Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[NH:16][C:17](=O)[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]2[CH2:30][C:29](=[O:31])[N:28]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH2:27]2)=[CH:20][CH:19]=1.[OH-].[Na+]>CO>[F:38][C:35]1[CH:36]=[CH:37][C:32]([N:28]2[C:29](=[O:31])[CH2:30][CH:26]([CH2:25][O:24][C:21]3[CH:22]=[CH:23][C:18]([C:17]4[NH:16][C:3]5[C:4](=[O:15])[N:5]([CH2:12][CH2:13][CH3:14])[C:6](=[O:11])[N:7]([CH2:8][CH2:9][CH3:10])[C:2]=5[N:1]=4)=[CH:19][CH:20]=3)[CH2:27]2)=[CH:33][CH:34]=1
Reactant: CCCn1c(N)c(NC(=O)c2ccc(OCC3CC(=O)N(c4ccc(F)cc4)C3)cc2)c(=O)n(CCC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(-c3ccc(OCC4CC(=O)N(c5ccc(F)cc5)C4)cc3)nc2n(CCC)c1=O
Yield: 83 %

Procedure:
N-(6-Amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-4-[1-(4-fluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethoxy]-benzamide obtained in step 3 (0.90 g, 0.167 mmol) was dissolved in MeOH (4 mL) and 10% NaOH (0.020 g, 0.502 mmol) and stirred at 80° C. for 7 h. MeOH was distilled off and the residue was taken up in H2O (2 mL), acidified with 2NHC1 to pH 4-5. The precipitate was filtered, washed with water and methanol to provide the title compound as white solid (0.072 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=O)=[C:4]([CH2:14][CH3:15])[CH:3]=1.CCN(CC)CC.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[N:45]1([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:48]2[CH2:47][CH2:46][N:45]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:50][CH2:49]2)=[O:13])=[C:4]([CH2:14][CH3:15])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCc1cc(Cl)c(Cl)cc1NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc(Cl)c(Cl)cc1NCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
To a stirred mixture of 2-(4,5-dichloro-2-ethylphenylamino)acetic acid (100 mg, 0.403 mmol), Et3N (122 mg, 1.21 mmol) in DCM (3 mL) at 0° C., EDCI.HCl (123 mg, 0.604 mmol) and HOBt (8 2 mg, 0.604 mmol) were added. The resulting mixture was stirred at 0° C. for 30 min, and then tert-butyl piperazine-1-carboxylate (90 mg, 0.483 mmol) was added. The mixture was stirred at room temperature for 16 h and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=5:1) to afford the desired product (120 mg, 71.5% yield) as an off-white solid. ESI-MS m/z: 414.3 [M−H]−.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](I)[CH:13]=1)(=[O:3])[CH3:2].CS(C)=O.[C:31]1([S:37]([O-:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CNCCNC>C(OCC)(=O)C.O>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([S:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:39])=[O:38])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: O=S([O-])c1ccccc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(I)c1
Agent: CNCCNC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(S(=O)(=O)c2ccccc2)c1
Temperature: 130 °C
Yield: 43 %

Procedure:
0.495 g (1 mM) of 5-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside, 4 ml of DMSO, 0.025 g (0.05 mM) of benzene/copper trifluoro-methanesulfonate complex, 0.196 g (1.2 mM) of phenyl sulfinate and 0.0088 g (0.1 mM) of N,N′-dimethylethylenediamine are mixed under an argon atmosphere in a reactor adapted for microwaves. The mixture is heated at 130° C. for 3 hours by microwaves. Water is added to the cooled reaction mixture and extraction is carried out with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel using a toluene/acetone mixture (9/1; v/v) as the eluent to give the expected product in the form of a white solid with a yield of 43%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[CH:8][S:7](=O)(=O)[C:6]=2[CH:18]=1.O1CCCC1.[H-].C([Al+]CC(C)C)C(C)C.[H][H]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)=[CH:8][S:7][C:6]=2[CH:18]=1
Reactant: O=S1(=O)C=C(N2CCNCC2)c2ccc(Cl)cc21
Reactant: [H][H]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Clc1ccc2c(N3CCNCC3)csc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 111.3 %

Procedure:
To a mixture of 6-chloro-3-piperazinyl-benzo[b]thiophene-1,1-dioxide (6.0 g) and tetrahydrofuran (THF) (30 mL) under a nitrogen atmosphere was added a solution of D1BAL-H (diisobutylaluminum hydride) (0.084 mol) in toluene (84 mL) dropwise with ice bath cooling. The reaction mixture was stirred at 0° C. for 2 hours then overnight at room temperature. To the yellow solution was added, with vigorous stirring, water (5 ml) at a rate to control hydrogen evolution. Then 5NNaOH (5 mL) was added with rapid stirring. The resulting precipitate was filtered off and washed with dichloromethane and ether. The filtrate was concentrated in vacuo. The residue was taken up in dichloromethane (150 mL), washed with water (75 mnl) and brine (100 ml), dried over sodium sulfate and concentrated in vacuo to yield 5.93 g of a viscous gummy material which was triturated with ether. The ether fraction was concentrated in vacuo to yield 2.75 g of residue which was chromatographed (silica gel, 50% MeOH/CH2 Cl2) to yield 1.53 g product as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:38])=[C:5]([C:29]([O:36][CH3:37])=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21]CC2C=CC=CC=2)=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[C:4]([CH3:38])=[C:5]([C:29]([O:36][CH3:37])=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:21])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:13]
Reactant: [H][H]
Reactant: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Agent: [Pd]
Solvent: CCO
Product: COc1c(C)c(Cc2ccc(O)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Yield: 93.3 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoyl]piperidine (1.02 g, 2.09 mmol) was dissolved in ethanol (50 ml) and the resulting solution was added to an ethanol suspension (5 ml) of 5% Pd—C (0.200 g) and stirred at room temperature for 16 hours in a hydrogen stream. The reaction solution was filtered, the filtrate was concentrated and the obtained residue was recrystallized from ether to obtain the titled compound (0.760 g, 1.95 mmol, 93%).
Reaction SMILES: Cl[C:2]1[C:3]2[C:4](=[N:14][N:15]([CH3:17])[CH:16]=2)[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.C[NH:19][CH2:20][CH2:21][CH3:22].[CH:23]1C=CC=CC=1>CCOCC>[CH3:17][N:15]1[CH:16]=[C:3]2[C:4]([N:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:7]=[C:2]2[NH:19][CH:20]([CH3:23])[CH2:21][CH3:22])=[N:14]1
Reactant: CCCNC
Reactant: c1ccccc1
Reactant: Cn1cc2c(Cl)cc(-c3ccccc3)nc2n1
Solvent: CCOCC
Product: CCC(C)Nc1cc(-c2ccccc2)nc2nn(C)cc12

Procedure:
14.6 g. of 4-chloro-2-methyl-6-phenyl-2H-pyrazolo [3,4-b]pyridine (0.06 mol.) and a solution of 100 ml. of methylpropylamine in 150 ml. of benzene are heated at 220° in an autoclave for 20 hours. After cooling, the mixture is evaporated in vacuo, and to the residue 100 ml. of water and 100 ml. of chloroform are added. After agitation, the chloroform extract is separated and dried with Na2SO4. Evaporation yields an oily product which, after treatment with ether, becomes solid. 14.3 g. of 2-methyl-N-(1-methylpropyl)-6-phenyl-2H-pyrazolo[3,4-b]pyridin-4-amine, (m.p. 148°-151° ), are recrystallized from ethyl acetate giving a pure product of the melting point 156°-157°.
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]([F:12])[C:3]=1[C:4]#[N:5].Cl.[NH2:14][OH:15].[OH-].[Na+]>CCO>[F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]([F:12])[C:3]=1[C:4]([NH:14][OH:15])=[NH:5]
Reactant: NO
Reactant: COc1ccc(F)c(C#N)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(F)c(C(=N)NO)c1F
Yield: 43.6 %

Procedure:
To a solution of 2,6-difluoro-3-methoxybenzonitrile (0.30 g, 1.70 mmol) in EtOH (10 ml) was added hydroxylamine hydrochloride (0.12 g, 1.70 mmol) and NaOH (0.071 g, 1.70 mmol). The resulting reaction mixture was refluxed for 15 h. After the completion of the reaction (TLC monitoring), the mixture was concentrated, added EtOH and filtered. The filtrate was evaporated in vacuo and the crude residue was purified over silica gel (60-120 M, 30% EtOAc-Hexane) to get the desired product (0.15 g, 42%) as a white solid.
Reaction SMILES: C([C:5](C(C)(C)C)([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([OH:37])[CH2:17][NH:18][C:19]([C:21]2[S:22][C:23]3[CH2:24][NH:25][CH:26](C(OC(C)(C)C)=O)[CH2:27][C:28]=3[N:29]=2)=[O:20])=[CH:12][C:11]=1[O:38][CH2:39][C:40]([O-:42])=[O:41])[C:6]([O-:8])=[O:7])(C)(C)C.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].C(OC(C)C)(C)C>C1(OC)C=CC=CC=1>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[N:29]1[C:28]2[CH2:27][CH2:26][NH:25][CH2:24][C:23]=2[S:22][C:21]=1[C:19]([NH:18][CH2:17][CH:16]([C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:5][C:6]([OH:8])=[O:7])=[C:11]([O:38][CH2:39][C:40]([OH:42])=[O:41])[CH:12]=1)[OH:37])=[O:20]
Reactant: CC(C)(C)OC(=O)C1Cc2nc(C(=O)NCC(O)c3ccc(OC(C(=O)[O-])(C(C)(C)C)C(C)(C)C)c(OCC(=O)[O-])c3)sc2CN1
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(C(O)CNC(=O)c2nc3c(s2)CNCC3)cc1OCC(=O)O
Yield: 77.8 %

Procedure:
To the solution of the compound prepared in (a) (115.3 mg, 0.174 mmole) in anisole (0.5 ml) was added trifluoroacetic acid (2.0 ml) at 0° C. Crystals were deposited by the addition of isopropyl ether at 0° C., collected by filtration, and lyophilized to give 82.1 mg of a crude product, which was purified on a LH column (50% methanol) to give 76.6 mg of the title compound as a colorless crystal (yield, 77.8%).
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][CH:13]([C:16]1([CH:21]([CH2:23][CH3:24])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17]1)[CH2:14][CH3:15].S(C1C=CC(C)=CC=1)(O[CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])(=O)=O>O1CCCC1.O>[CH3:32][N:31]([CH2:30][CH2:29][C:17]1[C:16]([CH:13]([CH2:14][CH3:15])[CH3:12])([CH:21]([CH2:23][CH3:24])[CH3:22])[CH:20]=[CH:19][CH:18]=1)[CH3:33]
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)C)cc1
Reactant: CCC(C)C1(C(C)CC)C=CC=C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCC(C)C1(C(C)CC)C=CC=C1CCN(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Under a nitrogen atmosphere, a solution of n-butyllithium in hexane (31.2 ml; 1.6 mol/L; 50 mmol) was added dropwise to a cooled (0° C.) solution of di-(2-butyl)cyclopentadiene (8.90 g; 50.0 mmol) in dry tetrahydrofuran (150 ml) in a 250 mL three-necked round-bottomed flask provided with a magnetic stirrer and a dropping funnel. After 24 hours of stirring at room temperature, the 2-dimethylaminoethyl tosylate (50.0 mmol) was added. After 18 hours of stirring the conversion was found to be 96 %, and water (100 ml) was carefully added dropwise to the reaction mixture and the tetrahydrofuran was then distilled off. The crude product was extracted with ether and the combined organic phase was then dried with sodium sulphate, and boiled down. The residue was purified on a silica gel column, which resulted in 8.5 g of (dimethylaminoethyl)-di(2-butyl)cyclopentadiene.
Reaction SMILES: C([O:8][C@@H:9]([C:11]1[O:12][C:13]2[C:18]([C:19](=[O:28])[C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)=[CH:17][C:16]([F:29])=[CH:15][CH:14]=2)[CH3:10])C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[F:29][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([C@H:9]([OH:8])[CH3:10])=[C:20]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[C:19]2=[O:28]
Reactant: C[C@@H](OCc1ccccc1)c1oc2ccc(F)cc2c(=O)c1-c1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C[C@@H](O)c1oc2ccc(F)cc2c(=O)c1-c1cccc(F)c1
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To (R)-2-(1-(benzyloxy)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one (10.5 g, 26.69 mmol) in Dichloromethane (110 ml) cooled to 0° C., anhydrous Aluminium chloride (5.35 g, 40.03 mmol) was added portion wise and stirred for 1 h and then at RT for 2 h. The reaction mixture was quenched with dilute aq. HCl (10 ml), extracted with Dichloromethane (2×50 ml). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as off-white solid (6.5 g, 81%). 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.86 (dd, J=8.3, 3.0 Hz, 1H), 7.56 (dd, J=9.2, 4.2 Hz, 1H), 7.45 (m, 2H), 7.12-6.99 (m, 3H), 4.76 (q, J=6.6 Hz, 1H), 1.55 (d, J=6.6 Hz, 3H). Mass: 303.2 (M++1). Purity: 99.78%. [α]25D 0.287 (c=1, CHCl3). Enantiomeric excess: 97.74%, enriched in the late eluting isomer (retention time: 10.93 min.) as determined by HPLC on a chiralpak AD-H column.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:49])[CH2:19][C:20]3[NH:21][C:22]([CH2:42][CH2:43][C:44]4[S:45][CH:46]=[CH:47][N:48]=4)=[C:23]([C:38]([O:40][CH3:41])=[O:39])[CH:24]([C:30]4[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:37])[C:25]=3[C:26]([O:28][CH3:29])=[O:27])[CH2:14][CH2:13]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:50][S:51](Cl)(=[O:53])=[O:52].C(N(CC)CC)C>ClCCl>[Cl:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:37])[C:30]=1[CH:24]1[C:23]([C:38]([O:40][CH3:41])=[O:39])=[C:22]([CH2:42][CH2:43][C:44]2[S:45][CH:46]=[CH:47][N:48]=2)[NH:21][C:20]([CH2:19][C:18]([N:15]2[CH2:16][CH2:17][N:12]([CH2:11][C:5]3([CH2:4][NH:3][S:51]([CH3:50])(=[O:53])=[O:52])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]3)[CH2:13][CH2:14]2)=[O:49])=[C:25]1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)C1=C(CCc2nccs2)NC(CC(=O)N2CCN(CC3(CN)CCCCC3)CC2)=C(C(=O)OC)C1c1c(Cl)cccc1Cl
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1=C(CCc2nccs2)NC(CC(=O)N2CCN(CC3(CNS(C)(=O)=O)CCCCC3)CC2)=C(C(=O)OC)C1c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of dimethyl 2-[2-[4-[[1-(aminomethyl)cyclohexyl]methyl]-1-piperazinyl]-2-oxoethyl]-4-(2,6-dichlorophenyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate dihydrochloride (230 mg/0.28 mmol) methansulfonylchloride (0.2 ml/2.5 mmol) and triethylamine (0.5 ml/3.5 mmol) in dichloromethane (5.0 ml) was stirred for 5 hours at ambient temperature. The mixture was diluted with dichloromethane (50 ml), and then washed with water (10 ml) and brine (10 ml) successively. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (NH2 gel/200-350 mesh/20 g/dichloromethane) to give a yellow film (122 mg/55%).
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1OS(C(F)(F)F)(=O)=O)[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.[CH2:48]([O:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1B(O)O)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C(OCC)(=O)C>[CH2:48]([O:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[C:22]1[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[CH:26][C:21]=1[CH2:20][N:7]([CH2:6][C:5]1[CH:39]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:41]=[C:3]([C:2]([F:47])([F:1])[F:46])[CH:4]=1)[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:10][N:9]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: OB(O)c1ccccc1OCc1ccccc1
Reactant: O=S(=O)(Oc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: FC(F)(F)c1cc(CN(Cc2cc(C(F)(F)F)ccc2-c2ccccc2OCc2ccccc2)c2ncc(N3CCOCC3)cn2)cc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Trifluoromethanesulfonic acid 2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl ester (620 mg) is dissolved in 1,4-dioxane (10 ml) and thereto are added 2-benzyloxyphenyl boronic acid (398 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (142 mg) and cesium carbonate (567 mg), and the mixture is stirred under nitrogen atmosphere at 80° C. overnight. The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate, and the insoluble materials are removed by filtration through Celite™. The filtrate is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give (2′-benzyloxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (617 mg). MS (m/z): 747 [M+H]+
Reaction SMILES: C1N2CCN(CC2)C1.[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[C:19](Cl)=[C:18]([N+:27]([O-:29])=[O:28])[C:17]1=[O:30])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N:31]1([C:37]([C:39]2[S:40][CH:41]=[CH:42][CH:43]=2)=[O:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>CN1CCCC1=O.O>[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[C:19]([N:34]2[CH2:35][CH2:36][N:31]([C:37]([C:39]3[S:40][CH:41]=[CH:42][CH:43]=3)=[O:38])[CH2:32][CH2:33]2)=[C:18]([N+:27]([O-:29])=[O:28])[C:17]1=[O:30])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(c1cccs1)N1CCNCC1
Reactant: O=c1c([N+](=O)[O-])c(Cl)c2cccnc2n1Cc1ccccc1
Agent: C1CN2CCN1CC2
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(c1cccs1)N1CCN(c2c([N+](=O)[O-])c(=O)n(Cc3ccccc3)c3ncccc23)CC1
Temperature: 110 °C

Procedure:
DABCO (6.26 g, 55 mmol) was added to a solution of 1-benzyl-4-chloro-3-nitro-1,8-naphthyridin-2(1H)-one (126) (8.81 g, 28 mmol) and piperazine-1-yl-thiophene-2-yl-methanone (6.57 g, 33 mmol) in N-methylpyrrolidone at room temperature. The solution was heated at 110° C. for 2 h. The solution was cooled and poured into ice cold 10% ammonium chloride solution in water. The solids formed were filtered, washed by water, and dried to yield yellow solid. Yield 11 g (83%), mp 255° C. 1H-NMR (DMSO-d6): δ 3.26 (m, 4H), 3.90 (m, 4H), 5.61 (s, 2H), 7.15 (m, 1H), 7.25 (m, 5H), 7.47 (m, 2H), 7.80 (d, J=5.2 Hz, 1H), 8.43 (d, J=7.6 Hz, 1H), 8.76 (d, J=4.4 Hz, 1H); EIMS m/z 476 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([N+:16]([O-])=O)[C:10]=1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[CH2:1]([O:8][C:9]1[C:10]([CH3:19])=[C:11]([C:12]([CH3:15])=[CH:13][CH:14]=1)[NH2:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(OCc2ccccc2)c(C)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1ccc(OCc2ccccc2)c(C)c1N

Procedure:
Zinc dust is added in portions to a solution of 4 benzyloxy-2-nitro-m-xylene (83.8 g) in glacial acetic acid (715 ml) Addition is complete when the exothermic reaction subsides. The reaction mixture is filtered through celite and the pad washed with acetic acid. The filtrate is concentrated in vacuo and the residue diluted with H2O and made basic with ammonium hydroxide, and extracted with chloroform. The combined organic extracts are dried and concentrated in vacuo to give the desired aniline in quantitative crude yield.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:13])[NH:10][CH:11]=[CH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.N1([CH:30]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)[CH2:31][CH3:32])C2C=CC=CC=2N=N1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C>[CH2:1]([O:8][C:9](=[O:13])[NH:10][C@H:11]1[C:35]2[C:34](=[CH:39][CH:38]=[C:37]([C:40]([F:41])([F:42])[F:43])[CH:36]=2)[NH:33][C@@H:30]([CH2:31][CH3:32])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CNC(=O)OCc1ccccc1
Reactant: CCC(Nc1ccc(C(F)(F)F)cc1)n1nnc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC[C@H]1C[C@@H](NC(=O)OCc2ccccc2)c2cc(C(F)(F)F)ccc2N1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A one liter, four neck flask under nitrogen atmosphere was charged with N-vinyl-carbamic acid benzyl ester (27.66 g, 156 mmol, 1.0 equiv) and dry toluene (500 mL). (1-Benzotriazol-1-yl-propyl)-(4-trifluoromethyl-phenyl)-amine (50.0 g, 156 mmol, 1.0 equiv) and p-toluenesulfonic acid monohydrate (297 mg, 1.56 mmol, 0.01 equiv) were added, and the mixture heated to 70° C. After 2 h, the mixture was cooled to room temperature and transferred to a separatory funnel. Ethyl acetate (500 mL) was added. The mixture was washed 1×200 mL 1 N NaOH, 1×200 mL H2O, 1×200 mL brine, and dried (MgSO4). The mixture was filtered and the solids washed 1×50 mL ethyl acetate. The filtrate was concentrated to approximately 250 mL. 500 mL toluene were added, and the mixture concentrated to approximately 500 mL. 500 mL n-heptane were added, the slurry was stirred 1 h, filtered through a Buchner funnel, and dried. cis-(2-Ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin4-yl)-carbamic acid benzyl ester was isolated as a white powder (45.04 g, 76%): mp 155-157° C.; 1H NMR (DMSO-d6, 400 MHz) δ0.92 (t, 3H, J=7.5 Hz), 1.5 (m, 3H), 2.00 (m, 1H), 3.35 (m, 1H), 4.77 (m, 1H), 5.07 (d, 1H, J=12.5 Hz), 5.15 (d, 1H, J=12.5 Hz), 6.35 (s, 1H), 6.61 (d, 1H, J=8.5 Hz), 7.12 (s, 1H), 7.18 (dd, 1H, J=1.9, 8.5 Hz), 7.4 (m, 5H), 7.70 (d, 1H, J=9.1 Hz); 13C NMR (DMSO-d6, 100 MHz) δ157.03, 149.02, 137.79, 128.82, 128.23, 128.03, 125.9 (q, J=270 Hz), 125.06, 123.50, 121.73, 115.2 (q, J=31.7 Hz), 113.33, 65.85, 52.09, 47.83, 34.02, 28.68, 9.93; DEPT spectrum: quaternary carbons δ157.03, 149.02, 137.79, 125.9, 121.73, 115.2; CH carbons δ128.82, 128.23, 128.03, 125.06, 123.50, 113.33, 52.09, 47.83; CH2 carbons δ65.85, 34.02, 28.68; CH3 carbon δ9.93; IR (drifts) 3430 (m), 3303 (s), 2951 (m), 1686 (vs), 1542 (vs), 1088 (vs); MS (APCI+) m/z (rel. intensity) 379 (M+H+, 53), 228 (100); Anal. Calcd for C20H21N2O2F3: C, 63.48; H, 5.59; N, 7.40; Found: C, 63.69; H, 6.06, N, 7.36.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[CH3:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B(O)O.BrC1C=CC(N)=CC=1Cl.FC(F)(F)C1C=CC(B(O)O)=CC=1>>[CH3:10][O:9][C:3]1[CH:4]=[C:5]([NH2:6])[CH:7]=[CH:8][C:2]=1[C:13]1[CH:14]=[CH:15][C:16]([C:18]([F:19])([F:21])[F:20])=[CH:17][C:12]=1[CH3:11]
Reactant: COc1cc(N)ccc1Br
Reactant: Cc1cc(C(F)(F)F)ccc1B(O)O
Agent: Nc1ccc(Br)c(Cl)c1
Agent: OB(O)c1ccc(C(F)(F)F)cc1
Product: COc1cc(N)ccc1-c1ccc(C(F)(F)F)cc1C

Procedure:
The title compound was prepared as described in Example 159 substituting 4-bromo-3-methoxyaniline and (2-methyl-4-(trifluoromethyl)phenyl)boronic acid for 4-bromo-3-chloroaniline and (4-(trifluoromethyl)phenyl)boronic acid, respectively.