Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].O=[C:11]1[CH2:16][CH2:15][N:14]([CH:17]([CH3:31])[CH2:18][CH2:19][NH:20][C:21]([C:23]2[C:24]([CH3:30])=[N:25][CH:26]=[N:27][C:28]=2[CH3:29])=[O:22])[CH2:13][CH2:12]1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][CH:11]1[CH2:12][CH2:13][N:14]([CH:17]([CH3:31])[CH2:18][CH2:19][NH:20][C:21]([C:23]2[C:24]([CH3:30])=[N:25][CH:26]=[N:27][C:28]=2[CH3:29])=[O:22])[CH2:15][CH2:16]1
Reactant: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(=O)CC1
Reactant: Cc1cccc(CN)c1
Product: Cc1cccc(CNC2CCN(C(C)CCNC(=O)c3c(C)ncnc3C)CC2)c1
Yield: 72.1 %

Procedure:
Using general procedure A, 3-methylbenzylamine (30 μL, 0.23 mmol) and 4,6-dimethylpyrimidine-5-carboxylic acid [3-(4-oxo-piperidin-1-yl)-butyl]-amide (66 mg, 0.22 mmol) afforded 4,6-dimethyl-pyrimidine-5-carboxylic acid {3-[4-(3-methyl-benzylamino)-piperidin-1-yl]-butyl}-amide (65 mg, 72%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[NH2:14][CH:15]([CH:31]([CH3:33])[CH3:32])[C:16]([N:18]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[O:17]>>[CH2:24]([N:18]([CH2:19][CH2:20][N:21]([CH3:22])[CH3:23])[C:16](=[O:17])[C@@H:15]([NH:14][C:10]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:8][CH:7]=1)=[O:11])[CH:31]([CH3:32])[CH3:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)C(N)C(=O)N(CCN(C)C)Cc1ccccc1
Product: CC(C)[C@H](NC(=O)Nc1ccc(C(F)(F)F)cc1)C(=O)N(CCN(C)C)Cc1ccccc1

Procedure:
Compound 14c was prepared from 4-(trifluoromethyl)phenyl isocyanate and compound 13, using the method described in Example 22. MS (EI)=464 (M+).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=2)[C:20]([O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])=[CH:14][CH:13]=1)=[O:7])(C)(C)C.[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]1[CH:53]=[CH:52][C:48](C(O)=O)=[CH:47][CH:46]=1.C(P(=O)(OCC)OCC)#N>C(N(CC)CC)C>[CH:36]([C:33]1[CH:32]=[CH:31][C:30]([O:29][C@@H:19]([CH2:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:48]3[CH:47]=[CH:46][C:45]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=4)=[CH:53][CH:52]=3)=[CH:13][CH:14]=2)[C:20]([O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])=[CH:35][CH:34]=1)([CH3:37])[CH3:38]
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Reactant: CC(C)c1ccc(O[C@@H](Cc2ccc(OCCNC(=O)OC(C)(C)C)cc2)C(=O)OCC[Si](C)(C)C)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(O[C@@H](Cc2ccc(OCCNC(=O)c3ccc(-c4ccccn4)cc3)cc2)C(=O)OCC[Si](C)(C)C)cc1
Yield: 56.8 %

Procedure:
In a similar manner to that described in Example 73, a reaction was carried out using 2-trimethylsilylethyl (S)-3-[4-(2-t-butoxycarbonylaminoethoxy)phenyl]-2-(4-isopropylphenoxy)propionate (0.95 g), 4-pyridine-2-ylbenzoic acid (382 mg), diethyl cyanophosphonate (0.29 ml) and triethylamine (0.53 ml) and the reaction mixture was treated to afford the title compound (0.62 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH3:23])[N:16]=2)[N:3]=1.[C:24](=O)([O-])[O-].[K+].[K+].CB(O)O.O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:22]([O:21][C:17]1[N:16]=[C:15]([CH2:14][N:4]2[C:5]3[C:10](=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][CH:6]=3)[C:2]([CH3:24])=[N:3]2)[CH:20]=[CH:19][CH:18]=1)[CH3:23]
Reactant: O=C([O-])[O-]
Reactant: CCOc1cccc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)n1
Agent: [Pd]
Agent: CB(O)O
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CCOc1cccc(Cn2nc(C)c3c([N+](=O)[O-])cccc32)n1
Temperature: 25 °C
Yield: 28.4 %

Procedure:
A solution of 3-bromo-1-((6-ethoxypyridin-2-yl)methyl)-4-nitro-1H-indazole (0.500 g, 1.33 mmol) in dioxane (0.2M, 7 mL) was treated with potassium carbonate (0.916 g, 6.63 mmol), methylboronic acid (0.793 g, 13.3 mmol), water (0.239 mL, 13.3 mmol), followed by tetrakis(triphenylphosphine)palladium (0) (0.0766 g, 0.0663 mmol) at ambient temperature, purging under argon. The mixture was refluxed overnight, cooled to ambient temperature, filtered through glass fiber filter paper, concentrated and purified on silica (10-75% EtOAc in hexanes) to give 1-((6-ethoxypyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole (0.118 g, 28% yield).
Reaction SMILES: [F:1][C:2]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][NH:36]C(=O)C(F)(F)F)[CH:30]=4)[N:23]=3)=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:8]=1)=[O:5].O[Li].O>C1COCC1.O.CCOC(C)=O>[NH2:36][CH2:35][C:31]1[CH:30]=[C:29]([NH:28][C:24]2[N:23]=[C:22]([C:21]3[C:13]([C:9]4[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]5[CH:43]=[C:44]([F:47])[CH:45]=[CH:46][C:2]=5[F:1])[CH:12]=[CH:11][CH:10]=4)=[N:14][N:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=34)[CH:27]=[CH:26][N:25]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(CNC(=O)C(F)(F)F)c3)n2)c1)c1cc(F)ccc1F
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: NCc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5cc(F)ccc5F)c4)nn4ccccc34)n2)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 57.1 %

Procedure:
To a solution of 2,5-difluoro-N-[3-(3-{2-[(3-{[(trifluoroacetyl)amino]methyl}phenyl)-amino]-4-pyrimidinyl}pyrazolo[1,5-a]pyridin-2-yl)phenyl]benzamide (90 mg, 0.14 mmol) in THF (3 mL) and water (0.5 mL) was added LiOH.H2O (12 mg, 0.28 mmol). The solution was stirred at 50° C. for 2 h, then diluted with 25 mL EtOAc and washed with 1 M aqueous Na2CO3. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography to generate 42 mg of the title compound as a yellow solid (0.08 mmol, 55% yield). 1H NMR (400 MHz, d6-DMSO): δ 10.66 (s, 1H), 9.55 (s, 1H), 8.85 (d, J=7.0 Hz, 1H), 8.54 (d, J=8.8 Hz, 1H), 8.27 (d, J=5.1 Hz, 1H), 8.05 (s, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.77 (s, 1H), 7.35-7.59 (m, 7H), 7.11-7.23 (m, 2H), 6.97 (d, J=7.5 Hz, 1H), 6.51 (d, J=4.9 Hz, 1H), 3.72 (s, 2H). MS (ESI) m/z=548 [M+H]+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH:14]1[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:19][CH:14]1[N:13]([CH3:12])[CH2:18][CH2:17][N:16]([C:2]2[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=2)[CH2:15]1
Reactant: CC1CNCCN1C
Reactant: CCOC(=O)c1ccc(Br)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(N2CCN(C)C(C)C2)s1
Temperature: 110 °C
Reaction time: 23 h
Yield: 47.7 %

Procedure:
Palladium(II) acetate (0.112 g, 0.50 mmol) was added to a mixture of ethyl 5-bromothiophene-2-carboxylate (0.571 g, 5 mmol), 1,2-dimethyl-piperazine (1.175 g, 5 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.311 g, 0.50 mmol) and cesium carbonate (2.281 g, 7.00 mmol) in toluene (50.0 ml) at 20° C. under nitrogen. The resulting suspension was stirred at 110° C. for 23 h. The crude product was purified by ion exchange chromatography, using a SCX2 column. The crude material was dissolved in methanol and then applied to the column. The desired product was eluted from the column using 2M NH3 in methanol and pure fractions were evaporated to dryness to afford the crude product as a brown oil. This material was further purified by silica column chromatography, eluting with a gradient of to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford ethyl 5-(3,4-dimethylpiperazin-1-yl)thiophene-2-carboxylate (0.640 g, 47.7%) as a light brown solid.
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][NH2:25])=[O:18])([CH3:15])([CH3:14])[CH3:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][NH:25][CH2:6][C:5]1[S:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[CH:4]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Reactant: O=Cc1cc2ccccc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNCc1cc2ccccc2s1
Yield: 47.2 %

Procedure:
Experimental conditions were analogous to Example 1, from 0.28 g (1.78 mmol) of benzo[b]thiophene-2-carbaldehyde, 0.35 g (1.78 mmol) of (S)-2-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester, 10 mL dichloromethane, and 565 mg (2.64 mmol) of sodium triacetoxyborohydride. The reaction was quenched with aqueous sodium bicarbonate. The residue from the organic layer was purified using flash chromatography (ethyl acetate in hexane). The reaction gave 291 mg of the free base as a colorless oil. LC-MSD, m/z for C19H26N2O2S [M+H]+: 347.5
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13](#[N:15])[CH3:14].[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([O-])=[O:22])=[C:19]([F:26])[CH:18]=1>C1COCC1.CCCCCC>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](=[O:22])[CH2:14][C:13]#[N:15])=[C:19]([F:26])[CH:18]=1
Reactant: O=C([O-])c1ccc(Cl)cc1F
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: N#CCC(=O)c1ccc(Cl)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
A 1.6 M hexane solution of n-butyllithium (39.8 mL, 63.6 mmol) was added to a solution of diisopropylamine (9.45 mL, 66.3 mmol) in THF (100 mL) at −78° C. over 10 min. The resultant solution was stirred at 0° C. for 30 min and cooled to −78° C. Acetonitrile (3.32 mL, 63.6 mmol) dropwise. The mixture was stirred at −78° C. for 30 min and then added a solution of 4-chloro-2-fluorobenzoate (5.00 g, 26.5 mmol) in THF (5 mL) at −78° C. dropwise. After stirring for 1 h at −78° C., the reaction mixture was quenched with brine (20 mL), warmed to room temperature and adjusted to pH 1-2 with 1N aqueous HCl. Following addition of ethyl acetate (400 mL), the mixture was washed with water (40 mL), brine (40 mL), dried (MgSO4) and concentrated to provide 3-(4-chloro-2-fluorophenyl)-3-oxopropanenitrile as tan solid (5.10 g, 97%). MS (ES+) m/z: 198 (M+H).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[NH:15][C:14]([N+]([O-])=O)=[N:13][C:12]=3[N:11]([CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BrH:29]>>[CH:1]1([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[NH:15][C:14]([Br:29])=[N:13][C:12]=3[N:11]([CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=c1c2[nH]c([N+](=O)[O-])nc2n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Reactant: Br
Product: O=c1c2[nH]c(Br)nc2n(CC2CCCCC2)c(=O)n1CC1CCCCC1

Procedure:
The title compound was prepared from 1,3-di-cyclohexylmethyl-8-nitro xanthine (1 g, 0.0026 mol) and concentrated hydrobromic acid (40 ml, 48%) over 32 hours using an analogous procedure to that described in Example 15. The title product was obtained as a crystalline solid, m.pt. 247° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[C:11]2[C:16]([Cl:17])=[C:15]([CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[C:11]3[C:16]([Cl:17])=[C:15]([CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl
Reactant: Cc1ncc[nH]1
Product: Cc1sc2nc(-n3ccnc3C)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2,5-dichloro-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5-chloro-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:19]=[C:9]2[N:10]=[C:11](S(C)(=O)=O)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1.[CH2:20]1[NH:25][CH2:24][CH2:23][N:22]2[CH2:26][C@H:27]([CH2:30][OH:31])[CH2:28][CH2:29][C@@H:21]12>CS(C)=O>[NH2:14][C:13]1[N:8]2[N:7]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[N:19]=[C:9]2[N:10]=[C:11]([N:25]2[CH2:24][CH2:23][N:22]3[CH2:26][CH:27]([CH2:30][OH:31])[CH2:28][CH2:29][CH:21]3[CH2:20]2)[N:12]=1
Reactant: CS(=O)(=O)c1nc(N)n2nc(-c3ccco3)nc2n1
Reactant: OC[C@@H]1CC[C@H]2CNCCN2C1
Solvent: CS(C)=O
Product: Nc1nc(N2CCN3CC(CO)CCC3C2)nc2nc(-c3ccco3)nn12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2-Furan-2-yl-5-methanesulfonyl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (1 eq.; for reference, see J. Chem. Soc. Perkin Trans. 1, 801 (1995)) and cis-(octahydro-pyrido[1,2-a]pyrazin-7-yl)-methanol (1-2 eq; see U.S. Pat. No. 5,122,525) were dissolved in DMSO. The mixture was stirred at around 80° C. for 2 hours. The solution was then cooled to room temperature, filtered and purified by preparative HPLC using aqueous CH3CN solution (buffered with 0.1% TFA) to give the desired compound as a white solid. Alternatively, for scale up synthesis, the DMSO solvent was removed and the crude product was chromatographed on silica gel column using 5-10% MeOH/CH2Cl2 as eluant to afford the desired product. 1H NMR (400 Hz, CD3OD) δ 7.70 (d, J=2.0 Hz, 1H), 7.12 (d, J=3.5 Hz, 1H), 6.62 (dd, J=3.5, 2.0 Hz, 1H), 4.75 (d, J=12.0 Hz, 1H), 4.65 (d, J=12.5 Hz, 1H), 3.82 (dd, J=10.5, 7.5 Hz, 1H), 3.74 (dd, J=10.5, 7.5 Hz, 1H), 3.11 (dt, J=13.0, 3.0 Hz, 1H), 2.93 (d, J=11.5 Hz, 1H), 2.78 (d, J=11.5 Hz, 1H), 2.68 (dd, J=13.0, 10.5 Hz, 1H), 2.22 (dd, J=11.5, 3.0 Hz, 1H), 2.14 (dt, J=12.0, 3.0 Hz, 1H), 1.93 (m, 1H), 1.85 (brd, J=12.0 Hz, 2H), 1.60 (m, 1H), 1.43 (m, 2H). MS m/z: 371 [M+H]+.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[S:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1>O1CCCC1>[CH3:3][C:2]1([C:1]([OH:6])=[O:5])[CH2:4][CH:8]2[S:7][CH:11]1[CH:10]=[CH:9]2
Reactant: c1ccsc1
Reactant: C=C(C)C(=O)O
Solvent: C1CCOC1
Product: CC1(C(=O)O)CC2C=CC1S2
Temperature: 700 °C
Reaction time: 24 h

Procedure:
Tetrahydrofuran solvent (500 g), methacrylic acid (1.2 mole) and thiophene (1.0 mole) are introduced into a 2-liter flask. After stirring at 700° C. for 24 hours, the solvent and excessive methacrylic acid are removed by using a rotary evaporator. The residue is distilled in vacuo to obtain pure 2-methyl-7-thiabicyclo[2.2.1]hept-5-ene-2-carboxylic acid of Chemical Formula 150 (yield: 50%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:29]1[CH:30]=[N:31][C:32]([O:35][CH:36]2[CH2:41][CH2:40][CH:39]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:38][CH2:37]2)=[N:33][CH:34]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C(=O)(O)[O-].[Na+].O>[CH3:1][C:2]1[CH:7]=[C:6]([C:29]2[CH:30]=[N:31][C:32]([O:35][CH:36]3[CH2:41][CH2:40][CH:39]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:38][CH2:37]3)=[N:33][CH:34]=2)[CH:5]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][N:19]=2)[CH:3]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCOC(=O)C1CCC(Oc2ncc(Br)cn2)CC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)C1CCC(Oc2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)cn2)CC1
Temperature: 160 °C

Procedure:
A suspension of N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (150 mg, 0.396 mmol), ethyl 4-[(5-bromopyrimidin-2-yl)oxy]cyclohexanecarboxylate (130 mg, 0.396 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.026 g, 0.032 mmol), 1,4-dioxane (3.6 mL), water (0.36 mL), and aqueous sodium carbonate (2 M, 0.396 mL, 0.791 mmol) was placed under an argon atmosphere by performing 6 vacuum/argon cycles. The reaction mixture was then heated to 160° C. for 10 minutes using a microwave reactor. The resulting suspension was diluted with ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (15 mL). The layers were separated, and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/hexanes) to afford ethyl 4-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexanecarboxylate as a mixture of cis and trans isomers. MS ESI calc'd. for C25H27F3N5O3 [M+H]+ 502. found 502.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[OH-].[Na+].[C:11](=[N:24][NH2:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C([O-])(=O)C.C([O-])(=O)C.[Pd+2].CC(O)(CC)C>[C:11](=[N:24][NH:25][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ccc(Cl)cc1
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCC(C)(C)O
Product: Clc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
260 mL of 2-methyl-2-butanol are placed in a 500 mL round-bottomed flask, which is degassed with argon for 30 minutes. Once the degassing is complete, 60 mL of 2-methyl-2-butanol, palladium(II)diacetate (0.857 g, 1.27 mmol, 0.025 eq.) and the ligand MePHOS (0.928 g, 2.55 mmol, 0.05 eq.) are placed in a second dry round-bottomed flask under argon. The mixture is left stirring for 30 minutes at a temperature in the region of 25° C. Furthermore, 1,4-dichlorobenzene (7.49 g, 1 eq.) and sodium hydroxide powder (2.85 g, 1.4 eq.) are placed in the 500 mL round-bottomed flask. The catalyst is then transferred into the 500 mL round-bottomed flask, which is heated at a temperature in the region of 100° C. Finally, benzhydrylidenehydrazine (10 g, 50.9 mmol, 1 eq.) is added thereto. The resulting suspension is left stirring, and changes color quickly (dark red) until all of the halide has disappeared. The solvent is then evaporated to dryness and the residue is taken up in dichloromethane. The solid is filtered off through Celite® and then washed thoroughly with dichloromethane. The organic phase is washed with saturated ammonium chloride solution, dried over magnesium sulfate and then concentrated to dryness under vacuum. The residue is purified by chromatography on a column of silica gel, eluting at the start with an ethyl acetate/heptane mixture (10/90 by volume). N-Benzhydrylidene-N′-(4-chlorophenyl)hydrazine (85%) is thus obtained in the form of a yellow solid (Rf=0.35. EtOAc/Heptane 25/75 (v/v)).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[C@@H:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH2:25][CH2:26][CH3:27])[CH:22]=2)[C@H:17]([C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[C@H:16]1[C:37]([O:39]C)=[O:38])([O:3]C)=[O:2].[OH-].[Na+:42]>C(O)(C)C.O>[Na+:42].[Na+:42].[C:1]([CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[C@@H:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH2:25][CH2:26][CH3:27])[CH:22]=2)[C@H:17]([C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[C@H:16]1[C:37]([O-:39])=[O:38])([OH:3])=[O:2].[C:1]([CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[C@@H:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH2:25][CH2:26][CH3:27])[CH:22]=2)[C@H:17]([C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[C@H:16]1[C:37]([O-:39])=[O:38])([OH:3])=[O:2]
Reactant: CCCOc1ccc2c(c1)[C@@H](c1ccc(OC)cc1OCC(=O)OC)[C@H](C(=O)OC)[C@H]2c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCOc1ccc2c(c1)[C@@H](c1ccc(OC)cc1OCC(=O)O)[C@H](C(=O)[O-])[C@H]2c1ccc2c(c1)OCO2
Reaction time: 16 h

Procedure:
To a solution of (+) Methyl (1S, 2R, 3S)-3-(2-carbomethoxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (49.2 g) in isopropanol (1000 mL) and water (48 mL) was added a 50% aqueous solution of sodium hydroxide (179.4 g). The mixture was stirred under nitrogen for 16 hours then concentrated to approximately 200 mL. Water (400 mL) was added and the solution was extracted with t-butyl methyl ether (300 mL). The aqueous layer was acidified with dilute HCl and extracted twice with 300 mL portions of TBME. The organic layer was washed 4 times with water (4×200 mL), then concentrated under reduced pressure. Absolute ethanol was added (400 mL) and the solution was further concentrated to approximately 150 mL. The solution was diluted to 800 mL with absolute ethanol and 60 mL of water. The solution was titrated to pH=11-12 with 1.25 N sodium hydroxide solution then after stirring for 15 minutes, concentrated to an oil. Absolute ethanol (250 mL) was added and the solution reconcentrated to a solid which was triturated with hexane, and filtered. The solid was dried to a constant weight to afford (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid disodium salt.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:6][N:7]=1.[BH4-].[Na+].[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27]>CO.O.C(O)C>[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27].[CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=3)=[CH:9][CH:10]=[C:3]12
Reactant: CC1=NCCn2c1ccc2-c1ccc(C(F)(F)F)cc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: O
Product: CC1NCCn2c(-c3ccc(C(F)(F)F)cc3)ccc21
Yield: 70 %

Procedure:
3,4-Dihydro-1-methyl-6-[4-(trifluoromethyl)-phenyl]pyrrolo[1,2-a]pyrazine (2.5 g) was dissolved in a mixture of 130 ml of methanol and 13 ml of water under argon. The solution was treated portionwise with 1.0 g of sodium borohydride while stirring and stirred at room temperature overnight. Thereafter, the methanol was removed in a vacuum, the residue was taken up in 100 ml of methylene chloride and washed with 80 ml of 10% ammonia solution. The phases were separated and the aqueous phase was extracted twice with 50 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The crude product, 2.5 g of yellow-brown solid, was dissolved in a 20-fold amount of ethanol, treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol and concentrated to 40 ml. There were obtained 2.5 g (70%) of 1,2,3,4-tetrahydro-1-methyl-6-[4-(trifluoromethyl)phenyl]pyrrolo[1,2-a]pyrazine fumarate (1:1); m.pt.: 180°-183° C. (dec.).