The combined organic phase is washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. MPLC (CH3CN/H2O/TFA) purification of the crude material affords the title compound: MS: 270.0 [M-2]−; HPLC DtRet=4.9.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]([O-:12])=O)=[N:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Na+].[CH3:20][C@@H:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[F:30])[NH:22]1>>[Cl:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]([N:22]2[C:23]3[C:28](=[C:27]([F:30])[CH:26]=[CH:25][CH:24]=3)[CH2:29][C@H:21]2[CH3:20])=[O:12])=[N:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C[C@@H]1Cc2c(F)cccc2N1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)c(Cl)c(=O)[nH]1
Agent: [Na+]
Product: C[C@@H]1Cc2c(F)cccc2N1C(=O)Cc1nc(N2CCOCC2)c(Cl)c(=O)[nH]1
Yield: 33.8 %

Procedure:
The product is prepared by following the procedure described in example 1a (step 5a) using 220 mg of sodium (5-chloro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate and 110 mg of (R)-2-methyl-4-fluoro-2,3-dihydro-1H-indole (which can be prepared according to Krasnov, V. P. et al. (Mendeleev Commun. 2002, 12(1), 27-28)). After silica column purification: eluent 99/01 then 98/02 then 97/03 dichloromethane/methanol, 100 mg of 5-chloro-2-[2-((R)-2-methyl-4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][CH2:5][C:6]1[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18]S(C)(=O)=O)=[CH:10][CH:9]=[CH:8][C:7]=1[O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].O[C:37]1[CH:47]=[CH:46][C:40]2[C:41](=[O:45])[CH2:42][CH2:43][O:44][C:39]=2[C:38]=1[CH2:48][CH2:49][CH3:50].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CCOCC.C(#N)C>[CH3:1][O:2][C:3](=[O:35])[CH2:4][CH2:5][C:6]1[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:37]2[CH:47]=[CH:46][C:40]3[C:41](=[O:45])[CH2:42][CH2:43][O:44][C:39]=3[C:38]=2[CH2:48][CH2:49][CH3:50])=[CH:10][CH:9]=[CH:8][C:7]=1[O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)CCCCCCCOc1cccc(CCCCCCOS(C)(=O)=O)c1CCC(=O)OC
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: CCCc1c(OCCCCCCc2cccc(OCCCCCCCC(=O)OC)c2CCC(=O)OC)ccc2c1OCCC2=O
Yield: 94.4 %

Procedure:
A mixture of 0.68 g (1.3 mmol) of 2-[(8-methoxy-8-oxooctyl)oxy]-6-[6-[(methylsulfonyl)oxy]hexyl]benzenepropanoic acid methyl ester from the preceding example, 0.24 g (1.17 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, 0.26 g (1.88 mmol) of anhydrous granular potassium carbonate, 0.215 g (1.43 mmol) of anhydrous sodium iodide, and 10 mL of dry acetonitrile was stirred and refluxed for 24 hr. After being cooled, the reaction mixture was poured onto ice-water and worked-up with ether in the usual manner. The crude product was flash-chromatographed on silica gel, eluting with 2:1 hexane-ethyl acetate. There was obtained 0.69 g (94.5%) of 2-[(8-methoxy-8-oxo-octyl)oxy]-6-[6-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]hexyl]benzenepropanoic acid methyl ester as a colorless oil. A solution of this diester and 2.5 mL of 3N aqueous lithium hydroxide in 15 mL of tetrahydrofuran was stirred at room temperature for 24 hr. The solvent was removed under reduced pressure and the residue was dissolved in water. The resulting solution was extracted with ether (the extracts were discarded) and then acidified with 3N aqueous hydrochloric acid. Work-up with ether in the usual manner gave an oily acid product which was flash-chromatographed on silica gel, eluting with 90:10:1, chloroform-methanol-acetic acid. Recrystallization of the pure acid from hexane-ethyl acetate afforded 0.5 g (76%) of the title compound as a colorless solid, mp 79°-81° C.