Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10]C)=[O:9])(=O)[CH3:2].I[C:16]1[CH:21]=CC=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>[N+](C)([O-])=O.[Cu]>[NH:4]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([OH:10])=[O:9])[C:1]1[CH:18]=[CH:17][CH:16]=[CH:21][CH:2]=1
Reactant: Ic1ccccc1
Reactant: COC(=O)c1cccc(NC(C)=O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C[N+](=O)[O-]
Product: O=C(O)c1cccc(Nc2ccccc2)c1

Procedure:
In accordance with the method described in Zhur. Obshchei Khim 30, 2693 (1960), methyl 3-acetylaminobenzoate was reacted with iodo benzene in nitromethane in the presence of potassium carbonate and active copper powder to yield 3-anilinobenzoic acid and the intended product was obtained by the following steps. ##STR254##
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH:34]1[CH:38]=[C:37]([C:39](O)=[O:40])[CH:36]=[N:35]1>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[C:39]([C:37]3[CH:38]=[N:34][NH:35][CH:36]=3)=[O:40])=[CH:32][CH:33]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1
Reactant: O=C(O)c1cn[nH]c1
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)C(=O)c3cn[nH]c3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure H using methyl {4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]phenoxy}acetate and 1H-pyrazole-4-carboxylic acid as a colorless oil (95%). HPLC, Rt: 5.15 min (Purity: 69.2%).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.CON(C)[C:11]([C:13]1[S:17][C:16]([CH3:18])=[N:15][C:14]=1[CH3:19])=[O:12]>C1COCC1>[CH3:18][C:16]1[S:17][C:13]([C:11]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=2)=[O:12])=[C:14]([CH3:19])[N:15]=1
Reactant: Cn1cncc1Br
Reactant: CON(C)C(=O)c1sc(C)nc1C
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(=O)c2cncn2C)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a flask containing 5-bromo-1-methyl-1H-imidazole (390 mg, 2.42 mmol) was added THF (8 mL) and the solution was cooled to 0° C. To this solution was added isopropylmagnesium chloride-LiC1 complex (1.3 M in THF, 2.5 mL, 3.25 mmol) which resulted in a white suspension. The reaction mixture was stirred in a 0° C. bath for 30 minutes, then a THF (2 mL) solution of N-methoxy-N,2,4-trimethylthiazole-5-carboxamide (550 mg, 2.75 mmol, Intermediate 17: step a) was introduced. The reaction mixture was stirred at 50° C. for 18 hours, cooled to room temperature and quenched with aqueous NH4Cl solution. The aqueous portion was extracted with DCM (4×50 mL) and the combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. Chromatography on silica gel (25% EtOAc-DCM increasing to 5% MeOH-DCM) afforded the title compound as an amber solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:9](Cl)(=[O:12])[CH:10]=[CH2:11].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9](=[O:12])[CH:10]=[CH2:11])[CH2:4][CH2:3]1
Reactant: CN1CCCNCC1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)N1CCCN(C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution is prepared of 20 g (175 mM) of N-methylhomopiperazine in 100 ml of dichloromethane, to which is added, dropwise, at 0° C., a solution of 15.85 g (175 mM) of acryloyl chloride in 20 ml of dichloromethane. The reaction mixture is agitated for 1 hour at 0° C., and then for 2 hours at ambient temperature, and then hydrolysed with a solution of 12 g of sodium carbonate in 20 ml of water. The mixture is decanted, the organic phase is washed once with water and then dried over magnesium sulphate and concentrated under reduced pressure. 23 g of the compound sought after are thus obtained, as an orangy oil, which is used, without other purification, in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.[H-].[Na+].[CH2:13]([O:20][CH2:21]Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([O:20][CH2:21][N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([Cl:1])=[C:3]2[CH:10]=[N:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCOCc1ccccc1
Reactant: Clc1ccnc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccnc2c1cnn2COCc1ccccc1
Yield: 58.3 %

Procedure:
4-Chloro-1H-pyrazolo[3,4-b]pyridine (371 mg, 2.42 mmol) was dissolved in anhydrous DMF (1 mL), and sodium hydride (60%, 116 mg, 2.42 mmol) was added thereto. The resulting mixture was stirred under ice-cooling for 30 minutes, and then benzyloxymethyl chloride (0.48 mL, 3.39 mmol) was added thereto. The resulting mixture was stirred under ice-cooling for 1 hour and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (80 mL) and saturated brine (20 mL). The aqueous layer was further extracted with ethyl acetate (70 mL). The combined organic layer was washed with saturated brine, dried, and concentrated. The residue was purified by silica-gel column chromatography (Fuji Silysia, BW300, 70 g, n-hexane:EtOAc=5:1) to give 1-benzyloxymethyl-4-chloro-1H-pyrazolo[3,4-b]pyridine as a light-yellow syrup (386 mg, yield: 58%).
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12](Cl)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:16][N:17]([CH2:19][CH:20]([OH:30])[CH2:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)[CH3:18]>C(O)CCC.CO>[NH:1]([C:8]1[N:13]=[C:12]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([O:22][CH2:21][CH:20]([OH:30])[CH2:19][N:17]([CH3:16])[CH3:18])=[CH:24][CH:25]=2)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Reactant: Clc1ccnc(Nc2ccccc2)n1
Agent: Cl
Solvent: CO
Solvent: CCCCO
Product: CN(C)CC(O)COc1ccc(Nc2ccnc(Nc3ccccc3)n2)cc1
Temperature: 80 °C
Yield: 65.7 %

Procedure:
2-Anilino-4-chloropyrimidine (145 mg, 0.71 mmol) was dissolved in n-butanol (20 ml). To this solution was added a hot solution of 4-[3-(N,N-dimethyl)amino-2-hydroxy-propoxy]aniline hydrochloride (Reference Example D-1; 178 mg, 0.63 mmol) in methanol (2 ml). The reaction mixture was heated at 80° C. for 18 hours, allowed to cool to ambient temperature and then evaporated onto silica (3 ml). The residue was purified by column chromatography eluting with 0–8% 2.0M methanolic ammonia solution in DCM to give the title product as a colourless solid (157 mg, 65%). NMR (300 MHz): 2.18 (s, 6H), 2.33 (m, 2H), 3.83 (m, 3H), 4.77 (d, 1H), 6.11 (d, 1H), 6.86 (m, 3H), 7.19 (m, 2H), 7.51 (d, 2H), 7.69 (d, 2H), 7.96 (d, 1H), 9.01 (s, 1H), 9.08 (s, 1H); m/z: (ES+) 380.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH3:32])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.[NH2:33]C1C(C#N)=C(Cl)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]#[N:33])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH3:32])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C=O)CC1
Reactant: N#Cc1c(N)ncnc1Cl
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbaldehyde using 4-amino-6-chloropyrimidine-5-carbonitrile instead of 4-amino-6-chloropyrimidine-5-carbaldehyde. LC-MS: (M+1=446, obsd.=446).
Reaction SMILES: [NH2:1][C:2]1[C:22]([CH:23]2[CH2:25][CH2:24]2)=[CH:21][C:5]2[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.[Br:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.C(N(CC)CC)C>CCOC(C)=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:26][C:27]1[CH:32]=[C:31]([NH:1][C:2]2[C:22]([CH:23]3[CH2:25][CH2:24]3)=[CH:21][C:5]3[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:7]([C:9]4[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=4)[O:8][C:4]=3[CH:3]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(C3CC3)cc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(Nc3cccc(Br)c3)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.7 %

Procedure:
A mixture of ethyl 6-amino-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxylate (1.00 g, 2.95 mmol), (3-bromophenyl)boronic acid (1.184 g, 5.89 mmol), copper(II) acetate (0.803 g, 4.42 mmol), triethylamine (1.232 mL, 8.84 mmol) and 4 A molecular sieves (2 g) was stirred at room temperature for 24 hours. The reaction mixture was diluted with EtOAc and filtered through Celite. The solvent was evaporated and the residue was purified by chromatography on silica gel (hexane:EtOAc) to give ethyl 6-((3-bromophenyl)amino)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxylate (740 mg, 51%). LCMS (m/z, ES+)=494, 496 (M+H, M+2).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:23])[CH2:4]1.[Cl:24][C:25]1[C:34]([CH:35]=O)=[N:33][C:32]2[NH:31][C:30](=[O:37])[CH2:29][O:28][C:27]=2[CH:26]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)Cl>[Cl:24][C:25]1[C:34]([CH2:35][NH:1][CH2:2][C@@H:3]2[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][N:11]3[C:20]4[C:15](=[N:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=4)[CH:14]=[CH:13][C:12]3=[O:23])[CH2:4]2)=[N:33][C:32]2[NH:31][C:30](=[O:37])[CH2:29][O:28][C:27]=2[CH:26]=1
Reactant: O=Cc1nc2c(cc1Cl)OCC(=O)N2
Reactant: COc1cnc2ccc(=O)n(CCN3CCC[C@@H](CN)C3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3CCC[C@@H](CNCc4nc5c(cc4Cl)OCC(=O)N5)C3)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17 %

Procedure:
To a solution of 1-{2-[(3S)-3-(Aminomethyl)-1-piperidinyl]ethyl}-7-(methyloxy)-1,5-naphthyridin-2(1H)-one (0.149 g, 0.472 mmol) in 1:1 (MeOH/CH2Cl2) (25 mL) were added 7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (for a synthesis see WO2003064421, Example 15(c)) (0.100 g, 0.472 mmol) and sodium sulphate (0.100 g) and the resulting solution stirred for 18 hours at ambient temperature. Na(OAc)3BH (0.300 g, 1.42 mmol) was added and the solution stirred an additional 2 h. The reaction mixture was concentrated onto silica gel and chromatographed on a silica gel column [0-100% CHCl3/(90:10:1) CHCl3/MeOH/NH4OH)] to yield a colorless oil and then further purified by HPLC(CH3CN/H2O) to yield the title compound as a white powder (0.041 g, 17%).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:9]2[N:10]=[CH:11][N:12]=[C:8]2[N:7]=[CH:6][CH:5]=1)[CH3:3].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl>[Br:13][C:2]([C:4]1[N:9]2[N:10]=[CH:11][N:12]=[C:8]2[N:7]=[CH:6][CH:5]=1)([CH3:1])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1ccnc2ncnn12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(Br)c1ccnc2ncnn12

Procedure:
A mixture of 7-(1-methylethyl)-1,2,4-triazolo[1,5-a]pyrimidine (4.18 g), N-bromosuccinimide (4.59 g), and dibenzoylperoxide (70 mg) in tetrachloromethane (105 ml) was stirred and heated under reflux for 11 hours. The mixture was filtered and the solvent was removed from the filtrate to give 7-(1-bromo-1-methylethyl)-1,2,4-triazolo[1,5-a]pyrimidine. Yield 2.94 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12](COC(=O)C(C)(C)C)[C:11]=2[N:10]=[C:9]1[N:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1.[H-].[Na+].Cl>CO.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[NH:12][C:11]=2[N:10]=[C:9]1[N:28]1[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]1
Reactant: Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccccc2Cl)n(COC(=O)C(C)(C)C)c1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(=O)[nH]c2nc(N3CCN(C(=O)OC(C)(C)C)CC3)n(-c3ccccc3Cl)c2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
t-Butyl 4-[7-(2-chlorophenyl)-3-(2,2-dimethylpropionyloxy methyl)-1-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in a mixture of 10 ml of methanol and 20 ml of tetrahydrofuran, and 200 mg of sodium hydride was added thereto. The resulting mixture was stirred at room temperature overnight. 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then filtered. The filtrate was concentrated. The residue was suspended in ether and the mixture was filtered. Thus, 450 mg of the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([C:19]4[CH:31]=[CH:30][C:22]([CH2:23][NH:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:21][CH:20]=4)[N:15]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:32][C:33]1[CH:41]=[C:40]([NH:42][C:43](=[O:57])[CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=2[C:53]([F:56])([F:55])[F:54])[CH:39]=[CH:38][C:34]=1[C:35](O)=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[F:32][C:33]1[CH:41]=[C:40]([NH:42][C:43](=[O:57])[CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=2[C:53]([F:55])([F:56])[F:54])[CH:39]=[CH:38][C:34]=1[C:35]([N:24]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:23][C:22]1[CH:30]=[CH:31][C:19]([C:16]2[N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=4)=[CH:13][CH:12]=3)[O:18][N:17]=2)=[CH:20][CH:21]=1)=[O:36]
Reactant: COC(=O)CNCc1ccc(-c2noc(-c3ccc(-c4ccc(C)cc4)cc3)n2)cc1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)O)c(F)c2)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CN(Cc1ccc(-c2noc(-c3ccc(-c4ccc(C)cc4)cc3)n2)cc1)C(=O)c1ccc(NC(=O)Cc2ccc(OC)cc2C(F)(F)F)cc1F
Temperature: 25 °C
Yield: 98 %

Procedure:
Prepared using General Procedure 6. To a suspension of methyl 2-((4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)amino)acetate INT-77 (50 mg, 0.121 mmol) and 2-fluoro-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzoic acid INT-78 (44.9 mg, 0.121 mmol) in DMF (2 mL) were added HATU (50.6 mg, 0.133 mmol) and TEA (42.1 μL, 0.302 mmol). The reaction mixture was stirred at room temperature. After 60 h the reaction mixture was diluted with EA (20 mL) and washed with NaHCO3 (2×20 mL) and 1 M HCl (2×20 mL). The organics were dried over MgSO4 and concentrated in vacuo to afford 91 mg (98%) of methyl 2-(2-fluoro-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetate INT-79 as a pale yellow solid. LCMS-ESI (m/z) calculated for C42H34F4N4O6: 766; found 767 [M+H]+, tR=3.27 min (Method 10).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[CH:7]=[C:8]([N:20]2[CH2:24][C@H:23]([CH2:25]OS(C)(=O)=O)[O:22][C:21]2=[O:31])[CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[CH2:13]1>CN(C=O)C.C(OCC)(=O)C>[N:1]([CH2:25][C@@H:23]1[O:22][C:21](=[O:31])[N:20]([C:8]2[CH:9]=[CH:10][C:11]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[CH2:13]3)=[C:6]([F:5])[CH:7]=2)[CH2:24]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CN1CCN(c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)CC1=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)CC1=O
Temperature: 75 °C

Procedure:
Sodium azide (924 mg) was added to a solution of (5R)-3-(3-fluoro-4-{4-methyl-3-oxopiperazin-1-yl}phenyl)-5-(methanesulfonyloxymethyl)oxazolidin-2-one (950 mg) in dry DMF (50 ml), and the mixture heated at 75° C. for 2 hours. The mixture was diluted with ethyl acetate and washed with three portions of water. The aqueous layer was then back-extracted with two portions of ethyl acetate, and the combined organic extracts dried over MgSO4. Evaporation gave (5R)-5-azidomethyl-3-(3-fluoro-4-{4-methyl-3-oxopiperazin-1-yl}phenyl)oxazolidin-2-one product which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[N:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:28]3[CH2:29][CH2:30][CH:25]([N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:26][CH2:27]3)=[CH:8][C:6]=2[N:7]=1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(N4CCCCC4)CC3)cc2n1

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 from Example 3 and 4-piperidinopiperidine were reacted using General Procedure B-3 to give 1′-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-[1,4′]bipiperidinyl, which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine in General Procedure A. Purification on silica yielded 107. NMR (CDCl3): 1.46 (m, 2H, CH2), 1.61-1.68 (m, 6H, 6×CH), 1.82-1.85 (m, 2H, 2×CH), 2.09-2.14 (m, 2H, CH2), 2.30 (m, H, CH), 2.54 (m, 4H, 4×CH), 3.04-3.07 (m, 2H, 2×CH), 3.81 (s, 2H, CH2), 3.89-3.91 (m, 4H, 2×CH2), 4.04-4.06 (m, 4H, 2×CH2), 4.64 (sbr, 2H, NH2), 6.58 (d, H, ArH, J=8.59 Hz), 7.26 (s, H, ArH), 8.47 (dd, H, ArH, J=8.58 Hz, 2.25 Hz), 9.16 (d, H, ArH, J=1.86 Hz). MS: (ESI+): MH+=494.32
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=[O:17])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].IC.[C:21](=O)([O-])O.[K+]>CN(C=O)C>[CH3:21][O:17][C:16]([CH:13]1[CH2:14][CH2:15][N:11]([C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[CH2:12]1)=[O:18]
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)C1
Reactant: O=C([O-])O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.8 %

Procedure:
To a solution of N-carbobenzyloxypyrrolidine-3-carboxylic acid (10.15 g, 40.72 mmol) and iodomethane (5.08 mL, 81.44 mmol) in N,N′-dimethylformamide (80 mL) was added powdered potassium hydrogen carbonate (8.15 g, 81.44 mmol) and the reaction mixture stirred at ambient temperature for 5 hours. The mixture was partitioned between ethyl acetate and brine and the organic phase washed with water and concentrated. The residue was purified by flash chromatography on silica gel using 5-50% ethyl acetate in hexane to give the title compound (10.59 g, 99%). MS(DCI): m/z 264 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=1)#[CH:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17]([C:20]#[C:19][C:21]4[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cnc(N)nc1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Product: Cc1cc(-c2ccc(Cl)cc2)nc2c(C#Cc3cnc(N)nc3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-iodo-7-methyl-pyrazolo[1,5-a]pyrimidine (example 292) (185 mg, 0.5 mmol) and 5-ethynyl-pyrimidin-2-ylamine (example D.2 step 2) (60 mg, 0.5 mmol) according to general procedure II. Obtained as yellow solid (80 mg, 44%). MS (ISP) 361.4 [(M+H)+]; mp 280-282° C.
Reaction SMILES: [CH:1]1([CH:7]([CH:21]=[CH:22][CH2:23][CH2:24][CH3:25])[CH2:8][NH:9][C:10]2[CH:20]=[CH:19][C:13]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(F)(F)F.[CH3:30]COCC>CO>[CH:1]1([CH:7]([CH:21]=[CH:22][CH2:23][CH2:24][CH3:25])[CH2:8][NH:9][C:10]2[CH:20]=[CH:19][C:13]([CH2:14][CH2:15][C:16]([O:18][CH3:30])=[O:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOCC
Reactant: CCCC=CC(CNc1ccc(CCC(=O)O)cc1)C1CCCCC1
Agent: FB(F)F
Solvent: CO
Product: CCCC=CC(CNc1ccc(CCC(=O)OC)cc1)C1CCCCC1
Temperature: 0 °C

Procedure:
A solution of 50.5 g. of 4-(2-cyclohexylhept-3-enylamino)hydrocinnamic acid and 34.4 ml. of boron trifluoride etherate in 200 ml. of methanol is stirred under reflux for 44 hours, allowed to cool, and poured into 1.20 liters of ice-cold 5% aqueous sodium carbonate solution. The white solid is collected by filtration and recrystallized from benzene-ethanol to yield methyl 4-(2-cyclohexylhept-3-enylamino)hydrocinnamate.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([Br:9])=[C:4]([F:10])[C:3]=1[N+:11]([O-])=O.CCOC(C)=O>C(O)C.Cl.[Fe]>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([Br:9])=[C:4]([F:10])[C:3]=1[NH2:11]
Reactant: O=[N+]([O-])c1c(F)c(Br)cc(F)c1Br
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1c(F)c(Br)cc(F)c1Br
Temperature: 80 °C

Procedure:
2,5-Dibromo-3,6-difluoronitrobenzene (120 g, 0.37 mol) is dissolved in a mixture of ethanol (300 mL) and concentrated HCl (500 mL). The mixture is heated to 80° C. and treated with iron powder (100 g, 1.78 mol) by portion-wise addition over 2 hours. After stirring for an additional hour, the mixture is cooled to room temperature and EtOAc (800 mL) is added. The solids are removed by filtration and then the solution concentrated by rotary evaporator to remove most of the solvent. The residue is partitioned between EtOAc (1000 mL) and water (500 mL). The organic layer is washed with brine (2×250 mL), dried (MgSO4) and concentrated by rotary evaporator to give a brown oil. The crude product is then purified using flash chromatography (9:1 hexanes/EtOAc) to give 2,5-dibromo-3,6-difluoroaniline.
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12](=[O:38])[N:13]2[CH2:16][CH2:17][CH2:18][C:19]2([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]2)=[CH:8][CH:7]=1.[OH-].[Na+]>O>[CH3:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12](=[O:38])[N:13]2[CH2:16][CH2:17][CH2:18][C:19]2([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]2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(CCSc2cccs2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2ccc(=O)n(CCCC3(C(=O)O)CCN(CCSc4cccs4)CC3)c2c1
Temperature: 25 °C
Yield: 67 %

Procedure:
To 1 mL of an ethanol solution containing 90 mg of ethyl 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)-1-(2-(2-thienylthio)ethyl)piperidine-4-carboxylate, 0.3 mL of 20% aqueous sodium hydroxide solution was added and refluxed with heating for 1.5 hours. Then, more 0.3 mL of 20% aqueous sodium hydroxide solution was added and refluxed with heating for 3 hours. After the reaction mixture was cooled to room temperature, water was added, and the solvent was removed under reduced pressure. Water was added, and adjusted to pH 6.7 with 6.0 mol/L hydrochloric acid. The resulting solid was filtered to afford 57 mg of 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)-1-(2-(2-thienylthio)ethyl)piperidine-4-carboxylic acid as a white solid.