Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1.[C:21]1([CH2:27][C:28]2[O:32][N:31]=[C:30]([CH2:33][CH2:34][CH2:35]O)[N:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:35][CH2:34][CH2:33][C:30]3[N:29]=[C:28]([CH2:27][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:32][N:31]=3)[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCCC
Reactant: OCCCc1noc(Cc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CCCCCn1c(=O)n(CCCc2noc(Cc3ccccc3)n2)c(=O)c2[nH]c(Cl)nc21
Reaction time: 18 h
Yield: 16.7 %

Procedure:
To a stirred solution of 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.20, 0.67 mmol) in THF (5 ml) was added 3-[5-(phenylmethyl)-1,2,4-oxadiazol-3-yl]-1-propanol (0.162 g, 0.74 mmol), DBAD (0.186 g, 0.81 mmol) and triphenylphosphine (0.212 g, 0.81 mmol) and the solution stirred for 18 h. To the solution was added Pd(PPh3)4 (75 mg, 0.067 mmol) and morpholine (604 μl, 6.7 mmol) were added and stirred for at rt under nitrogen for a further 3 h. 75 mg of Pd(PPh3)4 was added and the mixture left to stir for another 3 h. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The crude material was purified by an aminopropyl SPE using MeOH to load the compound onto the column and wash through the impurities, then with 2-4% AcOH/MeOH to elute the compound. The product fractions were combined and concentrated then further purified by MDAP. The product fractions were combined and concentrated give the title compound as a white solid (51 mg, 20%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH3:34])(=[O:33])=[O:32])[C:6]([C@@H:12]([N:14]1[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]1=[O:24])[CH3:13])=[N:7]2.[C:35]([Zn]C#N)#[N:36]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].O1CCOCC1>[O:23]=[C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:24])[N:14]1[C@H:12]([C:6]1[C:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH3:34])(=[O:32])=[O:33])=[N:4][C:3]2[C:2]([C:35]#[N:36])=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1)[CH3:13]
Reactant: N#C[Zn]C#N
Reactant: C[C@@H](c1nc2cccc(Cl)c2nc1-c1ccccc1S(C)(=O)=O)N1C(=O)c2ccccc2C1=O
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: NCCc1[c-]cccc1
Solvent: C1COCCO1
Product: C[C@@H](c1nc2cccc(C#N)c2nc1-c1ccccc1S(C)(=O)=O)N1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
A 5 L three-necked round-bottomed flask equipped with a condenser, nitrogen inlet, overhead stirrer and thermocouple was charged with 2-((1S)-1-(5-chloro-3-(2-(methylsulfonyl)phenyl)quinoxalin-2-yl)ethyl)isoindoline-1,3-dione (400 g, 813 mmol), dicyanozinc (143 g, 1.22 mol) and 1,4-dioxane (4.0 L). The solution was stirred vigorously and degassed with Ar for 1 h. To the solution was then added XPhos precatalyst (66.1 g, 89 mmol). The mixture was then degassed with Ar for 1 h and heated to 90° C. The reaction was monitored by LC, and deemed complete after 8 h. The reaction was cooled to rt (20-21° C.) and divided into two batches. For each batch, EtOAc (2.0 L), NaHCO3 (400 mL) and water (400 mL) were added. The mixture was stirred for 10 min and a precipitate formed. The precipitates were filtered to afford the pure product as a white solid 201.5 g. The mother liquor was washed with brine (800 mL) and the organic layer concentrated to afford the crude product ˜400 g. The crude material was then slurried in EtOAc (1.2 L) for 30 min at rt. The solid was filtered, washed with EtOAc (2×400 mL) and dried to afford the product as a tan solid 220 g. All the solids were combined, dried on a glass frit under mild vacuum and a stream of N2 for 2 days to afford the product as white solid 378 g with 99.6% LC purity and 96% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.47-8.68 (m, 2H), 7.66-8.19 (m, 7H), 7.52 (dd, J=5.5, 3.0 Hz, 1H), 7.22-7.40 (m, 1H), 5.61-5.95 (m, 1H), 3.11-3.27 (m, 3H), 1.68-1.93 (m, 3H) Mass Spectrum (ESI) m/z=483.0 (M+1).
Reaction SMILES: [CH:1]1([NH:6][CH:7]2[CH2:11][CH2:10][CH2:9][CH:8]2[NH2:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:13]1([C:16]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:17]=2[C:18](O)=[O:19])[CH2:15][CH2:14]1>>[CH:1]1([NH:6][CH:7]2[CH2:11][CH2:10][CH2:9][CH:8]2[NH:12][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:23]([C:25]([F:26])([F:27])[F:28])=[CH:24][C:16]=2[CH:13]2[CH2:14][CH2:15]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C1CC1
Reactant: NC1CCCC1NC1CCCC1
Product: O=C(NC1CCCC1NC1CCCC1)c1ccc(C(F)(F)F)cc1C1CC1

Procedure:
The title compound, brown oil, MS: m/e=381.4 [(M+H)+], was prepared in accordance with the general method of example 5 from (1RS,2SR)-N-cyclopentyl-cyclopentane-1,2-diamine (intermediate AE) and 2-cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate K).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:9][NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[N:4][C:5]([F:8])=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[Br:1][C:2]1[C:3]([CH2:9][N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:36]([NH:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:37])=[N:4][C:5]([F:8])=[CH:6][CH:7]=1
Reactant: COc1ccc(CNCc2nc(F)ccc2Br)cc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(Cc2nc(F)ccc2Br)C(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
To a solution of (3-bromo-6-fluoro-pyridin-2-ylmethyl)-(4-methoxy-benzyl)-amine (637 mg, 2.0 mmol, 1.0 equiv) and N,N-diisopropylethylamine (700 μL, 4.0 mmol, 2.0 equiv) in dichloromethane (10 mL) was added phenyl isocyanate (260 μL, 2.4 mmol, 1.2 equiv) and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with dichloromethane, washed with H2O, dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, eluted with petrol—EtOAc 0-60%) to afford (1-(3-bromo-6-fluoro-pyridin-2-ylmethyl)-1-(4-methoxy-benzyl)-3-phenyl-urea (760 mg). MS: [M+H]+=445.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.[OH:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1.O>CN(C=O)C>[OH:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][N:31]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[CH:14]=3)=[CH:5][CH:4]=2)[CH2:30]1
Reactant: OCC1CCCNC1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CN4CCCC(CO)C4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.7 %

Procedure:
In DMF (3 ml) was dissolved (E)-N-[4-(chloromethyl)phenyl]-3-(4-methylphenyl)cinnamamide (200 mg), and to the solution were added 3-(hydroxymethyl)piperidine (191 mg). The mixture was stirred at room temperature for 72 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4-[3-(hydroxymethyl)piperidinomethyl]phenyl]-3-(4-methylphenyl)cinnamamide (Compound 66) (160 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]([CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:36])[CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:34])[CH2:18][CH2:17]1)[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.[NH4+:40].[Cl-]>>[C:11]([C:10]1[CH:14]=[CH:15][C:7]([N:6]([CH2:5][C:4]2[CH:37]=[CH:38][CH:39]=[C:2]([Cl:1])[CH:3]=2)[CH:16]2[CH2:17][CH2:18][N:19]([CH:22]([CH3:36])[CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]3[C:28]([CH3:34])=[CH:29][CH:30]=[CH:31][C:32]=3[CH3:33])[CH2:20][CH2:21]2)=[CH:8][CH:9]=1)(=[O:13])[NH2:40]
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(Cl)c2)c2ccc(C(=O)O)cc2)CC1
Reactant: [NH4+]
Agent: [Cl-]
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(Cl)c2)c2ccc(C(N)=O)cc2)CC1
Yield: 75 %

Procedure:
Using general procedure E (Wang, W.; McMurray, J. S. Tetrahedron Lett., 1999, 40, 2501-2504) 4-((3-chloro-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid (see EXAMPLE 86) (90 mg, 0.16 mmol) and NH4Cl (22 mg, 0.41 mmol) gave COMPOUND 90 as a white solid (64.1 mg, 0.12 mmol, 71%). 1H NMR (CDCl3) δ 0.95-1.09 (m, 1H), 1.01 (d, 3H, J=6.6 Hz), 1.10-1.25 (m, 1H), 1.48-1.58 (m, 1H), 1.68-1.83 (m, 3H), 2.13-2.24 (m, 1H), 2.31 (s, 6H), 2.52-2.63 (m, 1H), 2.73-2.94 (m, 3H), 3.23-3.34 (m, 1H), 3.64-3.76 (m, 1H), 3.83-3.93 (m, 1H), 3.85 (s, 2H), 5.67 (br s, 2H), 6.55 (d, 2H, J=8.4 Hz), 6.94-7.04 (m, 3H), 7.06-7.13 (m, 2H), 7.20-7.27 (m, 2H), 7.61 (d, 2H, J=8.4 Hz), 8.34 (br d, 1H, J=5.1 Hz). 13C NMR (CDCl3) δ 13.37, 19.05, 28.90, 30.19, 30.84, 39.72, 43.48, 48.09, 51.94, 55.68, 60.37, 111.78, 120.97, 124.13, 126.10, 126.93, 127.29, 128.40, 129.07, 129.77, 133.95, 134.40, 138.46, 141.59, 151.10, 169.07, 169.83. ESI-MS m/z 547 (MH)+, 549 (MH+2)+. Anal. Calcd. for C32H39ClN4O2.0.7CH2Cl2.0.3H2O: C, 64.18; H, 6.75; N, 9.15; Cl, 13.90. Found. C, 64.11; H, 6.58; N, 9.11; Cl, 13.99.
Reaction SMILES: C(#N)C.Cl[CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[OH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1>C(N(CC)CC)C>[OH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([O:21][CH2:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[O:20])=[CH:17][CH:16]=1
Reactant: O=C(CCl)N1CCCCC1
Reactant: O=C(O)c1ccc(O)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(OCC(=O)N1CCCCC1)c1ccc(O)cc1
Yield: 83.9 %

Procedure:
To 100 ml of acetonitrile were added 7.75 g of N-(α-chloroacetyl)piperidine, 5.0 g of 4-hydroxybenzoic acid and 4.3 g (5.9 ml) of triethylamine, and the mixture was refluxed with heating for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To the residue was added ice-water, and precipitated crystals were recrystallized from water to give 8.0 g of the title compound. Melting point: 160°-164° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.COC1CCNC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH:24]([O:25][CH3:28])[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: COC1CCNC1
Agent: Cl
Product: COC1CCN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-methoxypyrrolidine hydrochloride and isolated as colorless gum (13.2 mg, 70%), MS(m/e): 401.4 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].[NH:17]1[CH2:22][CH2:21][S:20][CH2:19][CH2:18]1>S(Cl)(Cl)=O.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]([N:17]2[CH2:22][CH2:21][S:20][CH2:19][CH2:18]2)=[O:9])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)([O-:3])=[O:2]
Reactant: C1CSCCN1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(c1cc([N+](=O)[O-])cc(C(F)(F)F)c1)N1CCSCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Nitro-5-(trifluoromethyl)benzoic acid (2.96 g, 12.6 mmol) was allowed to reflux in thionyl chloride (6 mL) for 6 h. The resulting solution was allowed to cool to room temperature and then concentrated under reduced pressure. The resulting solid was taken up in CH2Cl2 (20 mL) and iPr2Net (2.6 mL, 15.1 mmol) and thiomorpholine (1.4 mL, 13.8 mmol) was added. The reaction was stirred at RT for 1 h and then diluted with CH2Cl2 (50 mL). The organic layer was washed with aq. HCl (1M, 25 mL), 9% aq. Na2CO3 (25 mL), brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (3-nitro-5-(trifluoromethyl)phenyl)(thiomorpholino)-methanone.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:6](=[O:17])[NH:5][C:4](=[O:18])[CH:3]=1.C([O-])(O)=O.[Na+].[Br:24]Br>CO>[NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:6](=[O:17])[NH:5][C:4](=[O:18])[C:3]=1[Br:24]
Reactant: BrBr
Reactant: COc1ccc(Cn2c(N)cc(=O)[nH]c2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cn2c(N)c(Br)c(=O)[nH]c2=O)cc1
Temperature: 5 °C
Yield: 95 %

Procedure:
300 g of 6-amino-1(p-methoxybenzyl)-uracil are taken up in 1200 ml of methanol and mixed with 105 g of NaHCO3. After cooling to 5° C., 66 ml of bromine are added dropwise with stirring. After the conversion is complete (about 2 hours) the resulting suspension is suction filtered, the residue is washed with methanol (2×100 ml) and the product is isolated in the form of bright yellow crystals (374 g, 95%) (melting point: 247° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:10][O:9][N:8]=[C:7]([N:11]([CH3:13])[NH2:12])[C:6]=2[CH:14]=1.[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)([O-:17])=[O:16]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:10][O:9][N:8]=[C:7]([N:11]([CH3:13])[N:12]=[CH:22][C:21]3[CH:24]=[CH:25][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=3)[C:6]=2[CH:14]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CN(N)C1=NOCc2ccc(Cl)cc21
Solvent: CCO
Product: CN(N=Cc1ccc([N+](=O)[O-])cc1)C1=NOCc2ccc(Cl)cc21
Reaction time: 2 h
Yield: 74 %

Procedure:
An amount of 1.4 g. of 6-chloro-4-(1-methylhydrazino)-1H-2,3-benzoxazine is dissolved in 70 ml. of ethanol by heating at 50° C, then 1.12 g. of p-nitro-benzaldehyde are added. The solution is stirred, then allowed to stand for 2 hours. The formed crystals are collected by filtering and recrystallized from 500 ml. of benzene. An amount of 1.7 g. (74%) of 6-chloro-4-[1-methyl-2-(4-nitro-benzylidene)-hydrazino]-1H-2,3-benzoxazine are obtained; m.p. 251° C with decomposition.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][C:33]=1[N+:40]([O-:42])=[O:41].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:36][C:35]2[CH:38]=[CH:39][C:32]([OH:31])=[C:33]([N+:40]([O-:42])=[O:41])[CH:34]=2)[CH2:21][CH2:20]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCNCC1
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(O)c([N+](=O)[O-])c2)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.35 mmol), 4-hydroxy-3-nitrobenzaldehyde (1.22 mmol), methanol (3.8 mL), and acetic acid (0.175 mL) was added NaBH3CN (1.58 mmol) in methanol (3.2 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Variant™ SCX column, and washed with CH3OH. Product was eluted off using 2 N NH3 in CH3OH and concentrated. The resulting material was dissolved into ethyl acetate/methanol=5/1, loaded onto Varian™ Si column, eluted off using ethyl acetate/methanol 5/1 (10 mL), and concentrated to give 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(4-hydroxy-3-nitrobenzyl)piperidine (175 mg, 87%).
Reaction SMILES: C([O:8][C:9]([CH:11]1[CH:16]([C:17](=[O:27])[CH2:18][P:19]([O:24]CC)([O:21]CC)=[O:20])[CH2:15][CH2:14][CH2:13][N:12]1C(OCC1C=CC=CC=1)=O)=[O:10])C1C=CC=CC=1.Cl.C(O)C>C(O)(C)C>[P:19]([CH2:18][C:17]([CH:16]1[CH2:15][CH2:14][CH2:13][NH:12][CH:11]1[C:9]([OH:10])=[O:8])=[O:27])([OH:21])([OH:24])=[O:20]
Reactant: CCOP(=O)(CC(=O)C1CCCN(C(=O)OCc2ccccc2)C1C(=O)OCc1ccccc1)OCC
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: O=C(CP(=O)(O)O)C1CCCNC1C(=O)O
Yield: 91.1 %

Procedure:
Mix N-carbobenzoxy-3[(diethoxyphosphinyl)acetyl]piperidine-2-carboxylic acid benzyl ester (3.6 g) and 6N hydrochloric acid (400 mL) and reflux for 24 hours. Condense with a stream of nitrogen and dissolve the residue in a mixture of absolute ethanol (75 mL) and isopropanol (75 mL). Filter and add propylene oxide until a white precipitate develops. Filter the precipitate, wash with isopropanol and dry to give the title compound as a white powder (1.55 g, 91%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[F:23])[CH:3]=1.[C:24]([CH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)#[N:25].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:31]2[CH:32]=[C:27]([CH2:26][C:24]#[N:25])[CH:28]=[CH:29][CH:30]=2)[CH:3]=1
Reactant: COc1nc(Cl)cc(NCCc2ccc(C(F)(F)F)cc2F)n1
Reactant: N#CCc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1nc(NCCc2ccc(C(F)(F)F)cc2F)cc(-c2cccc(CC#N)c2)n1
Reaction time: 1 h

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethyl]-amine [800 mg, 2.29 mmol, see Example 52, step 1], (3-cyanomethyl-phenyl)-boronic acid, pinacol ester (563 mg, 3.43 mmol), and Cs2CO3 (1.86 g, 5.72 mmol) in ethylene glycol dimethyl ether (15 mL) and water (4 mL) is degassed by bubbling with Argon gas for 5 minutes, and treated with tetrakis(triphenylphosphine)palladium(0) (132 mg, 0.11 mmol) at room temperature. After 1 h at 85° C., the mixture is diluted with water (50 mL), and extracted with EtOAc (2×50 mL). The extracts are dried (MgSO4), filtered through a pad of SiO2, and concentrated to afford (3-{6-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-acetonitrile (1.2 g). LCMS: RT=2.47 minutes, 92% purity. MS: 431 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH:15]([NH:18][NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:17])[CH3:16].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[C:3]=1[O:4][CH2:5][C:6]([N:18]([CH:15]([CH3:17])[CH3:16])[NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:8]
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: O=C(O)COc1c(F)cc(F)cc1Br
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1c(F)cc(F)cc1Br
Yield: 32.5 %

Procedure:
A solution of (2-bromo-4,6-difluoro-phenoxy)-acetic acid (0.92 g, 3.45 mmol) and benzoic acid N′-isopropyl-hydrazide (738 mg, 4.14 mmol) in DMF (20 ml) was treated with diisopropylethyl amine (1.5 ml, 8.625 mmol) and PyBroP (2.41 g, 5.175 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was successively washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-30% ethyl acetate/hexanes gradient to afford the product as a white solid (478 mg, 1.12 mmol, 32%).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:22]I.O>CN(C=O)C>[CH3:22][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=2)[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:10]1
Reactant: COC(=O)c1ccc2c(-c3ccccc3)c[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(-c3ccccc3)cn(C)c2c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
NaH (60% dispersion in mineral oil, 4.52 mmol, 186 mg) was added portion-wise to a solution of methyl 3-phenyl-1H-indole-6-carboxylate (2.07 mmol, 757 mg) in DMF at 0° C. and the mixture was stirred for 20 min. Methyl iodide (2.28 mmol, 0.14 mL) was added and the reaction mixture was maintained at 0° C. for 1 h. Water was then added and the reaction was extracted with EtOAc. The organics were concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give 16c.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]2[C:8]([O:14]C(=O)C)=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:5]=2[C:4]=1[C:18](=[O:31])[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[NH:38]1[CH:42]=[CH:41][N:40]=[CH:39]1>C(#N)C>[N:38]1([CH2:2][C:3]2[O:7][C:6]3[C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:5]=3[C:4]=2[C:18](=[O:31])[C:19]2[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)[CH:42]=[CH:41][N:40]=[CH:39]1
Reactant: COc1cc(C(=O)c2c(CBr)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(=O)c2c(Cn3ccnc3)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Reaction time: 8 h
Yield: 19.3 %

Procedure:
To a stirred suspension of 2-bromomethyl-3-(3,4,5-tri-methoxy-benzoyl)-6-methoxy-7-acetoxy-benzo[b]furan (Example 33) (35 mg, 0.071 mmol) and potassium carbonate (20 mg, 0.15 mmol) in dry acetonitrile (1.5 mL) was added imidazole (19 mg, 0.28 mmol) and the reaction mixture was stirred for overnight (tlc). The solvent was distilled under vacuum and the crude was taken in ethyl acetate, filleted and purified over silica gel plate to afford the title compound as a light yellow solid (6 mg, 19%). 1H NMR (300 MHz, CDCl3) δ-7.66 (s, 1H), 7.19 (s, 1H), 7.09 (s, 2H, benzoyl Hs), 7.07 (s, 1H), 6.85 (d, J=8.63 Hz, 1H), 6.74 (d, J=8.63 Hz, 1H), 5.37 (s, 2H), 4.00 (s, 3H, OMe), 3.95 (s, 3H, OMe), 3.79 (s, 6H, 2×OMe).