Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([F:23])[CH:14]=2)[N:8]([CH2:24][C:25](O)=[O:26])[N:7]=1)=[O:5])[CH3:2].[CH2:28]([O:35][C@H:36]1[CH2:41][CH2:40][CH2:39][CH2:38][C@@H:37]1[NH2:42])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.ON1C2C=CC=CC=2N=N1.N=C=N.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O.CC1C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[C:15]([F:23])[CH:14]=2)[N:8]([CH2:24][C:25](=[O:26])[NH:42][C@H:37]2[CH2:38][CH2:39][CH2:40][CH2:41][C@@H:36]2[O:35][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: N[C@H]1CCCC[C@@H]1OCc1ccccc1
Reactant: CCOC(=O)c1cc(OCc2cc(F)cc(C(F)(F)F)c2)n(CC(=O)O)n1
Agent: CC[NH+](CC)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N=C=N
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(OCc2cc(F)cc(C(F)(F)F)c2)n(CC(=O)N[C@H]2CCCC[C@@H]2OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 58.5 mg (0.15 mmol) of 1-carboxymethyl-5-(3-fluoro-5-trifluoromethyl-benzyloxy)-1H-pyrazole-3-carboxylic acid ethyl ester (3) in 5 mL of tetrahydrofuran was added 123 mg (0.60 mmol) of (1S, 2S)-2-benzyloxy-cyclohexylamine, 40 mg (0.30 mmol) of 1-hydroxybenzotriazole (HOBt) and 500 mg (0.60 mmol) of PS-carbodiimide resin, and the mixture was shaken at rt overnight. The reaction mixture was then treated with 200 mg (0.60 mmol) of MP-carbonate resin and 225 mg (0.9 mmol) of PS-TsOH resin, and shaken at rt for 4 h. The resulting mixture was filtered and washed with tetrahydrofuran (2×2 mL), and the combined tetrahydrofuran extracts were concentrated to afford crude 1-[((1S, 2S)-2-benzyloxy-cyclohexylcarbamoyl)-methyl]-5-(3-fluoro-5-trifluoromethyl-benzyloxy)-1H-pyrazole-3-carboxylic acid ethyl ester (4) which was used in the next reaction without any further purification.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)(=O)C.[OH-].[Na+].Cl>CO>[F:24][C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:8]2[C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([OH:4])[CH:6]=3)[N:11]=[CH:10][N:9]=2)=[CH:23][CH:22]=1
Reactant: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.8 %

Procedure:
To a suspension of 4-((4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl acetate (2.42 g) and methanol (30 mL) was added 5 mol/L NaOH (5.00 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 h, and was adjusted to pH 7 with 0.1 N HCl (aq). The mixture was filtered to give the title compound as a white solid (1.83 g, 86.90%).
Reaction SMILES: C([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:29]=[C:28]([NH2:30])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)(C)(C)C>FC(F)(F)C(O)=O>[NH2:30][C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([N:17]2[CH2:18][CH2:19][CH:14]([NH:13][C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:31])=[O:5])=[CH:8][CH:9]=3)[CH2:15][CH2:16]2)[N:29]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCN(c3nc(N)c4ccccc4n3)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(N2CCC(Nc3ccc(C(=O)O)cc3)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 151.3 %

Procedure:
A solution of (17) (0.058 g, 0.14 mmol) in trifluoroacetic acid (2 mL) was capped with a drying tube and stirred at 25° C. for 12 h. The reaction mixture was evaporated to a light brown oily residue (0.077 g, quantitative yield); 1H NMR (DMSO) δ 11.8 (br s, 1H), 9.07 & 8.95 (br s, 2H), 8.20 (d, 1H, J=7.8), 7.82 (t, 1H, J=7.8), 7.68 (d, 3H, J=8.5), 7.42 (t, 1H, J=7.4), 6.65 (d, 2H, J=8.8), 4.47 (d, 2H, J=13.2), 3.73 (m, 1H), 3.42 (t, 2H, J=11.3), 2.07 (d, 2H, J=10.7), 1.50 (m, 2H); 13C NMR (DMSO) δ 167.4, 162.1, 151.4, 139.8, 135.4, 131.2, 124.6, 120.0, 117.3, 117.0, 111.2, 109.1, 47.8, 43.4, 30.9. Anal. (C20H21N5O2 ·11/2CF3COOH) C, H, N.
Reaction SMILES: C[Zn]C.[CH:4]([Mg]Br)=[CH2:5].[F:8][C:9]1[CH:10]=[C:11]([CH:20]=[C:21]([I:23])[CH:22]=1)/[CH:12]=[N:13]/[S@@:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15]>C1COCC1>[F:8][C:9]1[CH:10]=[C:11]([C@H:12]([NH:13][S@@:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])[CH:4]=[CH2:5])[CH:20]=[C:21]([I:23])[CH:22]=1
Reactant: CC(C)(C)[S@@](=O)/N=C/c1cc(F)cc(I)c1
Reactant: C=C[Mg]Br
Agent: C[Zn]C
Solvent: C1CCOC1
Product: C=C[C@@H](N[S@](=O)C(C)(C)C)c1cc(F)cc(I)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Dimethyl zinc (1.2M in toluene) (7.29 mL, 8.75 mmol) and vinylmagnesium bromide (45.5 mL, 45.5 mmol) was mixed at room temperature for 20 min under argon before cooling down to −78° C., then (R,E)-N-(3-fluoro-5-iodobenzylidene)-2-methylpropane-2-sulfinamide in dry THF (117 mL) as added dropwise about 30 min. The internal temperature between −74 C to −72° C., after addition the reaction mixture was stirred at −78° C. for 1 h, sample was taken quenched by Water, LCMS showed the desired product along with unreacted starting material. More vinylmagnesium bromide (12 mL, 12.0 mmol)) was added and reaction monitored by LCMS and after 30 min, reaction was deemed complete. The reaction mixture was poured over ice-cold by sat.NH4Cl and water, THF was removed in vacuo and the product extracted by EtOAc. The organic layer was washed by water and Brine, dried over anhydrous Na2SO4, filtered and concentrated and the crude product was purified by flash chromatography (0-70% EtOAc/heptane) to provide 8.99 g of (R)—N—((R)-1-(3-fluoro-5-iodophenyl)allyl)-2-methylpropane-2-sulfinamide as the desired product as a colorless yellow syrup. Yield (67.4%). The yield is for the 4 step sequence. Note: The major side-product corresponds to de-iodinated desired product. LCMS (m/z): 382.5 (MH+), 0.96 min; 1H NMR (400 MHz, CDCl3)) δ ppm 7.48 (s, 1H), 7.37 (dt, J=7.6, 1.9 Hz, 1H), 7.06 (d, J=9.0 Hz, 1H), 5.85 (ddd, J=17.0, 10.0, 7.4 Hz, 1H), 5.25-5.47 (m, 3H), 4.90 (d, J=7.0 Hz, 1H), 3.23-3.66 (m, 1H), 1.26 (s, 9H).
Reaction SMILES: [C:1]([Si:5]([CH3:44])([CH3:43])[O:6][CH2:7][CH2:8][O:9][C:10]1[C:15]([N+:16]([O-])=O)=[C:14]([NH:19][C:20]([C:22]2[N:23]([CH3:32])[N:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=2[Cl:27])=O)[CH:13]=[C:12]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:41])[F:40])[N:11]=1)([CH3:4])([CH3:3])[CH3:2].CC(O)=O.CCO>[Fe].CCOC(C)=O>[C:28]([C:25]1[C:26]([Cl:27])=[C:22]([C:20]2[NH:16][C:15]3[C:10]([O:9][CH2:8][CH2:7][O:6][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:44])[CH3:43])=[N:11][C:12]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]([F:40])([F:42])[F:41])=[CH:13][C:14]=3[N:19]=2)[N:23]([CH3:32])[N:24]=1)([CH3:29])([CH3:30])[CH3:31]
Reactant: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)Nc1cc(-c2ccccc2C(F)(F)F)nc(OCCO[Si](C)(C)C(C)(C)C)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1nc(C(C)(C)C)c(Cl)c1-c1nc2cc(-c3ccccc3C(F)(F)F)nc(OCCO[Si](C)(C)C(C)(C)C)c2[nH]1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-yl]-amide (428 mg, 0.650 mmol, prepared as described in the previous step) and iron powder (291 mg, 5.22 mmol) in 1:1 AcOH/EtOH (7 mL) was stirred at 100° C. under Ar for 1 h. After cooling to room temperature, the mixture was treated with EtOAc (20 mL) and filtered through diatomaceous earth. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (0:100-10:90 EtOAc/hexanes) to yield 2-(5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-6-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridine as a white solid. 1H-NMR (400 MHz, CD3OD) δ: 7.81 (d, 1H), 7.65-7.71 (m, 1H), 7.55-7.62 (m, 2H), 7.31 (s, 1H), 4.64 (t, J=4.9 Hz, 2H), 4.02-4.10 (m, 5H), 1.44 (s, 9H), 0.86 (s, 9H), 0.06 (s, 6H). Mass Spectrum (LCMS, ESI pos.) Calculated For C29H37ClF3N5O2Si: 608.2 (M+H). Measured: 608.3.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[SH:12][C:13]1[N:14]([CH3:18])[CH:15]=[CH:16][N:17]=1>>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[S:12][C:13]1[N:14]([CH3:18])[CH:15]=[CH:16][N:17]=1
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Reactant: Cn1ccnc1S
Product: Cn1ccnc1Sc1c(Cl)cccc1[N+](=O)[O-]
Yield: 74.2 %

Procedure:
Starting with 1.92 g (10 mmoles) of 2,3-dichloronitrobenzene and 1.14 g (10 mmoles) of 2-mercapto-1-methylimidazole and following the procedure described in Example 1 there was obtained 2 g (74%) of the product as yellow prisms, mp 102°-104° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:9]=[C:10]([C:19]([F:22])([F:21])[F:20])[CH:11]=[C:12]2[C:16]=1[NH:15][CH:14]=[C:13]2[CH:17]=O>C1COCC1>[Br:7][C:8]1[CH:9]=[C:10]([C:19]([F:22])([F:20])[F:21])[CH:11]=[C:12]2[C:16]=1[NH:15][CH:14]=[C:13]2[CH3:17]
Reactant: O=Cc1c[nH]c2c(Br)cc(C(F)(F)F)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c[nH]c2c(Br)cc(C(F)(F)F)cc12
Reaction time: 0.67 h
Yield: 57.3 %

Procedure:
Lithium aluminum hydride (16.98 ml, 16.98 mmol) was added to a −40° C. solution of 7-bromo-5-(trifluoromethyl)-1H-indole-3-carbaldehyde (1.24 g, 4.25 mmol) in THF (10 ml). The reaction was stirred between −30° C and −10° C. for 40 min and was quenched with saturated aqueous ammonium chloride (1 mL) and filtered through celite and washed with ethyl acetate (20 mL). The filtrate was evaporated and the residue was purified by chromatography on SiO2 with a gradient of 4% to 30% ethyl acetate/hexanes. The product 7-bromo-3-methyl-5-(trifluoromethyl)-1H-indole (677 mg, 2.435 mmol, 57.3% yield) was obtained as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.35 (s, 1H), 7.80(d, J=1.2 Hz, 1H), 7.57 (d, J=0.9 Hz, 1H), 7.12,(q, J=1.2 Hz, 1H), 2.33(d, J=1.2 Hz, 3H). LC (HPLC method 4): tR=3.45 min.
Reaction SMILES: IC1C=C2C(=CC=1)N(C)C(=O)N(C[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1)C2=O.C(N(C(C)C)CC)(C)C.[C:34]([Si:38]([CH3:50])([CH3:49])[O:39]C1C=CC(CC#C)=CC=1)([CH3:37])([CH3:36])[CH3:35].O>CN(C=O)C.[Cu]I>[C:34]([Si:38]([CH3:50])([CH3:49])[O:39][C:15]1[CH:16]=[CH:17][C:18]([CH:19]=[O:21])=[CH:22][CH:23]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: Cn1c(=O)n(Cc2ccc(C(=O)O)cc2)c(=O)c2cc(I)ccc21
Reactant: C#CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To 0.65 g (1.5 mmol) 4-(6-Iodo-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzoic acid and 0.77 g (6.0 mmol) di-isopropyl ethylamine in 15 ml DMF is added bis-triphenylphosphine palladium di-chloride (catalytic) followed by CuI (catalytic). 0.5 g (2.0 mmol) tert-Butyl-dimethyl-(4-prop-2-ynyl-phenoxy)-silane is added and the mixture is heated to 70° C. for 6 hours. The mixture is allowed to cool to room temperature and stir overnight. Water is added and the mixture stirred 30 minutes. Filter and dry under reduced pressure. Purify by flash chromatography (EtOAc/hexane eluent)
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[C:22]1([C:28]([CH2:35][CH2:36][CH3:37])([CH2:32][CH2:33][CH3:34])[C:29](Cl)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[C:22]1([C:28]([CH2:35][CH2:36][CH3:37])([CH2:32][CH2:33][CH3:34])[C:29]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCC(CCC)(C(=O)Cl)c1ccccc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCC(CCC)(C(=O)C(C(=O)OCC)C(=O)OCC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
A solution of diethyl malonate (3.03 g, 18.77 mmol) and anhydrous magnesium chloride in acetonitrile (36 mL) at 0° C. was treated with triethylamine (5.2 mL, 37.55 mmol), stirred at 0° C. for 30 min, stirred at 25° C. for 3 hours, cooled to 0° C. and treated dropwise with a solution of the product of Example 1D (18.77 mmol) in acetonitrile (15 mL) over 10 min and stirred at 50° C. for 18 hours. The solution was cooled to 25° C. and concentrated in vacuo. The solids were suspended in ethyl acetate and cooled to 0° C., treated with 4N HCl solution until all solids had dissolved. The organic layer was extracted with water (2×) and with saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (4.51 g, 66%). 1H NMR (300 MHz, CDCl3): δ 7.32 (m, 5 H), 4.50 (s, 1 H), 4.04 (q, J=7.35 Hz, 4 H), 1.97 (m, 4 H), 1.28 (m, 3 H), 0.98 (m, 10 H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[NH:4][C:3]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>>[C:24]([O:23][C:21](=[O:22])[CH2:20][N:4]1[C:5]2[C:10](=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=2)[C:2]([CH3:1])=[C:3]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(C#N)cc12
Product: Cc1c(-c2cccnc2)n(CC(=O)OC(C)(C)C)c2ccc(C#N)cc12

Procedure:
3-Methyl-2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 6) and tert-butyl bromoacetate are processed according to the method described in Example 68 to give (5-cyano-3-methyl-2-pyridin-3-yl-indol-1-yl)-acetic acid tert-butyl ester. 1H NMR (400 MHz, MeOD) δ ppm 1.38 (s, 9H), 2.31 (s, 3H), 4.83 (s, 2H), 7.56 (d, J=1.3 Hz, 2H), 7.66 (ddd, J=7.8, 4.9, 0.9 Hz, 1H), 7.95 (dt, J=7.8, 1.9 Hz, 1H), 8.09 (s, 1H), 8.63 (d, J=1.3 Hz, 1H), 8.71 (dd, J=4.9, 1.6 Hz, 1H). HRMS (ESI) m/z 348.1719 [(M+H)+ Calcd for C21H22N3O2: 348.1712].
Reaction SMILES: Cl[C:2]1[O:3][C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:6](=[O:8])[CH:7]=1.[F:15][C:16]1[C:29]2[C:28](=[O:30])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[S:21][C:20]=2[C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].N#N>O1CCOCC1.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:15][C:16]1[C:29]2[C:28](=[O:30])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[S:21][C:20]=2[C:19]([C:2]2[O:3][C:4]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:5][C:6](=[O:8])[CH:7]=2)=[CH:18][CH:17]=1
Reactant: O=c1cc(Cl)oc(N2CCOCC2)c1
Reactant: CC1(C)OB(c2ccc(F)c3c(=O)c4ccccc4sc23)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=c1cc(-c2ccc(F)c3c(=O)c4ccccc4sc23)oc(N2CCOCC2)c1
Temperature: 90 °C
Yield: 3.9 %

Procedure:
2-Chloro-6-morpholin-4-yl-pyran-4-one (3) (100 mg, 0.46 mmol), 1-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thioxanthen-9-one (12) (110 mg, 0.31 mmol), and ground potassium carbonate (63 mg, 0.62 mmol) were suspended in dioxane (5 ml) and degassed (sonication for 5 minutes then saturated with N2). Pd(PPh3)4 (18 mg, 0.016 mmol) was then added and the reaction mixture was then heated at 90° C. for 24 hours under a vigorous stirring and a N2 atmosphere. The solvent were removed in vacuo and the residue was then suspended in water (50 ml) and extracted with ethyl acetate (3×50 ml). The organics were combined, washed with saturated brine and dried over sodium sulphate. The solvent was removed in vacuo and the residue was purified by column chromatography (silica; ethyl acetate:ethanol; 9:1) to give the title compound as a white solid (5 mg, 4%). m/z (LC-MS, ESP): 410 (M++1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:32]=[CH:31][C:16]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:15][CH:14]=2)[N:3]=1.[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][C:42]([O:44][CH3:45])=[O:43])#[CH:34].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:45][O:44][C:42](=[O:43])[CH2:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:33]#[C:34][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:32]=[CH:31][C:16]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:15][CH:14]=2)[N:3]=1
Reactant: C#Cc1ccccc1CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 30 %

Procedure:
tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate (I94) (0.500 g, 1.06 mmol) and methyl 2-(2-ethynylphenyl)acetate (I4) (0.203 g, 1.17 mmol) were dissolved in DMF (10 mL) and bis(triphenylphosphine)palladium(II) chloride (37 mg, 5 mol %) was added. The mixture was degassed with nitrogen for ten minutes, then copper(I) iodide (10 mg, 5 mol %) and triethylamine (0.738 mL, 5.30 mmol) were added. The mixture was heated under microwave irradiation (100° C./20 minutes) then concentrated. Chromatography of the residue (12 g silica cartridge, 0-100% ethyl acetate/petroleum benzine 40-60° C.) gave the title compound (I95) (192 mg, 30% yield) as a brown oil; 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 7.68 (dd, J=7.6, 1.0 Hz, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.50 (s, 1H), 7.42 (dd, J=7.5, 1.4 Hz, 1H), 7.38-7.29 (m, 4H), 3.95 (s, 2H), 3.70 (s, 3H), 3.50 (s, 2H), 3.45-3.40 (m, 4H), 2.43-2.35 (m, 4H), 1.45 (s, 9H). LCMS Method C: rt 5.30 min; m/z 610.1 [M+H]+, m/z 608.2 [M−H]−.
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1)[CH2:6][N:7]([C@H:26]1[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:28]2[CH:37]=[C:38]([C:42]([F:45])([F:44])[F:43])[C:39]([CH3:41])=[CH:40][C:27]1=2)[C:8]1[N:9]=[N:10][N:11]([CH2:13][CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)[N:12]=1.O.NN>CO>[NH2:15][CH2:14][CH2:13][N:11]1[N:10]=[N:9][C:8]([N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:53])[F:54])[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:46]=2)[C@H:26]2[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:28]3[CH:37]=[C:38]([C:42]([F:44])([F:45])[F:43])[C:39]([CH3:41])=[CH:40][C:27]2=3)=[N:12]1
Reactant: Cc1cc2c(cc1C(F)(F)F)N(CC1CC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCN2C(=O)c3ccccc3C2=O)n1
Agent: NN
Solvent: CO
Solvent: O
Product: Cc1cc2c(cc1C(F)(F)F)N(CC1CC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCN)n1

Procedure:
Heat the mixture of (S)-2-(2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopropylmethyl-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amino]-tetrazol-2-yl}-ethyl)-isoindole-1,3-dione (0.140 g, 0.183 mmol) and hydrazine hydrate (0.114 mL, 3.66 mmol) in methanol (2 mL) at 60° C. overnight. Evaporate the solvents.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][C:17]3[CH:18]=[C:19]([NH:23]C(=O)OC(C)(C)C)[CH:20]=[N:21][CH:22]=3)[CH:12]=[CH:13][CH:14]=2)[C:5]([Cl:31])=[CH:4][N:3]=1.CO.[ClH:34]>O1CCOCC1>[ClH:1].[ClH:34].[NH2:23][C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][C:11]2[CH:10]=[C:9]([NH:8][C:6]3[C:5]([Cl:31])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:14]=[CH:13][CH:12]=2)[CH:22]=[N:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(CCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cncc(CCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
Into the reaction vessel were added tert-butyl [5-(2-{3-[(2,5-dichloropyrmidin-4-yl)amino]phenyl}ethyl)pyridin-3-yl]carbamate (0.20 g, 0.43 mmol) and methanol (2.0 mL) and 4.0 M hydrogen chloride in 1,4-dioxane (2.0 mL). The reaction mixture was stirred at rt for 2 h and then concentrated under vacuum to give the desired product as an off-white powder (140 mg, 96%). LCMS for C17H16Cl2N5 (M+H)+: m/z=360.0, 362.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1.[BH3-]C#N.[Na+].[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][C:24]([N:26]2[CH:35]3[CH:30]([CH2:31][CH2:32][CH2:33][CH:34]3[N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[NH:29][CH2:28][CH2:27]2)=[O:25])[CH:19]=[CH:20][C:21]=1[Cl:22].C([O-])([O-])=O.[Na+].[Na+]>CO.C(O)(=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][C:24]([N:26]2[CH:35]3[CH:30]([CH2:31][CH2:32][CH2:33][CH:34]3[N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[N:29]([CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:28][CH2:27]2)=[O:25])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: COc1ccc(C=O)cc1
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CN2CCN(C(=O)Cc3ccc(Cl)c(Cl)c3)C3C(N4CCCC4)CCCC32)cc1
Reaction time: 8 h

Procedure:
Anisaldehyde (361 mg, 2.6 mmol) was dissolved in 5 ml of MeOH and NaBH3CN (170 mg, 2.6 mmol) was added. The pH was adjusted to 5 with concentrated acetic acid. 2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (105 mg, 0.26 mmol), dissolved in MeOH (15 ml), was then added to the mixture and the mixture was stirred overnight. After addition of saturated Na2CO3 solution (15 ml), the mixture was stirred at room temperature for 15 minutes. The precipitate formed was filtered off. The aqueous phase of the filtrate was washed three times with CH2Cl2 and the combined organic phases were dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH3 9.5:0.5:0.1, l=15 cm, V=5 ml). The fractions containing the product were evaporated, the residue was taken up in CH2Cl2 and the solution was extracted by shaking three times with HCl (1 N). The aqueous phase was then brought to pH 8 with NaOH (2 N) and extracted by shaking three times with CH2Cl2. The organic phases were dried over Na2SO4 and evaporated in vacuo. A yellowish resin was isolated.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:23]N1C(=O)CCC1=O>CN(C=O)C>[Br:23][C:4]1[CH:3]=[CH:2][C:1]([N:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:11][CH2:12]2)=[CH:6][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(OCc1ccccc1)N1CCN(c2ccccc2)CC1
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCN(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
Benzyl 4-phenylpiperazine-1-carboxylate (2.1 g) was dissolved in DMF (80 ml), and N-bromosuccinimide (1.4 g) was added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and subjected to liquid separation by the addition of CHCl3 and a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated and dried over Na2SO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain benzyl 4-(4-bromophenyl)piperazine-1-carboxylate (2.3 g).