Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(OCC)=O)C.[Cl:19][C:20]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O.O>C1(C)C=CC=CC=1.C1COCC1>[Cl:19][C:20]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:21]=1/[CH:22]=[CH:11]/[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: O=Cc1cccc([N+](=O)[O-])c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/c1cccc([N+](=O)[O-])c1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon, 98 mg (2.46 mmol, 60% pure) of sodium hydride were suspended in 2 ml of toluene and 2 ml of THF, and the suspension was cooled to 0° C. 0.6 ml (2.57 mmol) of tert-butyl (diethoxyphosphoryl)acetate was then slowly added dropwise, and the mixture was stirred at 0° C. for 30 min. 415 mg (2.24 mmol) of 2-chloro-3-nitrobenzaldehyde were then added to the reaction mixture, and the reaction mixture was then warmed to room temperature. The mixture was stirred at room temperature for 2 hours, and 5 ml of water were then added. After removal of the organic phase, the aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were dried over sodium sulfate. After filtration, the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 429 mg (1.51 mmol, 59% of theory) of the title compound.
Reaction SMILES: C([O:5][C:6](=[O:51])[C:7]([CH3:50])([CH3:49])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([C:17]2[C:18]([CH2:27][N:28]3[C@@H:32]([CH3:33])[C@@H:31]([C:34]4[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[C:36]([C:44]([F:47])([F:46])[F:45])[CH:35]=4)[O:30][C:29]3=[O:48])=[N:19][C:20]([N:23]3[CH2:26][CH2:25][CH2:24]3)=[CH:21][CH:22]=2)[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[K+].C(O)(=O)C>ClCCl.C(OCC)(=O)C>[N:23]1([C:20]2[N:19]=[C:18]([CH2:27][N:28]3[C@@H:32]([CH3:33])[C@@H:31]([C:34]4[CH:35]=[C:36]([C:44]([F:46])([F:45])[F:47])[CH:37]=[C:38]([C:40]([F:41])([F:43])[F:42])[CH:39]=4)[O:30][C:29]3=[O:48])[C:17]([C:11]3[CH:10]=[C:9]([CH2:8][C:7]([CH3:49])([CH3:50])[C:6]([OH:51])=[O:5])[CH:14]=[CH:13][C:12]=3[O:15][CH3:16])=[CH:22][CH:21]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc(CC(C)(C)C(=O)OC(C)(C)C)cc1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CC(C)(C)C(=O)O)cc1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tert-butyl3-{3-[6-azetidin-1-yl-2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyridin-3-yl]-4-methoxyphenyl}-2,2-dimethylpropanoate (48 mg, 0.067 mmol) was dissolved in dichloromethane (1 mL). TFA (0.1 mL, 1.298 mmol) was added and the reaction was stirred at room temperature for 4 hours. The reaction was then concentrated and the residue was dissolved in methanol (1 mL). 4M KOH (0.333 mL, 1.330 mmol) was added, and the reaction was stirred for 10 min. at room temperature. Next, acetic acid (0.076 mL, 1.330 mmol) was added. The reaction was diluted with ethyl acetate (10 mL), washed with water (2×8 mL) and brine (8 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by PTLC (50% ethyl acetate/hexanes) to afford 3-{3-[6-azetidin-1-yl-2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyridin-3-yl]-4-methoxyphenyl}-2,2-dimethylpropanoic acid. LCMS=666.2 (M+H)+. 1H NMR (CDCl3, 500 MHz) δ 7.85 (s, 1H), 7.74 (s, 2H), 7.29 (d, J=7.6 Hz, 1H), 7.12 (dd, J=8.3, 2.2 Hz, 1H), 7.10-6.90 (m, 1H), 6.85 (d, J=8.5 Hz, 1H), 6.25 (d, J=8.2 Hz, 1H), 5.80-5.55 (m, 1H), 4.76 (m, 2H), 4.20-3.80 (m, 5H), 3.73 (s, 3H), 2.82 (m, 2H), 2.42 (bs, 2H), 1.35-1.15 (m, 6H), 0.75-0.58 (m, 3H).
Reaction SMILES: [Mg].BrCCBr.CC([Si](C)(C)[O:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)(C)C>C1COCC1>[Br:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][OH:11])=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: OCCCc1ccc(Br)cc1

Procedure:
To 2.67 g of magnesium (shavings) in 5 ml of THF under inert atmosphere and at ambient temperature, is added in 50 minutes at the reflux after priming to 1.2-dibromoethane, a solution of 32.9 g of (1.1-dimethylethyl) dimethyl [[3-(4-bromophenyl)propyl]oxy]silane (stage C) in 100 ml of THF and maintained 5 hours at reflux. (Heading by iodometry: 0.86M)
Reaction SMILES: CCOCC.[C:6]1([C@H:12]([NH:14][C:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C:16]=2[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(#N)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(O)(=O)C>[C:6]1([C@H:12]([NH:14][C@@H:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH2:17][C@@H:16]2[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)C1=C(N[C@H](C)c2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N[C@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
A 1L 3-neck round bottom flask equipped with a mechanical stirrer and addition funnel was charged with 252B (14.7 g, 39 mmol) and acetonitrile (200 mL) and acetic acid (100 mL). The solution was cooled to 0° C. and Na(OAc)3BH (33.3 g, 157 mmol) was added in three portions over 2 hours. The reaction was stirred for two hours at this temperature after the final addition. The mixture was then cooled to −10° C. and slowly quenched by addition of 1 N NaOH (100 mL), 4 N NaOH (100 mL), 6 N NaOH (100 mL) followed by 50% NaOH (50 mL). The reaction was warmed to room temperature and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×250 mL) and the combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (10% to 30% EtOAc/hexane gradient) on silica gel afforded 6.0 g (yield: 41%) of Compound 252C.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:24]C2CCCCC2)[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.Cl.[NH2:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[C:37]([C:39]#[N:40])[CH:38]=1>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:32][C:33]1[CH:38]=[C:37]([CH:36]=[C:35]([C:13]2[CH:14]=[C:15]3[C:5]4([C:4](=[O:23])[N:3]([CH3:24])[C:2]([NH2:1])=[N:6]4)[CH2:7][CH:8]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[O:9][C:10]3=[CH:11][CH:12]=2)[CH:34]=1)[C:39]#[N:40]
Reactant: NC1=NC2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(=O)N1CC1CCCCC1
Reactant: N#Cc1cc(N)cc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cc(N)cc(C#N)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 16 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-(cyclohexylmethyl)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-amino-5-cyanophenylboronic acid hydrochloride (21 mg, 0.104 mmol). The mixture was heated at 120° C. under microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC followed by preparative HPLC to give pure 3-amino-5-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro [chroman-4,4′-imidazole]-6-yl)benzonitrile (3.53 mg, 16%). 1H-NMR (MeOD): 2.44 (m, 1H), 2.60 (m, 1H), 5.24 (d, 0.3H), 5.85 (d, 0.7H), 6.91 (m, 1H), 7.14 (m, 3H), 7.48 (m, 6H), 7.60 (m, 1H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([O:15][CH3:16])[CH:8]=1.Cl[C:18](=[O:26])[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23].C(Cl)Cl>ClCCCl>[O:26]=[C:18]([C:8]1[C:9]([O:15][CH3:16])=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:7]=1[O:6][CH3:5])[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)CCCC(=O)Cl
Reactant: COc1cc(OC)cc(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)CCCC(=O)c1c(OC)cc(OC)cc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) suspension of aluminum chloride (9.316 g; 69.87 mmol) in anh. DCE (50 ml) was treated with commercially available 1,3,5-trimethoxybenzene (7.664 g; 45.56 mmol), and stirring at 0° C., under nitrogen, was continued for 10 min. Commercially available methyl 5-chloro-5-oxopentanoate (5.000 g; 30.37 mmol) was then added, and the mixture was stirred at rt for 26 h. The resulting reaction mixture was poured onto crushed ice (150 g), and DCM (100 ml) was added. The separated aq. layer was further extracted with DCM (3×50 ml). The mixed organic layers were washed successively with water (75 ml) and brine (2×75 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=10/1 to AcOEt) afforded methyl 5-oxo-5-(2,4,6-trimethoxyphenyl)pentanoate as a yellow oil. LC-MS (conditions D): tR=0.94 min.; [M+H]+: 297.13 g/mol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]2=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:3]=1.[NH2:22][C:23]1(B2OC(C)(C)C(C)(C)O2)[N:28]=[CH:27][CH:26]=[CH:25][NH:24]1>>[NH2:22][C:23]1[N:28]=[CH:27][C:26]([C:2]2[N:7]=[C:6]3[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]3=[C:4]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[N:3]=2)=[CH:25][N:24]=1
Reactant: COc1cccc(Nc2nc(Cl)nc3c2c(C)nn3C)c1
Reactant: CC1(C)OB(C2(N)N=CC=CN2)OC1(C)C
Product: COc1cccc(Nc2nc(-c3cnc(N)nc3)nc3c2c(C)nn3C)c1

Procedure:
(6-Chloro-1,3-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(3-methoxy-phenyl)-amine was reacted with 2-amino-pyrimidine boronic acid pinacol ester using General Procedure A to give 118. NMR (CDCl3): 2.74 (3H, s), 3.90 (3H, s), 4.04 (3H, s), 5.28 (2H, br), 6.76 (1H, d), 6.99 (1H, br), 7.35 (1H, d), 7.34 (1H, t), 7.55 (1H, s), 9.38 (2H, s). MS: MH+ 363.22 (25%)
Reaction SMILES: O1CCCC1.[OH-].[Na+].[NH2:8][C:9]1[C:14]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1.Cl[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[N:31]=1>CN(C)C=O>[F:36][C:32]1[N:31]=[C:30]([CH2:29][O:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:17]3[CH:16]=[C:15]([C:14]4[C:9]([NH2:8])=[N:10][CH:11]=[CH:12][CH:13]=4)[O:19][N:18]=3)=[CH:22][CH:23]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: Fc1cccc(CCl)n1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3cccc(F)n3)cc2)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.7 %

Procedure:
Tetrahydrofuran (3 mL) and a 5 N aqueous sodium hydroxide solution (36.0 μL, 0.18 mmol) were added to 4-(5-(2-amino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (48.2 mg, 0.18 mmol) described in Manufacturing Example 5-1-1, which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction mixture was then concentrated under a reduced pressure to obtain a white solid. This solid and 2-chloromethyl-6-fluoro-pyridine (63.2 mg, 0.43 mmol) described in Manufacturing Example 45-1-1 were added to N,N-dimethylformamide (3 mL), which was stirred for 3 hours at room temperature. This mixture was partitioned into water and ethyl acetate. This organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (47.9 mg, 59%).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([I:11])[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=1[Cl:16])(=O)C.C(Cl)(=O)C.O>CO>[NH2:4][C:5]1[CH:10]=[C:9]([I:11])[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=1[Cl:16]
Reactant: COC(=O)c1nc(I)cc(NC(C)=O)c1Cl
Solvent: O
Solvent: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1nc(I)cc(N)c1Cl
Yield: 78.6 %

Procedure:
To solution of 4-acetylamino-3-chloro-6-iodopyridine-2-carboxylic acid, methyl ester (5.0 g, 14 mmol) in methanol (25 mL) was added acetyl chloride (1 mL) and the solution heated under reflux for 1 hour. The solution was cooled and water (25 mL) added and the precipitate was collected. Recrystallization from methanol gave 4-amino-3-chloro-6-iodopyridine-2-carboxylic acid, methyl ester (3.5 g, 11 mmol) mp 152-153° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]=[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[N:11]([C:13](I)=[CH:14][N:15]=2)[CH:12]=1)[CH3:6].C(=O)([O-])[O-].[Na+].[Na+].[CH2:24]([O:26][C:27]1[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][C:30]([CH:36]([CH3:38])[CH3:37])=[CH:29][C:28]=1B(O)O)[CH3:25]>C1(C)C=CC=CC=1.[Cl-].[Na+].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>[CH3:1][O:2][C:3](=[O:17])[CH:4]=[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[N:11]([C:13]([C:28]3[CH:29]=[C:30]([CH:36]([CH3:38])[CH3:37])[CH:31]=[C:32]([CH:33]([CH3:35])[CH3:34])[C:27]=3[O:26][CH2:24][CH3:25])=[CH:14][N:15]=2)[CH:12]=1)[CH3:6]
Reactant: CCOc1c(B(O)O)cc(C(C)C)cc1C(C)C
Reactant: COC(=O)C=C(C)c1ccc2ncc(I)n2c1
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: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1c(-c2cnc3ccc(C(C)=CC(=O)OC)cn23)cc(C(C)C)cc1C(C)C
Temperature: 90 °C
Yield: 76.4 %

Procedure:
3-(3-Iodo-imidazo[1,2-a]pyridin-6-yl)-but-2-enoic acid methyl ester (168 mg, 0.49 mmol), tetrakis(triphenylphosphine)palladium(0) (57 mg, 0.05 mmol), followed by 2M sodium carbonate solution (1 ml) were added to a solution of 2-ethoxy-3,5-diisopropyl-phenyl-boronic acid (246 mg, 0.98 mmol) (see Example 5, step B) in toluene (10 mL). The reaction mixture was heated to 90° C. overnight, then poured into brine (20 mL) and extracted with ethyl acetate (2×20 mL). The organic layers were combined, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography (chromatotron, 2μ plate, 50% ethyl acetate in hexanes) to give a 3-[3-(2-ethoxy-3,5-diisopropyl-phenyl)-imidazo[1,2-a]pyridin-6-yl]-but-2-enoic acid methyl ester as a yellow oil (157.5 mg, 76%). 1H NMR (250 MHz, CDCl3): δ 8.19 (bs, 1H), 7.75 (s, 1H), 7.68 (d, 1H, J=9.4), 7.42 (dd, 1H, J=9.4, J=1.2), 7.25 (d, 1H, J=2.5), 7.15 (d, 1H, J=2.5), 6.24 (d, 1H, J=0.62), 3.28 (s, 3H), 3.44 (m, 1H), 3.35 (q, 2H, J=8.1), 2.97 (m, 1H), 2.59 (d, 3H, J=0.62), 1.35 (s, 3H), 1.33 (s, 3H), 1.32 (s, 3H), 1.30 (s, 3H), 1.29 (t, 3H, J=8.1). MS [EI+] 421 (M+1)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C([Li])(C)(C)C.[CH3:16][C:17]1([CH3:48])[CH:26]=[C:25](OS(C(F)(F)F)(=O)=O)[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:35]#[C:36][C:37]3[CH:47]=[CH:46][C:40]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:39][CH:38]=3)[CH:23]=2)[O:18]1>C1COCC1.CCCCC.[Cl-].[Cl-].[Zn+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:2][CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:35]#[C:36][C:37]4[CH:47]=[CH:46][C:40]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:39][CH:38]=4)[CH:23]=3)[O:18][C:17]([CH3:16])([CH3:48])[CH:26]=2)=[CH:6][CH:5]=1)[CH3:3]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CC(C)(C)O3)cc1
Reactant: CC(C)c1ccc(Br)cc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C(C)C)cc2)=CC(C)(C)O3)cc1
Temperature: 25 °C

Procedure:
A solution of 4-iso-propylbromobenzene (250.0 mg, 1.25 mmol) in 3.0 mL of THF was cooled to -78° C. and tert-butyllithium (160.8 mg, 2.51 mmol, 1.5 ml of a 1.7M solution in pentane) was added to give a yellow solution. After 30 minutes a solution of ZnCl2 (345.0 mg, 2.53 mmol) in 5.0 mL THF was slowly added via cannula. The resulting solution was warmed to room temperature and transferred via cannula to a solution of ethyl 4-((2,2-dimethyl-4-trifluoromethanesulfonyloxy-(2H)-chromen-6-yl)ethynyl)-benzoate (Compound 264, 150.0 mg, 0.31 mmol) and tetrakis(triphenylphosphine) palladium(0) (24.0 mg, 0.02 mmol) in 2.0 mL THF. This solution was heated to 50° C. for 2 hours, cooled to room temperature, and the reaction quenched by the addition of saturated aqueous NH4Cl. This solution was extracted with EtOAc and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound, 100.0 mg (72%), was isolated by column chromatography (2.5% EtOAc/hexanes) as a colorless solid. 1H NMR (300 MHz, CDCl3) δ: 7.99 (2H, d, J=8.3 Hz), 7.52 (2H, d, J=8.3 Hz), 7.36 (1H, dd, J=2.1, 8.3 Hz), 7.30-7.26 (5H, m), 6.88 (1H, d, J=8.3 Hz), 5.64 (1H, s), 4.38 (2H, q, J=7.1 Hz), 2.98 (1H, hept, J=7.0 Hz), 1.51 (6H, s), 1.40 (3H, t, J=7.1 Hz), 1.31 (6H, d, J=7.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]([CH3:14])[CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]1[C:27](O)=[O:28].C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[CH3:14][N:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:27]([C:19]2[N:18]([CH3:17])[C:26]3[C:21]([CH:20]=2)=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:28])=[CH:16][CH:15]=1)[CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: Cn1c(C(=O)O)cc2ccccc21
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN(Cc1ccc(NC(=O)c2cc3ccccc3n2C)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EDIC (0.33 mmol, 0.07 g) was added in one portion to a mixture of (4-amino-benzyl)-methyl-(tetrahydro-pyran -4-yl)-amine Compound 1d (0.25 mmol, 0.06 g), 1-methyl-1H-indole-2-carboxylic acid Compound 12a (0.22 mmol, 0.04 g) and HOBt (0.22 mmol, 0.03 g) in DMF (5.0 mL) at 0° C. The resulting suspension was warmed to r.t. and then a crystal of DMAP and Et3N (0.65 mmol, 0.11 mL) was added and the reaction mixture was stirred overnight. The resulting orange-yellow suspension was poured in water and was extracted with EtOAc (25 mL). The organic layer was washed with water (2×20 mL) followed by 5% NaOH solution (10 mL) and brine. The organic layer was separated, dried over Na2SO4 and filtered. The solvent was removed in vacuo and the resulting residue was purified by preparative TLC (15:1 CH2Cl2/MeOH) to yield 1-methyl-1H-indole-2-carboxylic acid (4-{[methyl-(tetrahydro-pyran -4-yl)-amino]-methyl}-phenyl)-amide Compound 12b as a pale yellow solid (0.05 g, 60%). MS m/e 378 (M+H, 100%).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20][N:19]=2)[C:3]1=[O:25].Cl[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([N:33]2[CH2:44][CH2:43][N:42]3[C:35](=[CH:36][C:37]4[CH2:38][C:39]([CH3:46])([CH3:45])[CH2:40][C:41]=43)[C:34]2=[O:47])[C:28]=1[CH:48]=[O:49].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[CH3:45][C:39]1([CH3:46])[CH2:38][C:37]2[CH:36]=[C:35]3[N:42]([CH2:43][CH2:44][N:33]([C:29]4[C:28]([CH:48]=[O:49])=[C:27]([C:6]5[CH:5]=[C:4]([NH:17][C:18]6[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20][N:19]=6)[C:3](=[O:25])[N:2]([CH3:1])[CH:7]=5)[CH:32]=[CH:31][N:30]=4)[C:34]3=[O:47])[C:41]=2[CH2:40]1
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1nccc(Cl)c1C=O)C3=O
Reactant: Cc1cc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)ncn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: Cc1cc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3C=O)cn(C)c2=O)ncn1
Temperature: 100 °C
Yield: 46.4 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 180b (239 mg, 0.70 mmol), 4-chloro-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridine-3-carbaldehyde 108a (239 mg 0.70 mmol), Pd(dppf)Cl2 (57 mg, 0.070 mmol), sodium acetate (115 mg, 1.4 mmol), K3PO4 (320 mg, 1.4 mmol), water (5 mL), and acetonitrile (15 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. After this time the reaction was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with 40:1 dichloromethane/methanol to afford 180c as a yellow solid (170 mg, 47%). MS-ESI: [M+H]+ 524.2.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.Br[CH2:14][CH2:15][CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1.C1CCN2C(=NCCC2)CC1>C(O)(C)C>[N:17]1([CH2:16][CH2:15][CH2:14][S:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]3)[CH:21]=[N:20][CH:19]=[N:18]1
Reactant: BrCCCn1cncn1
Reactant: O=C1CCc2cc(S)ccc2N1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)O
Product: O=C1CCc2cc(SCCCn3cncn3)ccc2N1

Procedure:
2.4 Grams (13.4 mM) of 6-mercapto-3,4-dihydrocarbostyril, 3,3 g (17.4 mM) of 1-(3-bromopropyl)-1,2,4-triazol, and 2.6 ml (17.4 mM) of DBU were added to 60 ml of isopropanol, and the whole mixture was refluxed by heating for 2 hours. After the reaction was completed, the reaction mixture was concentrated, the resulting residue was extracted with chloroform. The chloroform extract was washed with water, an aqueous solution saturated with sodium hydrogen carbonate, and water in this order, then dried with anhydrous sodium sulfate. The dried extract was concentrated by removing the solvent by evaporation, the residue was purified by means of a silica gel column chromatography (eluent: dichloromethane:methanol=20:1), and recrystallized from ethanol-n-hexane to yield 2.5 g of 6-[3-(1H-1,2,4-triazol-1-yl)propylthio]-3,4-dihydrocarbostyril. Colorless needle-like crystals. Melting point: 114.5°-115.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][CH:12]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:19].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([CH:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[C:24]([Cl:40])=[CH:23][N:22]=1>>[Cl:40][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([CH:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])=[N:26][C:21]([NH:19][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH:12]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:11][CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:22][CH:23]=1
Reactant: COCCNC1CCCc2c(ccc(N)c2OC)C1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: COCCNC1CCCc2c(ccc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)C(C)C)n3)c2OC)C1

Procedure:
The title compound was prepared from 1-methoxy-N(6)-(2-methoxyethyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2,6-diamine (60 mg, 0.2 mmol) and (2,5-dichloropyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine (78 mg, 0.23 mmol) in an analogous manner to Example 946 to afford a white foam (59 mg, 40%). Mp: 83-5° C. LCMS (m/e) 574 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.58 (s, 1H), 8.60 (d, J=8 Hz, 1H), 8.18 (s, 1H), 7.94 (d, J=8 Hz, 1H), 7.69 (d, J=8 Hz, 1H), 7.52 (br s, 1H), 7.30 (m, 1H), 6.87 (d, J=8 Hz, 1H), 3.75 (s, 3H), 3.54 (m, 2H), 3.37 (s, 3H), 3.25 (m, 1H), 3.10 (m, 1H), 2.92-2.80 (m, 4H), 2.63 (m, 2H), 2.10 (m, 1H), 1.97 (m, 1H), 1.71 (m, 1H), 1.55 (m, 2H), 1.33 (d, J=7 Hz, 6H).