Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:19]([O:21]CC)=[O:20])[C:5]([CH3:18])=[C:6]2[C:11]=1[S:10](=[O:13])(=[O:12])[CH2:9][CH2:8][C:7]12[O:17][CH2:16][CH2:15][O:14]1.[OH-].[K+].CO>O>[C:19]([C:4]1[C:5]([CH3:18])=[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=1)[S:10](=[O:13])(=[O:12])[CH2:9][CH2:8][C:7]12[O:17][CH2:16][CH2:15][O:14]1)([OH:21])=[O:20]
Reactant: CCOC(=O)c1cc(Cl)c2c(c1C)C1(CCS2(=O)=O)OCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)cc(Cl)c2c1C1(CCS2(=O)=O)OCCO1
Temperature: 80 °C
Yield: 86.4 %

Procedure:
A mixture containing 1.19 g (3.2 mmol) of 8-chloro-6-ethoxycarbonyl-4,4-ethylenedioxy-5-methylthiochroman-1,1-dioxide, 0.33 g (5.0 mmol) of potassium hydroxide, 8 ml of methanol and 2 ml of water was stirred under heat at 80° C. for 2 hours. After the completion of the reaction, 20 ml of water was added, and an aqueous layer was washed with methylene chloride. The aqueous layer was neutralized with 2 wt % hydrochloric acid and extracted with ethyl acetate. An organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and the solvent was distilled off to give 0.92 g (yield 84%) of 6-carboxy-8-chloro-4,4-ethylenedioxy-5-methylthiochroman-1,1-dioxide in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[CH3:36][N:37]([CH3:41])[CH2:38][CH2:39][NH2:40]>>[CH3:36][N:37]([CH3:41])[CH2:38][CH2:39][NH:40][C:20]([N:11]1[CH:12]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([CH3:35])[N:9]=[C:10]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH:32]([CH3:33])[CH3:34])=[O:21]
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Reactant: CN(C)CCN
Product: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)NCCN(C)C)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with N,N-dimethyl-1,2-ethanediamine (Aldrich) to give the title compound. LC-MS: 583.2 [(M+H)+]
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:15][CH2:16][OH:17])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.[H-].[Na+].[CH3:20]I.[Cl-].[NH4+]>CN(C)C=O.O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:15][CH2:16][O:17][CH3:20])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1
Reactant: CI
Reactant: COCOc1cc(CCO)cc(OCOC)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCc1cc(OCOC)cc(OCOC)c1
Temperature: 4 °C
Reaction time: 1 h

Procedure:
2-[3,5-Bis(methoxymethoxy)phenyl]ethanol (4.6 g, 19 mmol) obtained in Example 1, Step 2 was dissolved in N,N-dimethylformamide (40 mL), and a 60% sodium hydride dispersion in mineral oil (0.30 g, 7.5 mmol) was added thereto at 4° C. in an atmosphere of nitrogen, followed by stirring at 4° C. for 1 hour. Methyl iodide (3.6 mL, 58 mmol) was added dropwise to the reaction mixture, followed by stirring at 4° C. for 3 hours. To the reaction mixture were added a saturated aqueous solution of ammonium chloride (30 mL) and water (0.2 L), and the mixture was extracted with ethyl acetate (0.20 L). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/9-1/2) to obtain a quantitative yield of 1,3-bis(methoxymethoxy)-5-(2-methoxyethyl)benzene.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH:16]([CH3:18])[CH3:17])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[C:19]([C:21]1[CH:22]=[C:23]([CH:39]([CH3:41])[CH3:40])[C:24]2[O:28][C:27]([C:29]3[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=3)=[N:26][C:25]=2[CH:38]=1)#[N:20]>>[C:19]([C:21]1[CH:22]=[C:23]([CH:39]([CH3:41])[CH3:40])[C:24]2[O:28][C:27]([C:29]3[CH:37]=[CH:36][C:32]([C:33]([NH:1][CH2:2][C:3]4([CH:16]([CH3:18])[CH3:17])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:5][CH2:4]4)=[O:34])=[CH:31][CH:30]=3)=[N:26][C:25]=2[CH:38]=1)#[N:20]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12
Reactant: CC(C)C1(CN)CCN(C(=O)OC(C)(C)C)CC1
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4(C(C)C)CCN(C(=O)OC(C)(C)C)CC4)cc3)oc12

Procedure:
To a solution of tert-butyl 4-cyano-4-isopropylpiperidine-1-carboxylate (90 mg, 0.357 mmol) in ammonium hydroxide (2 ml) and ethanol (4 ml) was added Raney nickel (100 mg, 1.167 mmol). The mixture was flushed with nitrogen, then flushed with hydrogen and stirred overnight under a hydrogen balloon, at which point LC/MS analysis showed the desired product. The mixture was filtered through a plug of Celite, washing liberally with methanol, and then concentrated to a small volume and partitioned between 20 ml of 1 N sodium hydroxide and 25 ml of ethyl acetate. The aqueous phase was extracted with 2×20 ml of ethyl acetate, and then the combined organics were washed with brine, dried (sodium sulfate), and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25M column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 50% methanol in dichloromethane over 10 column volumes to provide tert-butyl 4-(aminomethyl)-4-isopropylpiperidine-1-carboxylate (48 mg). The title compound was then prepared from tert-butyl 4-(aminomethyl)-4-isopropylpiperidine-1-carboxylate (48 mg) and 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoic acid (57 mg, INTERMEDIATE 2) as described in EXAMPLE 35. Mass spectrum (ESI) 545.3 (M+1). 1H NMR (500 MHz, CDCl3): 8.33 (d, J=8.0 Hz, 1H), 7.94 (s, 1H), 7.92 (d, J=8.5 Hz, 2H), 7.51 (s, 1H), 6.14 (br t, J=6.0 Hz, 1H), 3.63 (m, 4H), 3.47 (septet, J=7.0 Hz, 1H), 3.33 (br t, J=10.5 Hz, 2H), 1.83 (septet, J=7.0 Hz, 1H), 1.54-1.66 (m, 4H), 1.46 (d, J=7.0 Hz, 6H), 1.45 (s, 9H), 0.99 (d, J=7.0 Hz, 6H).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]1[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:18][C:17]=1[C:31]1[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Product: N#Cc1ccccc1-c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 2′-fluoro-5′-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile as a yellow powder: δH (400 MHz, CDCl3) 7.29 (1H, d, J 7), 7.45 (1H, t, J 8), 7.56 (1H, ddd, J 8, 8 and 1), 7.62-7.68 (3H, m), 7.70 (1H, ddd, J 8, 8 and 1), 7.85 (1H, dd, J 8 and 1), 8.10 (1H, s), 9.06 (1H, d, J 7); m/z (ES+) 383 (M++H).
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12]2[CH:26]=[CH:27][C:28]([C:30]([OH:32])=O)=[CH:29][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[F:42][C:43]([F:54])([F:53])[C:44]1[CH:45]=[C:46]([CH:50]=[CH:51][CH:52]=1)[CH2:47][CH2:48][NH2:49]>C1COCC1>[F:42][C:43]([F:53])([F:54])[C:44]1[CH:45]=[C:46]([CH2:47][CH2:48][NH:49][C:30]([C:28]2[CH:27]=[CH:26][C:12]3[N:13]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:17][CH:16]=4)[C:9]([CH2:8][O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:10][C:11]=3[CH:29]=2)=[O:32])[CH:50]=[CH:51][CH:52]=1
Reactant: NCCc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: O=C(NCCc1cccc(C(F)(F)F)c1)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mmol of 2-phenoxymethyl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole-5-carboxylic acid were dissolved in 1 ml THF with 1 eq. DIC. After 15 min 1.5 eq of 3-trifluoromethylphenethylamine were added and the reaction stirred at room temperature for 16 h. The crude material was purified via reversed phase preparative HPLC MS(ISP): 614.6 (M+H)+.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:18]([CH:19]=1)=[N:17][C:16]1[C:11](=[CH:12][CH:13]=[C:14]([O:20][CH2:21][CH2:22]Cl)[CH:15]=1)[CH:10]=2.[CH2:24]([CH2:26][NH2:27])[OH:25]>>[OH:25][CH2:24][CH2:26][NH:27][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:18]([CH:19]=1)=[N:17][C:16]1[C:11](=[CH:12][CH:13]=[C:14]([O:20][CH2:21][CH2:22][NH:27][CH2:26][CH2:24][OH:25])[CH:15]=1)[CH:10]=2
Reactant: NCCO
Reactant: ClCCOc1ccc2cc3ccc(OCCCl)cc3nc2c1
Agent: Cl
Product: OCCNCCOc1ccc2cc3ccc(OCCNCCO)cc3nc2c1

Procedure:
The compound is prepared from 3,6-bis(2-chloroethoxy)acridine hydrochloride and ethanolamine as described in Example 15, giving 0.7 g. of the desired product as yellow crystals, m.p. 125°-127° C.
Reaction SMILES: [O:1]([C:8]1[CH:28]=[CH:27][C:11]([O:12][C:13]2[N:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[N:21]=3)[CH:14]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([CH2:32]/[CH:33]=[CH:34]/[C:35](Cl)=[O:36])C>CN1C(=O)CCC1.ClCCl>[O:1]([C:8]1[CH:28]=[CH:27][C:11]([O:12][C:13]2[N:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[N:21]=[C:22]([NH:26][C:35](=[O:36])[CH:34]=[CH:33][CH3:32])[CH:23]=[CH:24][CH:25]=3)[CH:14]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Nc2cc(Oc3ccc(Oc4ccccc4)cc3)ncn2)n1
Reactant: CN(C)C/C=C/C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CC=CC(=O)Nc1cccc(Nc2cc(Oc3ccc(Oc4ccccc4)cc3)ncn2)n1
Reaction time: 1 h

Procedure:
To a stirred solution of N2-(6-(4-phenoxyphenoxy)pyrimidin-4-yl)pyridine-2,6-diamine (0.65 g, 1.75 mmol) in NMP (10 mL) was added dimethylaminocrotonyl chloride (1.026 g, 7 mmol) at 0° C. The reaction mixture was allowed to come to room temperature and kept at it for 1 h. It was diluted with dichloromethane (10 mL), was washed with NaHCO3 solution (2 mL) and water (2 mL), and dried over Na2SO4. The dichloromethane solution was filtered and was concentrated under reduced pressure to give a residue that was purified by column chromatography (SiO2, 60-120, chloroform/methanol, 9/1) to give (E)-4-dimethylamino)-N-(6-(6-(4-phenoxyphenoxy)pyrimidin-4-ylamino)pyridin-2-yl)but-2-enamide (I-82) as an off white solid. 1H NMR (DMSO-d6) δ ppm: 2.19 (s, 6H), 3.08 (d, J=5.52 Hz, 2H), 6.50 (d, J=15.4 Hz, 1H), 6.77 (td, J=5.92 & 15.4 Hz, 1H), 7.00-7.07 (m, 5H), 7.15 (t, J=7.36 Hz, 1H), 7.21 (dd, J=2.2 & 8.92 Hz, 2H), 7.41 (t, J=7.52 Hz, 2H), 7.68 (t, J=7.96 Hz, 1H), 7.77 (d, J=7.96 Hz, 1H), 7.95 (s, 1H), 8.35 (s, 1H), 10.20 (s, 1H), 10.40 (s, 1H); LCMS: m/e 483 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:27])[CH:5]=[CH:6][C:7]=1B1OC(C)(C)C(C)(C)O1.[C:28]([O:32][C:33](=[O:47])[N:34]([CH2:39][C:40]1[CH:45]=[CH:44][C:43](Br)=[CH:42][CH:41]=1)[CH2:35][CH2:36][CH2:37][F:38])([CH3:31])([CH3:30])[CH3:29].CCO.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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].O>[C:28]([O:32][C:33](=[O:47])[N:34]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:7]2[CH:6]=[CH:5][C:4]([N:17]3[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]3=[O:27])=[CH:3][C:2]=2[F:1])=[CH:42][CH:41]=1)[CH2:35][CH2:36][CH2:37][F:38])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N(CCCF)Cc1ccc(Br)cc1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)C(=O)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(CN(CCCF)C(=O)OC(C)(C)C)cc3)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
A solution of boronic ester 123 (1.40 g, 3.7 mmol, 1.3 equiv) and (4-bromo-benzyl)-(3-fluoro-propyl)-carbamic acid tert-butyl ester 115 (1.0 g, 2.89 mmol, prepared as described in Example 1, above) in a mixture of 1,4-dioxane (21 mL), EtOH (7.0 mL) and H2O (7.0 mL) was treated with solid potassium carbonate (1.2 g, 8.7 mmol, 3.0 equiv) at room temperature. The resulting reaction mixture was degassed three times under a steady stream of argon before being treated with Pd(dppf)2Cl2 (118 mg, 0.144 mmol, 0.05 equiv) at room temperature. The reaction mixture was degassed three times under a steady stream of argon before being warmed to reflux for 2 h. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was cooled to room temperature before being treated with water (60 mL). The aqueous solution was then extracted with CH2Cl2 (3×20 mL), and the combined organic extracts were washed with water (2×20 mL) and saturated aqueous NaCl (20 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (0-5% MeOH—CH2Cl2 gradient elution) to afford the desired (5S)-{4′-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-(3-fluoro-propyl)-carbamic acid tert-butyl ester 121 (1.36 g, 91% yield) as a colorless oil, which solidified upon standing at room temperature in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[N+:13]([CH3:16])([O-:15])=[O:14]>O>[OH:12][C:5]1([CH2:16][N+:13]([O-:15])=[O:14])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=2)[NH:7][C:6]1=[O:11]
Reactant: C[N+](=O)[O-]
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Solvent: O
Product: Cc1ccc2c(c1)C(O)(C[N+](=O)[O-])C(=O)N2
Temperature: 50 °C
Reaction time: 24 h

Procedure:
5-methyl isatin (0.08 g) and nitromethane (0.15 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 50° C. for 24 hours. The product was extracted with ethyl acetate and purified by silica gel column chromatography using ethyl acetate/hexane as eluents to afford pure product.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:23][CH3:24])[CH2:4][N:5]1[CH:10]=[CH:9][C:8](=[O:11])[C:7]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]1[C:20]([OH:22])=[O:21].[C:25]([O-])(O)=O.[Na+].CI>CN(C=O)C.CC(OC)(C)C.CCOC(C)=O>[CH3:24][O:23][CH:3]([O:2][CH3:1])[CH2:4][N:5]1[CH:10]=[CH:9][C:8](=[O:11])[C:7]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]1[C:20]([O:22][CH3:25])=[O:21]
Reactant: O=C([O-])O
Reactant: COC(Cn1ccc(=O)c(OCc2ccccc2)c1C(=O)O)OC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: COC(C)(C)C
Product: COC(=O)c1c(OCc2ccccc2)c(=O)ccn1CC(OC)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude 1-[2,2-bis(methyloxy)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic acid 22 obtained as above was dissolved in DMF (500 mL). To this solution was added NaHCO3 (50.5 g, 0.6 mole). The suspension was stirred vigorously with a mechanic stirrer while CH3I in TBME (2.0 M, 300 mL) was introduced by addition funnel over 30 minutes. After addition, the reaction was stirred overnight at room temperature. The reaction mixture was then diluted with EtOAc (˜1.5 L) and washed with water and brine. The organic layer was dried over anhydrous Na2SO4. Evaporation of solvents gave methyl 1-[2,2-bis(methyloxy)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate 23 as brown oil, which was used directly for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]1[O:11][CH:10]1[CH2:12][OH:13]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]([OH:11])[CH2:12][OH:13])=[CH:4][CH:3]=1
Reactant: OCC1CO1
Reactant: Oc1ccc(Cl)cc1
Solvent: c1ccncc1
Product: OCC(O)COc1ccc(Cl)cc1
Yield: 67.1 %

Procedure:
A mixture of 25.7 g (0.2 mole) of 4-chlorophenol, 18.5 g (0.25 mole) of glycidol and 1 ml of pyridine was stirred and heated at 85°-90° C. overnight. The pot residue was partitioned between ethyl ether and water. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated to give a gum which crystallized when triturated with petroleum ether (boiling point range, 30°-60° C.). The solid was collected by filtration and recrystallized from isopropyl ether to yield 27.2 g (67%) of off-white solid, mp 73°-75° C. (lit1 mp 77° C.).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([F:17])[C:11]=1[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:7][NH2:8])#[CH:3].CN1CCOCC1.[CH3:25][C:26]1[C:31]([CH:32]=[CH:33][C:34](O)=[O:35])=[CH:30][CH:29]=[C:28]([C:37]([F:40])([F:39])[F:38])[N:27]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1>[C:2]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([F:17])[C:11]=1[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:7][NH:8][C:34](=[O:35])[CH:33]=[CH:32][C:31]1[C:26]([CH3:25])=[N:27][C:28]([C:37]([F:38])([F:39])[F:40])=[CH:29][CH:30]=1)#[CH:3]
Reactant: Cc1nc(C(F)(F)F)ccc1C=CC(=O)O
Reactant: C#Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2C)cc(F)c1NS(C)(=O)=O
Reaction time: 0.08 h
Yield: 75.2 %

Procedure:
To a suspension of 3-ethynyl-5-fluoro-4-methansulfonylaminobenzylamine hydrochloride (73 mg, 0.26 mmol) in THF (5 mL) was added N-methylmorpholine (43 μL, 0.39 mmol). After stirring for 5 minutes, 3-(2-methyl-6-trifluoromethylpyridin-3-yl)acrylic acid (60 mg, 0.26 mmol) and 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMTMM, 73 mg, 0.26 mmol) were added. The mixture was stirred at room temperature overnight, concentrated under reduced pressure, and diluted with EtOAc and water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by recrystallization from EtOAc/hexane to give N-(3-ethynyl-5-fluoro-4-methanesulfonylaminobenzyl)-3-(2-methyl-6-trifluoromethylpyridin-3-yl)acrylamide (89 mg, 75.5%) as solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.C(N(CC)CC)C.[CH3:20][C:21](=[CH2:24])[CH2:22][NH2:23]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][CH2:22][C:21]([CH3:24])=[CH2:20])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: C=C(C)CN
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=C(C)CNc1nc(Cl)nc2c(C)csc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
In DMF, 700 mg (3.4 mol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine was dissolved, and 759 mg (7.5 mmol) of triethylamine was added thereto, followed by adding 404 mg (3.8 mmol) of 2-methyl-2-propenylamine thereto, under ice cooling. The reaction solution was stirred at 0° C. for 1 hour and allowed to resume room temperature, followed by stirring for further 1 hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by a silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 687 mg (yield: 79.3%) of the title compound.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C@H:6]([CH3:18])[CH2:5][CH2:4]1)#[CH:2].Br[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1.C(N(CC)CC)C>CCOC(C)=O.[Cu]I.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:26][C:23]1[CH:24]=[CH:25][C:20]([C:2]#[C:1][C@@H:3]2[CH2:4][CH2:5][C@@H:6]([CH3:18])[N:7]([CH2:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[CH2:8]2)=[N:21][CH:22]=1
Reactant: Fc1ccc(Br)nc1
Reactant: C#C[C@@H]1CC[C@@H](C)N(Cc2ccc(OC)cc2)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(CN2C[C@H](C#Cc3ccc(F)cn3)CC[C@H]2C)cc1
Temperature: 90 °C

Procedure:
A solution of (2R,55)-5-ethynyl-1-(4-methoxybenzyl)-2-methylpiperidine (284 mg, 1.17 mmol), 2-bromo-5-fluoropyridine (226 mg, 1.28 mmol), copper (I) iodide (67 mg, 0.35 mmol), and triethylamine (2.12 mL, 15.2 mmol) was purged subsurface with nitrogen. Palladium tetrakis (135 mg, 0.117 mmol) was added and the reaction was capped and heated at 90° C. overnight. The reaction was diluted with EtOAc and washed with water and then brine. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting with 0-85% EtOAc in hexanes to provide 5-fluoro-2-{[(3S,6R)-1-(4-methoxybenzyl)-6-methylpiperidin-3-yl]ethynyl}pyridine as a yellow oil, which gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 339.2 for M+H+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>>[CH3:11][Si:12]([C:15]#[C:16][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2)([CH3:14])[CH3:13]
Reactant: C#C[Si](C)(C)C
Reactant: Ic1ccc2[nH]ncc2c1
Product: C[Si](C)(C)C#Cc1ccc2[nH]ncc2c1
Yield: 45.8 %

Procedure:
In an adaption of GP 8a, 5-Iodo-1H-indazole (0.98 g, 4.02 mmol) was reacted with trimethylsilyl acetylene (0.60 mL, 4.22 mmol) at 90° C. for 5 h to give 395 mg (46%) of pure 5-(trimethylsilyl)ethynyl-1H-indazole.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[CH:6]=1.[OH-].[K+].O>C1COCC1.CO>[CH3:12][C:7]1[CH:6]=[C:5]([C:4]#[CH:3])[CH:10]=[C:9]([CH3:11])[CH:8]=1
Reactant: Cc1cc(C)cc(C#C[Si](C)(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cc(C)cc(C)c1
Reaction time: 1 h
Yield: 82.7 %

Procedure:
A solution of crude 1-trimethylsilyl-2-(3,5-dimethylphenyl)acetylene (105 mmol, theoretical maximum) in THF (70 mL) and MeOH (280 mL) was cooled in an ice/water bath during addition of 8N KOH (16 mL, 128 mmol) and water (25 mL) and the reaction was then removed from ice/water bath. After 1 h, approximately half of the organic solvent was removed in vacuo. Hexanes (1 L) and water (400 mL) were added. The organic layer was washed with saturated brine, dried (Na2SO4), and concentrated to give 11.3 g of 1-(3,5-dimethylphenyl)acetylene as a brown oil:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([CH:16]=O)[CH:13]=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[O:19]([NH2:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:20][O:19][N:21]=[CH:16][C:12]1[CH:13]=[N:14][CH:15]=[C:10]([C:9]#[C:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:11]=1
Reactant: O=Cc1cncc(C#Cc2cccc(F)c2)c1
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CON=Cc1cncc(C#Cc2cccc(F)c2)c1
Temperature: 25 °C
Yield: 47 %

Procedure:
Heat a mixture of 5-(3-fluorophenylethynyl)-pyridine-3-carbaldehyde, (prepared essentially as described in EXAMPLE 89), (90 mg, 0.38 mmol) and methoxylamine hydrochloride (160 mg, 3.02 mmol) and potassium carbonate (260 mg, 1.89 mmol) in ethanol at 80° C. overnight. Cool to room temperature, filter solids and concentrate. Purify the residue by silica gel chromatography, eluting with 5:45:45 ethyl acetate:chloroform:hexanes, to give the title compound as a white solid (45 mg, 47%).