Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:13][N:12]([C:14](OC(C)(C)C)=O)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C(O)=O)(F)(F)F.[C:28]([N:35]1[CH2:38]C(=O)[CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([NH:9][CH:10]1[CH2:11][N:12]([CH:14]2[CH2:38][N:35]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:36]2)[CH2:13]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)c2ccccc2)C1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(N2CC(NC(=O)c3ccccc3)C2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.5 %

Procedure:
To a solution of 1c (1.45 g, 5.25 mmol) in CH2Cl2 (20 mL) at room temperature was added CF3CO2H (5 mL). The reaction was stirred at room temperature for 1.5 h. The reaction was concentrated and the resulting residue was dissolved in a mixed solution of 1,2-dichloroethane (10 mL) and acetic acid (0.5 mL). To the resulting solution at room temperature was added 1-Boc-azetidin-3-one 1d (0.99 g, 5.79 mmol), followed by Na(OAc)3BH (1.23 g, 5.80 mmol). The reaction mixture was stirred at room temperature for 20 h. Additional 1-Boc-azetidin-3-one 1d (0.50 g, 2.92 mmol) and Na(OAc)3BH (0.62 g, 2.92 mmol) was added. The reaction was stirred for another 6 h before it was quenched by the addition of aq. NaHCO3. The resulting mixture was extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, 4% MeOH/CH2Cl2) gave compound 1e (0.93 g).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH2:18][CH3:19])[C:4]=1[S:20][CH:21]([CH3:23])[CH3:22].C1C=C(Cl)C=C(C(OO)=[O:33])C=1.C1C=C(Cl)C=C(C(O)=O)C=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH2:18][CH3:19])[C:4]=1[S:20]([CH:21]([CH3:22])[CH3:23])=[O:33]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(SC(C)C)c1CC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C(O)c1cccc(Cl)c1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(S(=O)C(C)C)c1CC

Procedure:
Prepared from product of Example 11 (5.89 g, 15.86 mmol) and MCPBA (3.22 g of an 85% mixture with MCBA, 15.86 mmol) as described above. Recrystallization (ether/petroleum ether) afforded the product as a white solid (6.2 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][C:5]2[CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=3)[CH:9]=[CH:10][C:4]=2[O:3]1.[CH3:22][NH:23][O:24][CH2:25][CH3:26]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:21])[CH2:6][C:5]2[CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([N:23]([O:24][CH2:25][CH3:26])[CH3:22])=[O:20])=[CH:14][CH:13]=3)[CH:9]=[CH:10][C:4]=2[O:3]1
Reactant: CCONC
Reactant: CC1(C)Cc2cc(Oc3ccc(N=C=O)cc3)ccc2O1
Solvent: Cc1ccccc1
Product: CCON(C)C(=O)Nc1ccc(Oc2ccc3c(c2)CC(C)(C)O3)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96.5 %

Procedure:
1.8 g of 4-(2,3-dihydro-2,2-dimethyl-5-benzofuranyloxy)phenyl isocyanate was dissolved in 20 ml of toluene, and 2.0 g of N-methyl-O-ethylhydroxylamine dissolved in 5 ml of toluene, was dropwise added thereto over a period of 20 minutes at room temperature. The mixture was stirred at room temperature for 2 hours, and then the solvent was distilled off. The residue was purified by silica gel column chromatography by using a solvent mixture of ethyl acetate/n-hexane=1/4 as the developer, to obtain 2.2 g of compound No. 29 as identified in Table 1.
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:5])[NH2:4].[Cl:6][C:7]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:8]=1[CH:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12]>>[NH2:14][CH2:13][C:10]1[C:11]([NH2:12])=[N:5][C:3]([S:2][CH3:1])=[N:4][C:9]=1[C:8]1[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:7]=1[Cl:6]
Reactant: CSC(=N)N
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: CSc1nc(N)c(CN)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
The title compound, MS: m/e=315.2 (M+), was prepared from 2-methyl-isothiourea and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([N+:12]([O-])=O)[CH:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[K+].[K+].NN>C(Cl)Cl.[Ni]>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[NH2:12])(=[O:10])=[O:9])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Cl
Agent: [Ni]
Agent: NN
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(Cl)cc2N)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
The mixture of 4-Chloro-2-nitro-benzenesulfonyl chloride (255 mg, 1 mmol), 4-Amino-piperidine-1-carboxylic acid tert-butyl ester (200 mg, 1 mmol) and K2CO3 (276 mg, 2 mmol) in DCM (3 mL) was stirred at room temperature for 1 hr. The mixture was concentrated in vacuo, the residue was dissolved in methanol, and then Ra—Ni (0.5 g) and hydrazine (1 mL, 17 mmol) was added. The resulting mixture was stirred at room temperature for 2 hr, filtered concentrated in vacuo. The residue was purified by column chromatography to give 380 mg 4-(2-Amino-4-chloro-benzenesulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester as pale white solid. MS: [M+H]+=390
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7]([CH3:11])([CH3:10])[CH2:8][OH:9])=O.S(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[C:4]1[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[N:6]=1
Reactant: CC(C)(CO)NC(=O)c1ccc(F)cc1Cl
Solvent: O=S(Cl)Cl
Product: CC1(C)COC(c2ccc(F)cc2Cl)=N1

Procedure:
Reaction of 2-chloro-4-fluoro-N-(1-hydroxy2-methyl-2-propyl)benzamide and thionyl chloride by the method described in Example 1b provides 2-(2-chloro-4-fluorophenyl)-4,4-dimethyl-2-oxazoline as a liquid; hydrochloride salt, m.p. 138°-139°.
Reaction SMILES: Cl[C:2]1[N:3]([C@H:24]2[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)[N:5]=2.[CH3:33][C@H:34]1[CH2:39][NH:38][CH2:37][C@@H:36]([CH3:40])[NH:35]1>CS(C)=O>[CH3:33][C@H:34]1[NH:35][C@@H:36]([CH3:40])[CH2:37][N:38]([C:2]2[N:3]([C@H:24]3[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:25]3)[C:4]3[C:9]([N:10]=2)=[C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:7]=[C:6]([C:17]2[CH:22]=[N:21][C:20]([NH2:23])=[N:19][CH:18]=2)[N:5]=3)[CH2:39]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: CS(=O)(=O)N1CC[C@H](n2c(Cl)nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc32)C1
Solvent: CS(C)=O
Product: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2[C@H]2CCN(S(C)(=O)=O)C2)C[C@H](C)N1
Temperature: 140 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
Dimethyl sulfoxide (1 ml) was added to 5-{8-chloro-9-[(3S)-1-(methylsulfonyl)pyrrolidin-3-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (100 mg, 0.21 mmol) and cis-2,6-dimethylpiperazine (119 mg, 1.04 mmol) and the resulting mixture was stirred at 140° C. for 1 hour. The reaction mixture was partitioned with chloroform and water, the organic layer was dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=9:1) to give the title compound (95 mg, 82%) as a light brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:29][CH2:30][NH:31]CC4CC4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.[CH:36](N)([CH3:38])[CH3:37]>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:29][CH2:30][NH:31][CH:36]([CH3:38])[CH3:37])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2cn(CCNCC3CC3)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F
Reactant: CC(C)N
Product: Cc1cc(-c2cn(CCNC(C)C)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using isopropylamine instead of cyclopropylmethylamine. LC-MS: (M+1=463, obsd.=463).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([C:11](O)=[O:12])[C:3]=1[C:14](O)=[O:15].B>O1CCCC1>[F:1][C:2]1[C:3]([CH2:14][OH:15])=[C:4]([CH2:11][OH:12])[C:5]([F:10])=[C:6]([F:9])[C:7]=1[F:8]
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: OCc1c(F)c(F)c(F)c(F)c1CO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 10 tetrahydrofuran (THF) is added 3,4,5,6-tetrafluoro-1,2-benzenedicarboxylic acid (2 g, 8.4 mmol). After cooling to 0°, 21.0 ml (20.9 mmol) of 1 M borane in THF is slowly added. The reaction mixture is allowed to rise to RT and stirred at RT for 18 hours and then is cooled and quenched with 10% HCl. The reaction mixture is added to ether, and the organic phase is washed with water, sat. sodium bicarbonate and brine, dried over sodium sulfate and evaporated under vacuum to yield 3,4,5,6-tetrafluoro-1,2-bis(hydroxymethyl)benzene.
Reaction SMILES: [CH2:1]([NH:3][NH2:4])[CH3:2].[C:5](OCC)(=[O:10])[CH2:6][C:7]([CH3:9])=O>CCO>[CH2:1]([N:3]1[C:5](=[O:10])[CH2:6][C:7]([CH3:9])=[N:4]1)[CH3:2]
Reactant: CCNN
Reactant: CCOC(=O)CC(C)=O
Solvent: CCO
Product: CCN1N=C(C)CC1=O
Temperature: 80 °C
Yield: 38.3 %

Procedure:
3.05 g of Ethylhydrazine and 6.54 g of Ethyl acetoacetate was dissolved in 10 mL of EtOH and the mixture was heated at 80° C. overnight. The mixture was cooled and partitioned between CHCl3 and water. The organic layer was drier over Na2SO4, concentrated to give 2.43 g of crude 2-ethyl-5-methyl-2,4-dihydro-3H-pyrazol-3-one. 2.35 g of the material was diluted with 4 mL of DMF and 6.2 mL of POCl3 was added dropwise thereto. The mixture was heated at 80° C. overnight, then cooled to room temperature. After addition of ice, the mixture was partitioned between CHCl3 and water. The organic layer was dried over Na2SO4 and concentrated to give 1.46 g of crude 5-chloro-1-ethyl-3-methyl-1H-pyrazole-4-carbaldehyde. 516 mg of the material was diluted with 10 mL of EtOH and 440 mg of HSCH2COOEt and 930 mg of K2CO3 was added thereto. The mixture was stirred at 80° C. overnight. The reaction mixture was cooled and 5 mL of 1N NaOHaq and 5 mL of MeOH was added thereto successively. Then the mixture was heated at 85° C. for 3 hrs. After cooled, the mixture was acidified with 1N HCl (to pH 1.5), then diluted with water. The precipitate was filtered, washed with water and n-hexane, dried in vacuo to afford 214 mg of the targeted compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[C:42]([O:45][CH:46]4[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1.C(N(C(C)C)CC)(C)C.[CH3:64][C:65]1[C:69]([C:70](O)=[O:71])=[C:68]([CH3:73])[O:67][N:66]=1>C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[C:42]([O:45][CH:46]4[CH2:47][CH2:48][N:49]([C:70]([C:69]5[C:65]([CH3:64])=[N:66][O:67][C:68]=5[CH3:73])=[O:71])[CH2:50][CH2:51]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: Cc1noc(C)c1C(=O)O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)c2c(C)noc2C)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 32.3 %

Procedure:
HATU (0.31 g) was added to a solution of N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and 3,5-dimethyl-4-isoxazolecarboxylic acid (0.141 g) in methylene chloride (9 ml). The resulting mixture was stirred at room temperature for 2.5 hrs. Methylene chloride (20 ml) was added and the organics washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The crudes were then purified by flash column chromatography eluting with methanol/methylene chloride (2.5/97.5). Fractions containing the desired product were evaporated to a white foam which was triturated with diethyl ether (20 ml) to give N-(3-chloro-2-fluorophenyl)-6-({1-[(3,5-dimethylisoxazol-4-yl)carbonyl]piperidin-4-yl}oxy)-7-methoxyquinazolin-4-amine as a white solid (0.107 g). 1H NMR Spectrum: (DMSO d6 373K) 1.80 (m, 2H), 2.01 (m, 2H), 2.20 (s, 3H), 2.40 (s, 3H), 3.47 (m, 2H), 3.75 (m, 2H), 3.96 (s, 3H), 4.76 (m, 1H), 7.23 (m, 1H), 7.23 (s, 1H), 7.40 (m, 1H), 7.58 (m, 1H), 7.89 (s, 1H), 8.39 (s, 1H), 9.25 (br s, 1H); Mass Spectrum: (M+H)+ 526.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([F:12])=[C:8]([CH:11]=1)[C:9]#[N:10])([O-])=O.[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([F:12])=[C:8]([CH:11]=1)[C:9]#[N:10]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: N#Cc1cc(N)ccc1F
Yield: 61 %

Procedure:
A mixture of 5-nitro-2-fluorobenzonitrile (10 g, 60.2 mmol), Fe powder (17 g, 0.3 mol), and NH4Cl (1.7 g, 30 mmol) in EtOH/H2O (100 mL, 9:1) was heated at reflux in 2 h. The mixture was filtered at hot. The filtrate was concentrated, taken up in H2O, stirred, filtered air-dried to obtain the title solid as a tan solid, (5.0 g, 71%). 1H NMR (400 MHz, DMSO-d6): d 5.54 (s, 2H), 6.85 (m, 2H), 7.16 (t, J=8.1 Hz, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH:9]=O)[CH3:2].[CH2:13]([SH:17])[CH2:14][CH2:15][SH:16].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([N:3]([CH2:11][CH3:12])[CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH:9]1[S:17][CH2:13][CH2:14][CH2:15][S:16]1)[CH3:2]
Reactant: CCN(CC)CC#CCCC=O
Reactant: SCCCS
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCN(CC)CC#CCCC1SCCCS1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.8 %

Procedure:
To a solution of 6-diethylaminohex-4-ynal (50 g, 290 mmol) in methylene chloride (600 mL) was added 1,3-propanedithiol (30 mL, 290 mmol). The solution was stirred at room temperature for 1 hour and then cooled in an ice-bath. Boron trifluoride etherate (40 mL, 290 mmol) was added and the solution was stirred at room temperature overnight. The mixture was washed with water (150 mL), 10% potassium hydroxide solution (2×300 mL), brine (3×100 mL) and dried (MgSO4). Evaporation of the solvent afforded an oil which was Kugelrohr distilled (oven 120° C., 0.1 mm Hg) to give 20 g of product. The residue was chromatographed on basic alumina (activity I) eluting with methylene chloride and the oil was redistilled by Kugelrohr to afford 14 g (45%) of product. 1H NMR (CDCl3) δ: 1.14 (t, 6H), 1.80-1.90 (m, 1H), 1.91 (q, 2H), 2.05-2.15 (m, 1H), 2.43 (t, 2H), 2.52 (q, 4H), 2.81-2.90 (m, 4H), 3.39 (d, 2H), 4.17 (t, 1H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.CC(C)([O-])C.[Na+].O>C1(C)C=CC=CC=1.[Pd].[Pd].C(Cl)(Cl)Cl.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:23][CH:22]=3)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COCCCCCOc1ccc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Temperature: 90 °C
Reaction time: 54 h
Yield: 91.4 %

Procedure:
A mixture of piperazin-1-carboxylic acid tert-butyl ester (0.64 g), 4-bromo-4′-(5-methoxypentyloxy)biphenyl (1 g), tris(dibenzylideneacetone) (chloroform) dipalladium(0) (59 mg), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.12 g) and sodium tert-butoxide (0.55 g) in toluene (10 ml) was stirred for 54 hours at 90° C. The reaction mixture was added to a mixture of water and ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 4-[4′-(5-methoxypentyloxy)biphenyl-4-yl]piperazin-1-carboxylic acid tert-butyl ester (1.19 g).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH:8]2[CH2:11][O:10][CH2:9]2)[C@H:5]([CH3:12])[CH2:4][N:3]1[C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:25](=[O:26])[N:24]([CH3:27])[CH:23]=[C:22]([C:28]3[C:33]([CH:34]=[O:35])=[C:32]([N:36]4[CH2:49][CH2:48][N:39]5[C:40]6[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=6[C:46]([F:47])=[C:38]5[C:37]4=[O:50])[N:31]=[CH:30][CH:29]=3)[CH:21]=2)=[N:17][CH:18]=1.[BH4-].[Na+]>CO>[CH3:1][C@H:2]1[CH2:7][N:6]([CH:8]2[CH2:9][O:10][CH2:11]2)[C@H:5]([CH3:12])[CH2:4][N:3]1[C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:25](=[O:26])[N:24]([CH3:27])[CH:23]=[C:22]([C:28]3[CH:29]=[CH:30][N:31]=[C:32]([N:36]4[CH2:49][CH2:48][N:39]5[C:40]6[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=6[C:46]([F:47])=[C:38]5[C:37]4=[O:50])[C:33]=3[CH2:34][OH:35])[CH:21]=2)=[N:17][CH:18]=1
Reactant: C[C@@H]1CN(c2ccc(Nc3cc(-c4ccnc(N5CCn6c7c(c(F)c6C5=O)CCCC7)c4C=O)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1CN(c2ccc(Nc3cc(-c4ccnc(N5CCn6c7c(c(F)c6C5=O)CCCC7)c4CO)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
A 50-mL round-bottomed flask equipped with a magnetic stirrer was charged with 156a (60 mg, 0.088 mmol), NaBH4 (17 mg, 0.44 mmol), and methanol (10 mL). The mixture was stirred at room temperature for 1 h. It was then quenched with water and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 156 (15 mg, 25%). MS-ESI: [M+H]+ 683.5. 1H NMR (500 MHz, CDCl3) δ 8.67 (d, J=2.5 Hz, 1H), 8.48 (d, J=5.0 Hz, 1H), 8.02 (d, J=2.5 Hz, 1H), 7.87 (s, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.37-7.35 (m, 2H), 6.81 (d, J=9.0 Hz, 1H), 4.99-4.59 (m, 6H), 4.45-4.32 (m, 2H), 4.12-4.03 (m, 2H), 3.85-3.73 (m, 2H), 3.71 (s, 3H), 3.19-3.16 (m, 1H), 2.91-2.89 (m, 1H), 2.75-2.69 (m, 2H), 2.57-2.47 (m, 5H), 1.97-1.76 (m, 5H), 0.89-0.87 (m, overlap, 6H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl.C(O)C>[Cl:15][C:16]1[CH:21]=[C:20]([C:2]2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Cl
Agent: Cl[Pd]Cl
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1-c1cccc(Cl)c1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
A mixture of methyl 2-chloro-4-nitrobenzoate (0.432 g, 2.0 mmol), 3-chlorophenylboronic acid (0.375 g, 2.4 mmol), trans-dichlorobis(tricyclohexylphosphine)-palladium (II) (0.074 g, 0.1 mmol), and sodium carbonate (0.64 g, 6.0 mmol) in a mixture of toluene (10 mL), dioxane (10 mL), and ethanol (2 mL) was heated to reflux for 12 hours, cooled to room temperature, diluted with ethyl acetate (10 mL), washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 1:10 ethyl acetate/hexanes to provide 0.58 g (99%) of the desired product. MS (DCI/NH3) m/z 309 (M+NH4)+; 1H NMR (CDCl3) δ 8.27-8.22 (m, 2H), 8.00 (dd, 1H), 7.41-7.34 (m, 3H), 7.23-7.18 (m, 1H), 3.72 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.[C:23]([O-:28])(=[O:27])[C:24]([CH3:26])=[O:25].[Na+].C(=O)([O-])[O-].[Na+].[Na+].O>CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18](/[CH:19]=[CH:26]/[C:24](=[O:25])[C:23]([OH:28])=[O:27])=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(C=O)cc1
Reactant: CC(=O)C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(/C=C/C(=O)C(=O)O)cc1
Reaction time: 6 h
Yield: 44.5 %

Procedure:
A mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde (2.9 g), sodium pyruvate (3.3 g), sodium carbonate (3.2 g), water (80 ml) and methanol (80 ml) was stirred for 6 hours under reflux. The reaction mixture was concentrated under reflux to about 1/3 of the initial volume. The concentrate was subjected to extraction with ethyl acetate. The aqueous layer was acidified with conc. HCl. Resulting crystalline precipitate was collected by filtration to obtain (E)-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylidenepyruvic acid (1.6 g, 44%). Recrystallization from chloroform-methanol gave colorless needles, m.p.197-198° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[S:29])=[CH:23][CH:22]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[NH:1][C:28]([NH:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:26][CH:25]=1)=[S:29]
Reactant: FC(F)(F)c1ccc(N=C=S)cc1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1ccc(C(F)(F)F)cc1
Yield: 83.8 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.198 g, 0.82 mmol) and 4-(trifluoromethyl)phenyl isothiocyanate (0.169 g, 0.83 mmol) to give the product (0.306 g); m.p. 194-196° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21](N2CCN(S(C)(=O)=O)CC2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:33][CH:34]([S:36]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)(=[O:38])=[O:37])[CH3:35].C(S(Cl)(=O)=O)(C)C.N1(C(OC(C)(C)C)=O)CCNCC1>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:42]2[CH2:41][CH2:40][N:39]([S:36]([CH:34]([CH3:33])[CH3:35])(=[O:37])=[O:38])[CH2:44][CH2:43]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)N1CCNCC1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(C)S(=O)(=O)Cl
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)C(C)C)CC4)cc3c2)CC1
Yield: 87 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride (example 1, intermediate b) and 1-(1-methylethylsulfonyl)piperazine (prepared in analogy to WO2003064413 using isopropylsulfonyl chloride and tert-butyl 1-piperazinecarboxylate) to afford the desired product as a light-brown solid (87%). MS (ISP): 490.3 (M+H)+.