Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:17]=[CH:16][C:5]([O:6][CH:7]([CH3:15])[CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:2]3[CH:17]=[CH:16][C:5]([O:6][CH:7]([CH3:15])[CH2:8][N:9]4[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]4)=[CH:4][CH:3]=3)=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: CC(CN1CCCCC1)Oc1ccc(I)cc1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: CC(CN1CCCCC1)Oc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1

Procedure:
Prepared according to general working method I from 1-[2-(4-iodo-phenoxy)-propyl]-piperidine (173 mg, 0.50 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (107 mg, 0.50 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:25](Br)([CH3:27])[CH3:26].O>CN(C)C=O>[CH:25]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1)([CH3:27])[CH3:26]
Reactant: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc2c(=O)c(-c3ccccc3)coc2c1

Procedure:
12 g of 7-hydroxy-isoflavone are boiled for 2 hours under a reflux condenser with 10 g of potassium carbonate and 9 g of isopropyl bromide in 40 ml of dimethyl formamide. On pouring the reaction mixture into water, the separated product is recrystallized from acetone, yielding 7-isopropoxy-isoflavone. In a similar way all the other isoflavone derivatives described in Example 7 can be prepared.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[N:6][CH:7]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18].C(N(CC)CC)C>[Cu]I.C1COCC1>[CH3:16][Si:17]([C:20]#[C:21][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[N:6][CH:7]=1)([CH3:19])[CH3:18]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1cncc(Br)c1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cncc(C#C[Si](C)(C)C)c1
Temperature: 50 °C
Yield: 62.6 %

Procedure:
To a solution of tert-butyl (5-bromopyridin-3-yl)carbamate (3.00 g, 11.0 mmol) and THF (30 mL) was added (trimethylsilyl)acetylene (1.60 g, 16.3 mmol), (triphenylphosphine)palladium(II) chloride (0.31 g, 0.44 mmol), copper(I) iodide (84 mg, 0.44 mmol) and triethylamine (1.7 mL, 12 mmol) under nitrogen atmosphere. The mixture was heated at 50° C. overnight. The solvent removed in vacuo. The residue was diluted with EtOAc and water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (2.0 g, 63%). LCMS calculated for C15H23N2O2Si(M+H)+: m/z=291.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([CH2:21]O)[CH:18]=[CH:19][CH:20]=3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]1(=[O:52])[NH:46][C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([CH2:21][N:46]4[C:45](=[O:47])[C:44]5=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]5[C:42]4=[O:52])[CH:18]=[CH:19][CH:20]=3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: OCc1cccc(OCc2nc(-c3ccc(Cl)cc3)cs2)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cccc(OCc2nc(-c3ccc(Cl)cc3)cs2)c1
Reaction time: 16 h

Procedure:
The phenylmethylalcohol compound (1.98 grams) (Scheme C, Compound C1) was dissolved in tetrahydrofuran (100 mL). Triphenylphosphine (1.84 grams), phthalimide (1.03 grams) and diethylazodicarboxylate (1.10 mL) were added to the mixture which was then stirred for 16 hours before being evaporated in vacuo. The residue was column chromatographed (silica gel) using a mobile phase of hexane-ethyl acetate 2:1 to give a N-[3-[[4-(4-chlorophenyl)-2-thiazolyl]methoxy]phenylmethyl]phthalimide (Scheme C, Compound C2). Mp 156.5–157.5° C.; MS 461 (MH+).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([NH:12][CH2:13][CH2:14][OH:15])[CH3:11]>CS(C)=O>[CH2:10]([N:12]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:13][CH2:14][OH:15])[CH3:11]
Reactant: N#Cc1ccc(F)cc1
Reactant: CCNCCO
Solvent: CS(C)=O
Product: CCN(CCO)c1ccc(C#N)cc1
Temperature: 140 °C
Yield: 21335.1 %

Procedure:
A solution of 10 g (82.6 mmol) of 4-fluorobenzonitrile and 15 g (0.17 mmol) of 2-(ethylamino)ethanol in 30 ml of DMSO was stirred under heat at 140° C. for 3 hours, followed by extraction with ethyl acetate. The solvent was distilled out under reduced pressure, followed by washing with ethyl acetate, whereby 6.9 g of white powder were obtained (yield: 44%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].C1[C:33](=O)[N:32](Br)[C:30](=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.C(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH2:20][N:32]([CH3:33])[CH3:30])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CN(C)Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Yield: 268.3 %

Procedure:
Preparation of(S)-ethyl 2-(3-(bromomethyl)-1-(4-chlorophenyl)naphthalen-2-yl)-2-tert-butoxyacetate: To a solution of (S)-ethyl 2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)acetate (3K, 43 mg, 0.0105 mmol) in CCl4 (2 mL) was added NBS (24 mg, 0.13 mmol) and AIBN (cat. amount). The reaction mixture was refluxed for 5 h. After cooling to room temperature, the reaction mixture was diluted by DCM, washed with sat. NaHCO3, extracted with DCM and the organic layers were combined and dried over MgSO4, filtered, concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to provide 12 mg of the desired product. 1H-MNR 400 MHz (CDCl3) δ: 8.01 (s, 1H), 7.77 (d, J=4 Hz, 1H), 7.43-7.15 (m, 7H), 5.11 (d, J=5.2 Hz, 1H), 5.06 (s, 1H), 5.00 (d, J=5.2 Hz, 1H), 4.07-4.02 (m, 2H), 1.20-1.15 (m, 3H), 0.96 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:20]=3)[NH:15]2)[CH:9]=1)([CH3:6])[CH3:5].Cl>O1CCCC1.[OH-].[Li+].O>[CH3:29][S:26]([C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]([C:10]1[CH:9]=[C:8]([NH:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:30])=[O:2])[CH:13]=[CH:12][CH:11]=1)[C:23]([CH3:25])([CH3:24])[CH2:22]2)(=[O:28])=[O:27]
Reactant: COC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(S(C)(=O)=O)cc3CC2(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(Nc1cccc(C2Nc3ccc(S(C)(=O)=O)cc3CC2(C)C)c1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 19.8 %

Procedure:
A mixture of 2-[3-(6-methanesulfonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid methyl ester (100 mg, 0.23 mmol) in tetrahydrofuran (20 mL), 2M lithium hydroxide in water (10 mL) was stirred at 25° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(6-methanesulfonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (19 mg, 7%) as a white solid: LC/MS m/e calcd for C22H28N2O4S (M+H)+: 417.54, observed: 417.0.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:26].[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[N:35]=[C:36]=[O:37]>C1(C)C=CC=CC=1>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:24]=[CH:25][C:2]([NH:1][C:36]([NH:35][C:29]2[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:28]=2[F:27])=[O:37])=[C:3]([F:26])[CH:4]=1)#[N:18]
Reactant: COCCOc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1C#N
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: Cc1ccccc1
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(F)c3)c2cc1C#N

Procedure:
4-(4-Amino-3-fluorophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (352 mg) was suspended in toluene (20 ml) and the suspension was heated to reflux for dissolution, after which 2,4-difluorophenyl isocyanate (236 μl) was added dropwise and the mixture was heated to reflux for 30 minutes. After cooling, the precipitated solid was filtered out, washed with ether and ethyl acetate and dried to obtain 380 mg of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].[CH3:16][O:17][C:18](=[O:46])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:23][C:22]=1[O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]OS(C)(=O)=O>>[CH3:16][O:17][C:18](=[O:46])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:23][C:22]=1[O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)CCCOc1ccc(CCC(=O)OC)c(OCCCCCOS(C)(=O)=O)c1
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Product: CCCc1c(OCCCCCOc2cc(OCCCC(=O)OC)ccc2CCC(=O)OC)ccc2c1OCCC2=O
Yield: 75 %

Procedure:
Using the procedure of example 11 and starting with 0.28 g (1.4 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 0.65 g (1.41 mmol) of 2-[[5-[(methylsulfonyl)oxy]pentyl]oxy]-4-(4-methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester (from example 137), 4-(4-methoxy-4-oxobutoxy)-2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid methyl ester was obtained in 75% yield (0.6 g) as a solid, mp 58°-59° C. This diester (1.05 mmol) was saponified with 3 mL of 3N aqueous lithium hydroxide in 30 mL of tetrahydrofuran, at room temperature, for 16 hr. Work-up as in example 4 but using dichloromethane rather than ether gave a solid acid which was flash-chromatographed on silica gel, eluting with 95:5:1 chloroform-methanol-acetic acid. Recrystallization from ethyl acetate gave 0.44 g (78%) of pure 4-(3-carboxypropoxy)-2-[5[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid as a colorless solid, mp 163°-164° C.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH:6]1([C:9](=[O:33])[C:10](=[CH:29]OCC)[C:11]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([O:23][CH2:24][CH2:25][O:26][CH3:27])[C:14]=2[Br:28])=[O:12])[CH2:8][CH2:7]1.Cl.[NH2:35]O>C(O)C>[Br:28][C:14]1[C:15]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[C:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:17]=[CH:18][C:13]=1[C:11]([C:10]1[CH:29]=[N:35][O:33][C:9]=1[CH:6]1[CH2:8][CH2:7]1)=[O:12]
Reactant: CCOC=C(C(=O)c1ccc(S(C)(=O)=O)c(OCCOC)c1Br)C(=O)C1CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COCCOc1c(S(C)(=O)=O)ccc(C(=O)c2cnoc2C2CC2)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
Sodium acetate (1.65 g) was added to a stirred mixture of 3-cyclopropyl-2-ethoxymethylene-1-[2-bromo-3-(2-methoxyethoxy)-4-methylsulphonylphenyl]propan-1,3-dione (8.5 g) and hydroxylamine hydrochloride (1.77 g) in ethanol. The mixture was stirred at room temperature overnight and then evaporated to dryness. The residue was dissolved in ethyl acetate and washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness. The residue was chromatographed on silica eluted with a mixture of ethyl acetate and cyclohexane (1:5) to give 4-[2-bromo-3-(2-methoxyethoxy) 4-methylsulphonylbenzoyl]-5-cyclopropylisoxazole (compound 181) as a yellow oil (3.3 g), NMR (CDCl3), 1.3(2H, m), 1.4(2H,m), 2.6(1H, m), 3.3(3H, s), 3.5(3H, s), 3.9(2H, m), 4.5(2H, m), 7.3(1H, d), 8.0(1H, s), 8.1(1H, d).
Reaction SMILES: OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[CH2:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:16]#[CH:17].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][CH2:33][OH:34]>C(#N)C>[CH2:15]([N:18]1[CH2:23][CH2:22][N:21]([CH2:31][CH2:32][CH2:33][OH:34])[CH2:20][CH2:19]1)[C:16]#[CH:17]
Reactant: C#CCN1CCNCC1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: C#CCN1CCN(CCCO)CC1
Temperature: 85 °C
Yield: 78.5 %

Procedure:
1-Prop-2-yn-1-ylpiperazine diTFA salt (704 mg, 2 mmol), (prepared as described for the starting material in Example 26), was dissolved in acetonitrile (5 ml). Potassium carbonate (1.38 g, 10 mmol) and 3-bromopropan-1-ol (180 μL, 2 mmol) were added and the mixture heated to 85° C. for 6.5 hours. The reaction mixture was cooled, filtered and concentrated to give an oil. This was triturated with diethyl ether to give a white solid, which was partitioned between dichloromethane and water. The organic phase was then dried (MgSO4) and concentrated to give 3-(4-prop-2-yn-1-ylpiperazin-1-yl)propan-1-ol (286 mg, 79%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[C:15](\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[CH2:16][CH3:17])/[C:12]([OH:14])=O)=[CH:7][CH:6]=1.Cl.Cl.[CH3:26][N:27]([CH3:38])[CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:26][N:27]([CH3:38])[CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:12](=[O:14])/[C:11](/[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=2)=[C:15](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)\[CH2:16][CH3:17])=[CH:33][CH:32]=1
Reactant: CN(C)CCOc1ccc(N)cc1
Reactant: CC/C(=C(\C(=O)O)c1ccc(OCOC)cc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC/C(=C(\C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(OCOC)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
To a mixture of 3 (2.90 g, 9.28 mmol), 4-(2-(dimethylamino)ethoxy)benzenamine dihydrochloride (2.58 g, 10.2 mmol), 4-Dimethylaminopyridine (56.7 mg, 0.464 mmol) in CH2Cl2 (100 ml) was added O-Benzotriazoyl-N,N,N′,N′-tetramethyluronium Hexafluorophosphate (3.87 g, 10.2 mmol) under ice cooling, and the mixture was stirred at 0° C. for 10 min. Then N,N-Diisopropylethylamine (4.19 g, 32.4 mmol) was added under ice cooling. The mixture was stirred at 0° C. for 5 min, and at room temperature for 15 h. The reaction was quenched with saturated aqueous NaHCO3 under ice cooling, and the whole was extracted with CHCl3, the organic layer was washed with brine, dried over Na2SO4, and then concentrated. Purification by Biotage (eluent: CH2Cl2 to CH2Cl2/MeOH, 6:1) gave the colorless solid. The solid was triturated with Et2O-hexane to give 4 (65%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][NH:6][N:5]=1)[CH3:2].Cl[CH2:17][C:18]1[CH:34]=[CH:33][C:21]([O:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][N:26]=2)=[CH:20][CH:19]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][N:26]=3)=[CH:33][CH:34]=2)[N:5]=1)[CH3:2]
Reactant: CCc1ccc(CCOc2ccc(CCl)cc2)nc1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCCc3ccc(CC)cn3)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
To a mixture of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl]propionate (318 mg), 2-[2-(4-chloromethylphenoxy)ethyl]-5-ethylpyridine (414 mg), and N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 60.0 mg) was added at 0° C., and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-1H-pyrazol-4-yl]propionate (520 mg, yield: 77%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[NH2:8].C(ON[C:14]([CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=N)C>C(O)C>[OH:9][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:14]([CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:1][C:2]=2[CH:3]=1
Reactant: CCONC(=N)C(C)C(=O)OCC
Reactant: Nc1ccc(O)cc1N
Solvent: CCO
Product: CCOC(=O)C(C)c1nc2cc(O)ccc2[nH]1
Yield: 91.2 %

Procedure:
A mixture comprising of 3,4-diaminophenol (3.661 g, 29.5 mL), ethyl 2-(N-ethoxyamidino)propionate (7.423 g, 38.4 mmol) and ethanol (30 mL) was heated at reflux for 6 hours and concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL) and the solution was washed with saturated aqueous sodium hydrogencarbonate (3×20 mL) and brine (1×20 mL), dried (MgSO4) and concentrated in vacuo to provide ethyl 2-(5-hydroxy-1H-benzoimidazol-2-yl)propionate (6.3 g, 91% yield) as a dark solid. The solid was further purified by silica gel flash chromatography (100% ethyl acetate); MS (PB-PCI) C12H14N2O3 m/e calc 234.28; found 235 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH:24](/B(O)O)=[CH:25]\[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O1CCOCC1>CO.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]>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:4]2[CH:3]=[C:2](/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: OB(O)/C=C/c1ccccc1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(/C=C/c3ccccc3)n3nccc3n2)cc1
Temperature: 110 °C
Yield: 0 %

Procedure:
A suspension of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 151 mmol), (E)-styrylboronic acid (45 mg, 302 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9 mg, 12 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (670 microliters of 1,4-dioxane and 330 microliters of saturated aqueous NaHCO3) was prepared in a 2 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 20 minutes. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC, 50-80% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (5.8 mg, 10%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6H) 3.85 (s, 3H) 6.59 (d, J=2.27 Hz, 1H) 7.22 (dd, J=8.08, 1.77 Hz, 1H) 7.55 (t, J=7.83 Hz, 1H) 7.59-7.70 (m, 4H) 7.98-8.09 (m, 3H) 8.20 (d, J=2.02 Hz, 1H) 11.27 (s, 1H). ESI-MS: m/z 399.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=2)=[CH:5][CH:4]=1.[H][H]>C(O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2=CC(=O)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C2CCC(=O)C2)cc1
Reaction time: 4 h
Yield: 52.1 %

Procedure:
3-(4-Methoxyphenyl)-2-cyclopenten-1-one (11.2 g) was dissolved in ethanol, and 10% palladium-carbon (1.1 g) was added thereto. After substituting the reaction vessel with hydrogen gas, hydrogen addition was carried out at normal pressure, 40° C. for 4 hours. After the reaction, the catalyst was filtered off and the solvent was distilled off under reduced pressure to produce a light yellow oily substance which was then purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to give 5.90 g of 3-(4-methoxyphenyl) cyclopentanone (52.2% yield).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13](OC)=[O:14]>C1COCC1.CO>[CH3:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[CH2:13][OH:14]
Reactant: COC(=O)c1nc2ccccn2c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(CO)nc2ccccn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
Sodium borohydride (1.5 g, 41.6 mmol) was added to a solution of methyl 3-methylimidazo[1,2-a]pyridine-2-carboxylate (2.0 g, 10.5 mmol) in THF (50 mL) and methanol (2.5 ml) at RT. The reaction mixture was stirred at RT for 2 h (the reaction was monitored by TLC) upon which the mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford (3-methylimidazo[1,2-a]pyridin-2-yl)methanol (0.8 g, 47.05%,) as off-white solid. 1H NMR: 200 MHz, CDCl3: δ 7.45 (d, 1H), 7.6 (d, 1H), 7.2 (t, 1H), 6.8 (t, 1H), 4.85 (s, 2H), 2.45 (s, 3H). MS: [M+H]+: m/z=162.9.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4]1.CCN(CC)CC.[S:17](Cl)([CH3:20])(=[O:19])=[O:18]>C(Cl)Cl>[CH3:20][S:17]([O:1][CH2:2][CH:3]1[CH2:4][CH2:5][CH2:6][C:7](=[O:9])[NH:8]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCCC(CO)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCCC(=O)N1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6-(Hydroxymethyl)piperidin-2-one (1.0 g, 7.8 mmol) and Et3N (1.1 ml, 7.8 mmol) in DCM (5 ml) was added into mesyl chloride (0.88 g, 7.8 mmol) in DCM (20 ml) at 0° C. The reaction mixture was stirred at room temperature for 15 mins. The reaction mixture was washed with 1 N HCl (20 ml) and brine (40 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give (6-oxopiperidin-2-yl)methyl methanesulfonate which was used in the next step without additional purification. Yield (quant.).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH2:6][S:7]([O-])(=[O:9])=[O:8].[Na+].P(Cl)(Cl)([Cl:19])=O>>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH2:6][S:7]([Cl:19])(=[O:9])=[O:8]
Reactant: O=S(=O)([O-])Cc1cccc(C(F)(F)F)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Product: O=S(=O)(Cl)Cc1cccc(C(F)(F)F)c1
Reaction time: 5 h
Yield: 90.2 %

Procedure:
10 g of sodium 3-trifluoromethylbenzylsulfonate was slowly added to 17.7 ml (29.1 g) of phosphorous oxychloride. The resulting slurry was stirred at 100° to 105° C. for five hours. The reaction mixture was then cooled and filtered. The filter cake was washed with methylene chloride, the washings were combined with the filtrate and then evaporated to dryness affording 8.9 g of 3-trifluoromethylbenzylsulfonyl chloride.