Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[C:22]2[N:21]=[CH:20][CH:19]=[N:18][C:17]=2[C:16]([C:23]([OH:25])=O)=[CH:15][CH:14]=1.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([NH:26][C:23]([C:16]2[C:17]3[N:18]=[CH:19][CH:20]=[N:21][C:22]=3[C:13]([C:3]3[C:2]([F:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=3[F:12])=[CH:14][CH:15]=2)=[O:25])[CH:28]=1
Reactant: COc1cc(OC)c(F)c(-c2ccc(C(=O)O)c3nccnc23)c1F
Reactant: Nc1cccnc1
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3cccnc3)c3nccnc23)c1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (Step 88.1), 3-aminopyridine, and stirring the reaction mixture for 72 h at rt. The crude product was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 96:3:1) followed by trituration in Et2O. Title compound: ESI-MS: 423.1 [M+H]+; tR=3.53 min (System 1); TLC: Rf=0.56 (DCM/MeOH/NH3aq, 96:3:1).
Reaction SMILES: [Br:1]Br.[N+:3]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=12)([O-:5])=[O:4]>ClCCl>[Br:1][C:14]1[C:7]2[C:8](=[N:9][CH:10]=[CH:11][C:6]=2[N+:3]([O-:5])=[O:4])[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=1
Reactant: BrBr
Reactant: C[Si](C)(C)CCOCn1ccc2c([N+](=O)[O-])ccnc21
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(Br)c2c([N+](=O)[O-])ccnc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., 18 μl (6.13 mmol) of bromine are added dropwise to a solution of 100 mg (340 μmol) of 4-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine in 10 ml of dichloromethane. After 1 h of stirring at 0° C. and 1 h of stirring at RT, the reaction solution is filtered through an Extrelut silica gel cartridge, the cartridge is washed with a little dichloromethane/methanol and the filtrate is concentrated under reduced pressure. The residue is purified by preparative RP-HPLC.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[CH2:7])[C:5]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[O:4][C:3]1=[O:13].C(N(CC)CC)C.[C:21]([C:24]1[CH:37]=[CH:36][C:35]2[S:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH2:38][CH2:39][CH2:40]Br)[C:26]=2[CH:25]=1)(=[O:23])[CH3:22]>C(C(C)=O)C(C)C>[C:21]([C:24]1[CH:37]=[CH:36][C:35]2[S:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH2:38][CH2:39][CH2:40][CH:8]3[CH2:9][NH:10][CH2:11][CH2:12][C:5]43[O:4][C:3](=[O:13])[N:2]([CH3:1])[C:6]4=[CH2:7])[C:26]=2[CH:25]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1ccc2c(c1)N(CCCBr)c1ccccc1S2
Reactant: C=C1N(C)C(=O)OC12CCNCC2
Solvent: CC(=O)CC(C)C
Solvent: CCN(CC)CC
Product: C=C1N(C)C(=O)OC12CCNCC2CCCN1c2ccccc2Sc2ccc(C(C)=O)cc21
Reaction time: 6 h
Yield: 84.5 %

Procedure:
A mixture containing 7.3 g of 3-methyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane, 9 ml of anhydrous triethylamine, 22.0 g of 3-(2-acetyl-10H-phenothiazin-10-yl)-propyl bromide and 80 ml of methyl isobutyl ketone is refluxed under argon while stirring for 6 hours. After cooling down the organic phase is washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The crude product obtained is purified by chromatography on a silica gel column by using first chloroform and then ethyl acetate as eluating agent. After combining the ethyl acetate eluate is evaporated under reduced pressure and the residue is recrystallized from ethanol to give the title compound in 84.5% yield, m.p.: 105°-106° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[C:6]([CH:9]=1)[CH:7]=O.[CH3:19][NH2:20].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[C:6]([CH:9]=1)[CH2:7][NH:20][CH3:19]
Reactant: CN
Reactant: O=Cc1cc(Br)ccc1Oc1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cc(Br)ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.3 %

Procedure:
To a mixture of 5-bromo-2-(3,4-dichloro-phenoxy)-benzaldehyde (4.74 g, 13.8 mmol) in MeOH (250 mL) was added MeNH2 (40% aq.; 20 mL, 260 mmol), and the resulting mixture was stirred at rt until homogeneous. The mixture was cooled to 0° C. and treated with NaBH4 (1.05 g, 27.8 mmol) portionwise. After 24 h, the mixture was concentrated and the residue was diluted with 1 N NaOH and extracted with DCM. The combined organic layers were dried (Na2SO4) and concentrated. The crude product was purified by FCC to provide the desired product (4.80 g, 97%). MS (ESI): mass calcd. for C14H12BrCl2NO, 358.95; m/z found, 360.1 [M+H]+. 1H NMR (CDCl3): 7.61 (d, J=2.5, 1H), 7.40-7.37 (m, 2H), 7.03 (d, J=2.8, 1H), 6.82-6.79 (m, 2H), 3.72 (s, 2H), 2.44 (s, 3H), 1.30-1.21 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][NH2:22])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:23]([CH2:31][CH2:32][C:33](O)=[O:34])(=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)CCC>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:21]4[C:33](=[O:34])[CH2:32][CH2:31][C:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[N:22]4)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCC(=O)c1ccccc1
Reactant: NNc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Solvent: CCCCO
Product: O=C1CCC(c2ccccc2)=NN1c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 11.6 %

Procedure:
To a suspension of (3-Chloro-phenyl)-[4-(2-hydrazino-pyridin-4-yl)-pyrimidin-2-yl]-amine (2 g) in n-Butanol (40 mL) was added of 1.14 g of 3-benzoylpropionic acid. The mixture was heated at reflux. After 3 h, the mixture was cooled at 0° C. and the 4-({4[2-(3-Chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-yl}-hydrazono)-4-phenyl-butyric acid (2.19 g, 72%) was recovered by filtration. Mp 144–146° C., 1H NMR (DMSO-d6).12.0 (1H, OH), 10.4 (1H, s, NH), 10.1 (1H, s, NH), 8.77 (1H, d, 5 Hz), 8.42 (1H, d, 5 Hz) 8.12 (1H, s), 8.06 (1H, s), 7.80 (3H, m), 7.6 (1H, d, 5 Hz) 7.53 (1H, d, 5 Hz), 7.45 (3H, m), 7.34 (1H, t, 8 Hz), 7.08 (1H, m) 3.4 (2H, m), 2.95 (2H, m), MS (ES+) 473 (MH+, 100),. MS (ES−) 471 (M−1, 100). To a solution of 4-({4-[2-(3-Chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-yl}-hydrazono)-4-phenyl-butyric acid (0.48 g) in tetrahydrofuranne (40 mL) was additionned N,N′-dicyclohexylcarbodiimide (0.23 g) and 1-Hydroxybenzotriazole (0.1401 g). The solution was stirred at reflux for 2 h then the solvent was evaporated. The crude was chromatographied, eluting with ethyl acetate to gave the title compound as a solid (0.3366 g, 78%). Mp 165–167° C., 1H NMR (CDCl3) 9.6 (1H,s, NH), 8.76 (1H, d, 5 Hz), 8.59 (1H, d, 5 Hz), 8.21 (1H, s), 7.86 (4H, m), 7.44 (4H, m), 7.26 (2H, m), 7.01 (1H, m), 3.18 (2H, t, 8 Hz), 2.87 (2H, t, 8 Hz). 13C NMR (CDCl3) 166.3, 162.4, 160.4, 159.8, 154.8, 152.9, 150.1, 146.7, 140.9, 135.7, 134.9, 130.5, 130.3, 129.0, 126.7, 122.9, 120.1, 119.6, 118.8, 117.55, 109.6, 28.4, 23.6. MS (ES+) 455 (MH+, 100), 909 (2 MH+, 10).
Reaction SMILES: C[Si](C)(C)[C:3]1[O:7][C:6]2[C:8](=[O:17])[C:9]3[C:14]([C:15](=[O:16])[C:5]=2[CH:4]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[Br:20]Br>C(#N)C>[Br:20][C:3]1[O:7][C:6]2[C:8](=[O:17])[C:9]3[C:14]([C:15](=[O:16])[C:5]=2[CH:4]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: BrBr
Reactant: C[Si](C)(C)c1cc2c(o1)C(=O)c1ccccc1C2=O
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)c2oc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
To the solution of 0.8 gram (3.0 mmoles) of 2-trimethylsilyl-naphtho[2,3-b]furan-4,9-dione in 20 mL of acetonitrile at room temperature, 0.53 grams (3.3 mmoles) of bromine in 20 mL of acetonitrile was added dropwise over 5 minutes. The mixture was further stirred for 30 minutes at room temperature, and then evaporated to dryness. The residue was crystallized in ethanol/water. Pure crystal product was filtered and dried under vacuum. 0.75 grams of product (yield 90%) was obtained and characterized by 1H NMR and mass spectrum. 1H NMR (in CDCl3) δ 6.96 (s, 1H), 7.76-7.82 (m, 2H), 8.18-8.25 (m, 2H). Mass (M+H) is 277 and 279.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH2:25][C:26]([F:27])([F:28])[F:29])[CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(Cl)cc1OCC(F)(F)F
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)cc2OCC(F)(F)F)c1
Yield: 81 %

Procedure:
The title compound was prepared in 81% yield from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-chloro-2-(2,2,2-trifluoroethoxy)phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 4.43 (2H, q, J=8.0 Hz), 5.26 (2H, s), 5.79 (1H, d, J=1.6 Hz), 6.91 (1H, d, J=1.6 Hz), 7.10 (1H, dd, J=2.0 Hz, 8.4 Hz), 7.40 (1H, dd, J=1.2 Hz, 5.2 Hz), 7.44 (1H, d, J=8.0 Hz), 7.58 (1H, d, J=2.0 Hz), 8.04 (1H, s), 8.69 (1H, d, J=5.2 Hz). [M+H] Calc'd for C18H12ClF3N4O2, 409, Found, 409.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([C:25]([F:28])([F:27])[F:26])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:29])[C:3]=1[OH:30].O[C@@H:32]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:33]([O:35]C)=[O:34].BrBr>CO>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([C:25]([F:27])([F:28])[F:26])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:29])[C:3]=1[O:30][C@H:32]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:33]([OH:35])=[O:34]
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(C(F)(F)F)c3sc4ccccc4c23)cc1Br
Agent: BrBr
Solvent: CO
Product: O=C(O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(C(F)(F)F)c3sc4ccccc4c23)cc1Br

Procedure:
Prepared from of 2,6-dibromo-4-(6-trifluoromethyl-benzo[b]naphtho[2,3-d ]thiophen-11-yl)-phenol (Example 61) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 96). White solid: mp 109-143° C.; [a]D25=+47.99° (10.002 mg/mL CH3OH); NMR (DMSO-d6); δ13.26 (s, 1 H), 8.30 - 8.27 (m, 1 H), 8.06 (d, J =7 Hz, 1 H), 7.87 - 7.81 (m, 3 H), 7.71 - 7.60 (m, 2 H), 7.52 (dd, J=8, 1 Hz, 1 H), 7.43 -7.24 (m, 6 H), 6.60 (d, J=8 Hz, 1 H), 5.33 (t, J=7 Hz, 1 H), 3.41 (d, J=7 Hz, 2 H); MS (EI): [M+], 2 bromine isotope pattern, 698 (8%), 700 (20%) 702 (15%); Anal. Calc. for C32H19Br2F3O3S: C, 54.88, H, 2.74, N, 0.00. Found: C, 55.29, H, 3.11, N, 0.10.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[CH2:9][CH2:10]Br)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([N:21]2[C:25](=[O:26])[CH2:24][N:23]([CH3:27])[C:22]2=[O:28])[CH:17]=[C:18]([Cl:20])[CH:19]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@:24]3([C:25](=[O:26])[N:21]([C:16]4[CH:17]=[C:18]([Cl:20])[CH:19]=[C:14]([Cl:13])[CH:15]=4)[C:22](=[O:28])[N:23]3[CH3:27])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CN1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Reactant: ClC(CCBr)c1ccc(Br)cc1
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CC[C@H]2c1ccc(Br)cc1

Procedure:
Using the same procedure as in Example 1 starting from 1-bromo-4-(3-bromo-1-chloropropyl)benzene (Preparation 7) and 3-(3,5-dichlorophenyl)-1-methylimidazolidine-2,4-dione, the above titled compound was obtained after reverse phase HPLC purification (gradient from CH3CN/H2O/TFA: 5/95/0.05 to CH3CN/H2O[[FA: 80/20/0.05). 1H NMR (CDCl3): 7.44 (2H, d, J=8.4 Hz), 7.25 (1H, m), 6.95–7 (4H, m), 4.05 (1H, t, J=10.1 Hz), 3.22 (3H, s), 2.65–2.85 (1H, br q), 2.4–2.65 (2H, m), 2.1–2.3 (1H, br q).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[N:9][N:10]=2)[CH:7]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.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>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[N:6]2[CH:7]=[C:2]([C:23]3[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: COc1ccccc1-c1nnc2ccc(Br)cn12
Reactant: Cc1ccc(B(O)O)cc1
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: O
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1nnc2ccc(-c3ccc(C)cc3)cn12
Yield: 86.3 %

Procedure:
To a solution of 6-bromo-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.329 mmol) in toluene (20 mL) and water (5 mL) was added 4-methylphenylboronic acid (67.1 mg, 0.493 mmol), Pd(PPh3)4 (18.4 mg, 0.016 mmol) and Cs2CO3 (55.3 mg, 0.658 mmol), and the reaction mixture was refluxed under Argon overnight. The mixture was filtered and the filtrate was washed with water (50 mL×2), dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=1:1) to give the title compound (89.5 mg, 50.6% yield) as yellow solids. 1H NMR (DMSO-d6): 8.09 (m, 1H), 7.93 (dd, J=9.6 and 0.9 Hz, 1H), 7.77 (d, J=9.6 and 1.8 Hz, 1H), 7.64-7.58 (m, 4H), 7.33-7.28 (m, 3H), 7.19 (t, J=7.2 Hz, 1H), 3.85 (s, 3H), 2.35 (s, 3H). MS: m/z 316.2 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+].Br[C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][C:29]([S:35]([N:38](CC1C=CC(OC)=CC=1OC)[C:39]1[S:43][N:42]=[CH:41][N:40]=1)(=[O:37])=[O:36])=[CH:30]2>O1CCOCC1.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>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][C:29]([S:35]([NH:38][C:39]1[S:43][N:42]=[CH:41][N:40]=1)(=[O:37])=[O:36])=[CH:30]2
Reactant: CC1(C)OB(c2ccc(Cl)cc2Br)OC1(C)C
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cccc3c2)c(OC)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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(Nc1ncns1)c1ccc2c(-c3ccc(Cl)cc3Br)cccc2c1
Temperature: 100 °C

Procedure:
A pressure vessel was charged with 2-(2-bromo-4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.732 g, 2.306 mmol), potassium carbonate (1.328 g, 9.61 mmol), 5-bromo-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (Intermediate D) (1 g, 1.922 mmol), tetrakis(triphenylphosphine)palladium(0) (0.222 g, 0.192 mmol) in dioxane (12.81 mL) and water (6.41 mL). The reaction was heated in an oil bath at 100° C. for 35 min. LC/MS indicated that the desired product (M+H=479.8) was generated. Water was added to the mixture and washed with EtOAc. The water layer was acidified with 5% HCl (15 mL) and washed with EtOAc again to afford a light yellow solid. The product was used in the next reaction without further purification. m/z (ESI) 480.0 (M+H)+.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[NH:25][C:24](=[O:26])[C:23]4[C:18](=[CH:19][C:20]([O:29][CH3:30])=[CH:21][C:22]=4[O:27][CH3:28])[N:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+]>Cl>[CH3:28][O:27][C:22]1[CH:21]=[C:20]([O:29][CH3:30])[CH:19]=[C:18]2[C:23]=1[C:24](=[O:26])[NH:25][C:16]([C:13]1[CH:14]=[CH:15][C:10]([N:7]3[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]3)=[CH:11][CH:12]=1)=[N:17]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(C)=O)CC4)cc3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
A mixture of 2-(4-(4-acetylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (1.93 g, 4.7 mmol) and 2 M HCl (200 mL) was heated at reflux for 9 hours. Then, the mixture was cooled to room temperature, basified to pH 8 with 2 N NaOH, extracted with CH2Cl2 (3×300 mL), dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with 92:7:1 to 6:3:1 CHCl3/MeOH/concentrated NH4OH, to afford the title compound (1.13 g, 66%). 1H NMR (300 MHz, DMSO-d6): δ 8.08 (d, J=8.9 Hz, 2H), 6.99 (d, J=8.9 Hz, 2H), 6.68 (d, J=2.3 Hz, 1H), 6.47 (d, J=2.3 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.19-3.23 (m, 4H), 2.81-2.84 (m, 4H); APCI MS m/z 367 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]#[CH:10])[CH:6]=[CH:7][CH:8]=1.C([Li])CCC.I[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O1CCCC1.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]#[C:10][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:6]=[CH:7][CH:8]=1
Reactant: C#Cc1cccc(OC)c1
Reactant: CCCCCCI
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCC#Cc1cccc(OC)c1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
3-Methoxyphenylacetylene [5.00 g, 0.032M, prepared by the method of E. Negishi et al, J. Org. Chem. 45 2526-8, (1980)] was dissolved in dry tetrahydrofuran (15 ml), cooled to -70° C. under nitrogen, and n-butyl lithium, 1.6M in hexane, (24.40 ml, 0.038M), added dropwise. After stirring for 0.5 h, iodohexane (8.00 g, 0.038M), dissolved in dry tetrahydrofuran, (15 ml) was added dropwise. The rection was warmed slowly to room temperature, refluxed overnight, then cooled. The solution was then quenched with water, acidified with dilute hydrochloric acid and extracted with diethyl ether (twice). The organic phases were combined, washed with water and dried, (MgSO4). Evaporation in vacuo affored 7.71 g of product as an orange oil.
Reaction SMILES: C(N)C=CC#CCC.[S:9]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16](/[CH:20]=[CH:21]/[CH2:22][O:23][CH2:24][CH2:25]O)[CH:17]=[CH:18][CH:19]=2)=[CH:10]1.[ClH:27].[CH2:28]([NH:30][CH2:31]/[CH:32]=[CH:33]/[C:34]#[C:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH3:29]>>[ClH:27].[CH2:28]([N:30]([CH2:25][CH2:24][O:23][CH2:22]/[CH:21]=[CH:20]/[C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:11]2[CH:12]=[CH:13][S:9][CH:10]=2)[CH:15]=1)[CH2:31]/[CH:32]=[CH:33]/[C:34]#[C:35][C:36]([CH3:37])([CH3:39])[CH3:38])[CH3:29]
Reactant: OCCOC/C=C/c1cccc(-c2ccsc2)c1
Reactant: CCNC/C=C/C#CC(C)(C)C
Agent: CCC#CC=CCN
Agent: Cl
Product: CCN(C/C=C/C#CC(C)(C)C)CCOC/C=C/c1cccc(-c2ccsc2)c1

Procedure:
Compounds of Examples 26 to 29 were obtained by performing the same reaction as in Example 25 except that the corresponding alcohol derivatives and/or 2-hepten-4-ynylamine derivatives were used instead of the starting compounds, (E)-2-[3-[3-(3-thienyl)phenyl]-2propenyloxy]ethanol and/or (E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride, which were used in the above-mentioned reaction.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:14][CH2:15][CH2:16][C@@H:17]([C:22]2[O:23][CH:24]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:26]=2)[CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH2:45]([O:52][NH2:53])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(N(CC)C(C)C)(C)C>O1CCCC1.C(OCC)(=O)C>[CH2:45]([O:52][NH:53][C:19](=[O:21])[CH2:18][C@H:17]([C:22]1[O:23][CH:24]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:26]=1)[CH2:16][CH2:15][CH2:14][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CCOC(=O)c1coc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1coc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.6 %

Procedure:
A mixture of (3R)-6-cyclohexyl-3-[4-(ethoxycarbonyl)-1,3-oxazol-2-yl]hexanoic acid trifluoroacetate (Preparation 63) (1.66 g, 3.68 mmol), 1,1′-carbonyldiimidazole (0.80 g, 4.93 mmol), O-benzylhydroxylamine hydrochloride (1.57 g, 9.84 mmol) and N,N-diisopropylethylamine (1.71 ml, 9.82 mmol) in anhydrous tetrahydrofuran (10 ml) was stirred at room temperature for 72 hours. The mixture was diluted with ethyl acetate (50 ml) and washed sequentially with a saturated solution of sodium hydrogen carbonate, aqueous citric acid solution (10% w/v) and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol (98:2) then further purified by column chromatography on silica gel eluting with ethyl acetate:pentane (50:50) to afford the title compound as an orange oil (1.41 g)
Reaction SMILES: [CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>CCOC(C)=O>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncccn1
Reactant: COc1ccc(N2CCNC(Cc3ccccc3)C2)cc1OC1CCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1ccc(N2CCN(c3ncccn3)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Temperature: 100 °C

Procedure:
Into a 25 mL screw-cap vial were added 3-benzyl-1-(3-cyclobutyloxy-4-methoxy-phenyl)-piperazine (149 mg, 0.42 mmol), 2-chloropyrimidine (60 mg, 0.53 mmol), diisopropylethylamine (150 μL, 0.86 mmol), and DMSO (2 mL). The reaction mixture was heated at 100° C. for 12 h then cooled to room temperature. The reaction mixture was diluted with EtOAc and washed 3× with water followed by brine, concentrated, and adsorbed onto silica gel and purified by silica gel flash chromatography with a 0-50% EtOAc/Hexanes gradient to afford the title compound as a an off-white solid (43 mg, 23%). LC/MS (Method B) 4.62 min, [[M+1]+ 431
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[CH:15]=[C:16]([C:18](=[O:23])N(OC)C)[N:17]=[C:13]2[N:12]=[C:11]([CH3:24])[C:10]=1[CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].[CH3:34][Mg+].[Br-]>C1COCC1>[C:18]([C:16]1[N:17]=[C:13]2[N:12]=[C:11]([CH3:24])[C:10]([CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:14]2[CH:15]=1)(=[O:23])[CH3:34]
Reactant: C[Mg+]
Reactant: CON(C)C(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(CNC(=O)OC(C)(C)C)c(C)nc2n1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(CNC(=O)OC(C)(C)C)c(C)nc2n1
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
To a stirred solution of tert-butyl (5-(2,4-dichlorophenyl)-2-(methoxy(methyl)carbamoyl)-7-methylimidazo[1,2-a]pyrimidin-6-yl)methylcarbamate (intermediate for Example 59, 15 mg, 0.03 mmol) in THF (1 mL) at 0° C. was added MeMgBr (3M in THF, 0.05 mL, 0.15 mmol). After 30 min, the reaction was quenched with satd aq NH4Cl and diluted with EtOAc. The organic layer was washed with satd aq NH4Cl and brine prior to drying over MgSO4. Filtration, concentration under reduced pressure and purification by silica gel chromatography afforded tert-butyl (2-acetyl-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-6-yl)methylcarbamate (10 mg, 73%) as a white solid.