Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.C[O:18][C:19](=O)[N:20]=[C:21](SC)[C:22]([C:36]1[CH:37]=[C:38]2[C:43](=[C:44]([O:46][CH3:47])[CH:45]=1)[O:42][CH2:41][CH2:40][CH2:39]2)=[N:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:34]=[C:33]([CH3:35])[O:32][N:31]=2)=[CH:26][CH:25]=1>CN(C=O)C>[F:1][C:2]1[C:3]([N:8]2[C:19](=[O:18])[NH:20][C:21]([CH:22]([C:36]3[CH:37]=[C:38]4[C:43](=[C:44]([O:46][CH3:47])[CH:45]=3)[O:42][CH2:41][CH2:40][CH2:39]4)[NH:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[N:34]=[C:33]([CH3:35])[O:32][N:31]=4)=[CH:26][CH:25]=3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc2c(c(OC)c1)OCCC2
Reactant: NNc1ncccc1F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccc3F)c(=O)[nH]2)cc2c1OCCC2
Temperature: 85 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
After adding 25 mg of (3-fluoropyridin-2-yl)hydrazine and 50 μl of triethylamine to a solution of 100 mg of {2-(8-methoxychroman-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (24a)) in 2 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature for 2 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 2-(3-fluoro-pyridin-2-yl)-5-{(8-methoxychroman-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2,4-dihydro-[1,2,4]triazol-3-one (60 mg).
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:20][F:21])[CH:8]=[C:7]([C:9](O)=[O:10])[C:6]2[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:5]=2[O:4]1.[C:22]([CH2:24][CH2:25][NH2:26])#[N:23].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:22]([CH2:24][CH2:25][NH:26][C:9]([C:7]1[C:6]2[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:5]=2[O:4][C:3]([CH2:2][F:1])([CH2:20][F:21])[CH:8]=1)=[O:10])#[N:23]
Reactant: N#CCCN
Reactant: O=C(O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CCCNC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 85.5 %

Procedure:
To an ice-cooled mixture of 2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran-4-carboxylic acid (0.20 g) and tetrahydrofuran (3 ml), N,N′-carbonyldiimidazole (0.12 g) was added with stirring and the mixture was stirred for 1 hour. Thereafter, 2-cyanoethylamine (0.06 g) was added and the mixture was stirred first under cooling with ice for 1 hour, then at room temperature for 12 hours. To the reaction mixture, an aqueous solution of potassium carbonate was added, followed by extraction with methylene chloride; the organic layer was washed with water and dried; the solvent was distilled off and the resulting residue was recrystallized with a solvent consisting of a mixture of ethyl acetate and hexane, thereby giving the titled compound (0.20 g) having a melting point of 135-136° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]=1>CO>[CH3:1][O:2][C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]=1
Reactant: C[O-]
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc(OC)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
Sodium methoxide in methanol (82.65 mL of a 1 M solution) is added slowly to a stirred solution of methyl 6-chloro-5-nitronicotinate (17 g) in anhydrous methanol (250 mL) and the mixture stirred for 8 hours. The mixture is concentrated, the residue treated with water and then extracted into ethyl acetate. The extracts are washed with water, treated with decolourising charcoal and dried (MgSO4). Concentration afforded methyl 6-methoxy-5-nitronicotinate (9.8 g) as an orange solid. Recrstallisation from cyclohexane afforded white needles, m.p.118-9° C.
Reaction SMILES: [Si]([O:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][O:13][C:14]1[C:15]([O:34][CH3:35])=[CH:16][CH:17]=[C:18]2[C:23]=1[O:22][C:21](=[O:24])[CH:20]=[C:19]2[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=1[Cl:33])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[Cl:33][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([Cl:32])[C:26]=1[NH:25][C:19]1[C:18]2[C:23](=[C:14]([O:13][CH2:12]/[CH:11]=[CH:10]\[CH2:9][OH:8])[C:15]([O:34][CH3:35])=[CH:16][CH:17]=2)[O:22][C:21](=[O:24])[CH:20]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OC/C=C\CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OC/C=C\CO

Procedure:
A solution of (Z)-8-(4-(tert-butyldimethylsilyloxy)but-2-enyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one and TBAF (2 mL, 2M THF) was maintained at rt for 18 h, poured into water, and then extracted with EtOAc. The extract was dried, filtered, concentrated, and purified by reverse-phase HPLC (25→100% MeCN/H2O) to give (Z)-4-(3,5-dichloropyridin-4-ylamino)-8-(4-hydroxybut-2-enyloxy)-7-methoxy-2H-chromen-2-one: 1H NMR (400 MHz, CD3OD-d6): δ 8.71 (s, 2H), 7.85 (d, 1H), 7.18 (d, 1H), 7.83 (m, 2H), 4.77 (m, 3H), 4.15 (d, 2H), 4.01 (s, 3H); MS (ESI): 422.8.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]([OH:36])=[C:19]([NH:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=3[Cl:35])=[O:26])[CH:20]=[CH:21][C:22]=2[Cl:23])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[Cl:23][C:22]1[CH:21]=[CH:20][C:19]([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2[Cl:35])=[O:26])=[C:18]([OH:36])[C:17]=1[S:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)(=[O:15])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c(Cl)ccc(NC(=O)Nc3cccc(Cl)c3Cl)c2O)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Cl)c(S(=O)(=O)N2CCNCC2)c1O)Nc1cccc(Cl)c1Cl
Yield: 66 %

Procedure:
Following the general procedure for Boc deprotection outlined in example 36, N-[3-[4-(tert-butoxycarbonyl)piperazin-1-yl]sulfonyl-4-chloro-2-hydroxyphenyl]-N′-(2,3-dichlorophenyl) urea (20 mg, 0.034 mmol) was stirred in trifluoroacetic acid to form the desired product (13.5 mg, 66%). EI-MS (m/z) 481.7, 483.7, 485.7 (M+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:33])([CH3:32])[C@@H:11]([O:22]CC1C=CC(OC)=CC=1)[C:12]([O:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:13])(=[O:7])=[O:6].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl.O>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:33])([CH3:32])[C@@H:11]([OH:22])[C:12]([O:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:13])(=[O:6])=[O:7]
Reactant: COc1ccc(CO[C@@H](C(=O)OCc2cccnc2)C(C)(C)COS(=O)(=O)CCCCl)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(COS(=O)(=O)CCCCl)[C@@H](O)C(=O)OCc1cccnc1
Yield: 8.8 %

Procedure:
Following the general procedure for the oxidative cleavage of (4-methoxy)benzyl ethers of Description 19, 3-pyridylmethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoate (37a) (0.30 g, 0.60 mmol) dissolved in a mixture of dichloromethane (DCM) and water (10:1) (5 mL) was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (190 mg, 0.84 mmol). After work-up, the crude material was purified by silica gel column chromatography using ethyl acetate (EtOAc) to provide 20 mg (9% yield) of the title compound (37b) as a white solid. 1H NMR (400 MHz, CDCl3): δ=0.96 (s, 3H), 1.08 (s, 3H), 2.29-2.36 (m, 2H), 3.28-3.32 (m, 2H), 3.67-3.70 (m, 2H), 3.98 (d, J=9.2 Hz, 1H), 4.08 (s, 1H), 4.15 (d, J=9.2 Hz, 1H), 5.20 (s, 2H), 7.32-7.35 (m, 1H), 7.72-7.75 (m, 1H), 8.60-8.65 (m, 2H) ppm. MS (ESI) m/z: 379.99 (M+H)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[S:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][CH:11]=1.ClC1C=CC=C(C(OO)=[O:33])C=1.CCCCCC.C(OCC)(=O)C>C(Cl)(Cl)Cl.C(N(CC)CC)C>[F:24][C:2]([F:1])([F:23])[S:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:22])=[C:14]([S:16]([CH2:17][C:18]([F:19])([F:20])[F:21])=[O:33])[CH:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(OCCCCCSC(F)(F)F)cc1SCC(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(OCCCCCSC(F)(F)F)cc1S(=O)CC(F)(F)F
Reaction time: 1 h
Yield: 76.4 %

Procedure:
In 100 ml of chloroform was dissolved 0.98 g (2.5 mmol) of 5-trifluoromethylthiopentyl-{4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}ether. Thereto was added, in portions in about 10 minutes, 0.58 g (2.5 mmol) of 3-chloroperbenzoic acid (purity: about 75%) at room temperature. A reaction was carried out for 1 hour. After confirmation of the completion of the reaction, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane:ethyl acetate:triethylamine=5:1:0.01), to obtain 0.78 g (yield: 77%) of an intended product.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[S:23][C:24]([CH3:26])=[CH:25][C:16]=12>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH:4][C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[S:23][C:24]([CH3:26])=[CH:25][C:16]=12
Reactant: Cc1cc2c(Cl)c(C#N)cnc2s1
Reactant: COc1cc(N)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3sc(C)cc23)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
A mixture of 2,4-dichloro-5-methoxyaniline (0.15 g, 0.73 mmol) and 60% sodium hydride (50 mg, 1.25 mmol) in 15 mL of tetrahydrofuran is heated at reflux for 1 hour. The solution is cooled and 4-chloro-2-methylthieno[2,3-b]pyridine-5-carbonitrile (0.06 g, 0.29 mmol) is added. The reaction mixture is heated at reflux for 3 hours then allowed to stir at room temperature overnight. The resultant black solution is partitioned between ethyl acetate and water. The organic layer is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 3:7 ethyl acetate:hexane The fractions containing product are combined and concentrated. Diethyl ether is added and the insoluble material collected by filtration to provide 79 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-methylthieno[2,3-b]pyridine-5-carbonitrile as a tan solid, mp 179-181° C.; 1H NMR (DMSO-d6) δ 2.57 (s, 3H), 3.85 (s, 3H), 7.32 (s, 1H), 7.39 (s, 1H), 7.74 (s, 1H), 8.35 (s, 1H), 9.61 (s, 1H); MS 362.1 (M−H)−.
Reaction SMILES: [Na+].[NH:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17]([O-:20])(=[O:19])=[O:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>Cl.C(#N)C>[NH:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17]([OH:20])(=[O:18])=[O:19])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)([O-])CCCCCCCCNc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: O=S(=O)(O)CCCCCCCCNc1ccccc1

Procedure:
8-Anilino-1-octanesulfonic acid sodium salt (10.0 g, 0.5 mol) is dissolved in aqueous 0.5 M HCl solution (30 mL) and acetonitrile (400 mL) is added to the solution. The solution is filtered and the filtrate is kept in a refrigerator overnight to obtain 8-anilino-1-octanesulfonic acid as white precipitates. The precipitates are collected by filtration, dissolved in water, neutralized by aniline, and then concentrated under reduced pressure to give a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([O:13]S(C2C(C)=CC=CC=2)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][C:25]1[NH:26][C:27]2[C:32]([C:33]=1[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])=[CH:31][C:30](O)=[CH:29][CH:28]=2.C(=O)([O-])[O-].[K+].[K+].CCCCCC.C(OCC)(=O)C>C(#N)C.CN(C=O)C>[CH2:37]([O:36][C:34]([C:33]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:13][CH:10]3[CH2:11][CH2:12][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9]3)[CH:31]=2)[NH:26][C:25]=1[CH3:24])=[O:35])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cc1[nH]c2ccc(O)cc2c1C(=O)OCc1ccccc1
Reactant: Cc1ccccc1S(=O)(=O)OC1CCN(Cc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1[nH]c2ccc(OC3CCN(Cc4ccccc4)C3)cc2c1C(=O)OCc1ccccc1
Reaction time: 24 h
Yield: 18 %

Procedure:
1-benzyl-3-toluenesulfonyloxypyrrolidine (0.662 g, 2.00 mmol, 1.0 eq, see Bio. Org. & Med. Chem. Lett., 1999;9:1379) was dissolved in dry acetonitrile (20 mL) and DMF (1 mL), and treated with 2-methyl-3-benzyloxycarbonyl-5-hydroxyindole (0.562 g, 2.00 mmol, 1 cq) and potassium carbonate (0.276 g, 2.0 mmol, 1.0 eq.). The reaction was heated to reflux and followed by TLC (hexane/ethyl acetate 1/1). After 24 hours, the reaction was loaded directly on silica gel and chromatographed (hexane/ethyl acetate 1/1) to afford a yellow oil: 0.162 g (18% yield). This was converted to the corresponding hydrochloride salt: LC/MS (ESI+) 441 (M+1), Anal. (C28H28N2O3.HCl.1.6H2O) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([C:22]([F:33])([F:32])[F:21])[CH:28]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3cccc(C(F)(F)F)c3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 3-trifluoromethyl-phenylboronic acid (44 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:49]([CH3:50])=[CH:48][C:39]([O:40][CH:41]2[CH2:45][CH2:44][N:43]([CH3:46])[C:42]2=[O:47])=[CH:38][C:37]=1[CH3:51].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:51][C:37]1[CH:38]=[C:39]([O:40][CH:41]2[CH2:45][CH2:44][N:43]([CH3:46])[C:42]2=[O:47])[CH:48]=[C:49]([CH3:50])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:13]=[CH:14][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:24]=2[CH:25]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(OC2CCN(C)C2=O)cc(C)c1Br
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OC6CCN(C)C6=O)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 3-(4-bromo-3,5-dimethylphenoxy)-1-methylpyrrolidin-2-one following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.60 min; Mass spectrum (ESI+): m/z=560 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:10]([C:11](=O)[C:12]#[C:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.Cl.[CH:29]1([NH:34][C:35]([NH2:37])=[NH:36])[CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.CCOCC>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:10]([C:11]3[CH:12]=[C:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:37]=[C:35]([NH:34][CH:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[N:36]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: N=C(N)NC1CCCC1
Reactant: O=C(C#Cc1ccccc1)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2cc(-c3ccccc3)nc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a solution of 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-3-phenyl-2-propyn-1-one (246 mg, 0.66 mmol) in N,N-dimethylformamide (10 mL) was added N-cyclopentylguanidine hydrochloride (320 mg, 1.97 mmol) followed by solid potassium carbonate (274 mg, 1.97 mmol). The resultant mixture was heated to 75° C. for 4 hours The reaction mixture was cooled to room temperature, diluted with water and ether was added. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (4:1, hexanes:ethyl acetate) provided 4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-6-phenyl-2-pyrimidinamine (265 mg, 84%) as a solid. 1H NMR (CDCl3) δ 8.49 (d, 1H), 7.80–7.75 (m, 4H), 7.44–7.41 (m, 3H), 7.33 (m, 1H), 7.22 (t, 2H), 7.09 (d, 1H), 6.82 (s, 1H), 5.25 (d, 1H), 4.49 (m, 1H), 2.22–2.12 (m, 2H), 1.88–1.61 (m, 6H); 19F NMR (CDCl3) δ −112.89; MS m/z 484 (M+1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]=[O:11])=[CH:2]1.O1CCCC1.[CH:17]1([Mg]Br)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.Cl>O1CCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[OH:11])=[CH:2]1
Reactant: Br[Mg]C1CCCCC1
Reactant: O=Cc1csc2ccccc12
Agent: Cl
Solvent: C1CCOC1
Product: OC(c1csc2ccccc12)C1CCCCC1
Reaction time: 1.5 h
Yield: 69 %

Procedure:
To a solution (40 mL) of 1-benzothiophene-3-carbaldehyde (2.25 g) in tetrahydrofuran was added dropwise 1.0M cyclohexylmagnesium bromide tetrahydrofuran solution (20.9 mL) at 0° C., and the mixture was stirred for 1.5 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:17, volume ratio) to give the title object compound (2.37 g, 69%) as an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:21])([CH3:20])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:19])[CH2:8][CH:9]=[CH:10][C:11]([CH3:18])=[CH:12][C:13](OCC)=[O:14].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[CH3:1][O:2][C:3]([CH3:20])([CH3:21])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:19])[CH2:8][CH:9]=[CH:10][C:11]([CH3:18])=[CH:12][CH2:13][OH:14]
Reactant: CCOC(=O)C=C(C)C=CCC(C)CCCC(C)(C)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COC(C)(C)CCCC(C)CC=CC(C)=CCO
Reaction time: 2 h

Procedure:
To a solution of 6.2 g. of ethyl 11-methoxy-3,7,11-trimethyldodeca-2,4-dienoate in 80 ml. of dry ether is added 3.2 ml. of lithium aluminum hydride (3.9M) in ether slowly, at -78°, with stirring, under argon. The mixture is stirred for 2 hours at -78° and then warmed to about -50°. After 1 hour, the mixture is warmed slowly to about -10° over 4 hours. Then there is added 0.5 ml. of water, 0.5 ml. of 15% sodium hydroxide and 1.5 ml. of water. The mixture is then poured into water, washed with water and brine, dried over magnesium sulfate and evaporated to yield 11-methoxy-3,7,11-trimethyldodeca-2,4-dien-1-ol.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Mg]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.BrCCCCCC1CCCCC1.[Mg].BrCCBr.[CH3:31][Si:32]([CH3:41])([CH3:40])[C:33]1[O:37][CH:36]=[C:35]([CH:38]=[O:39])[CH:34]=1.S(=O)(=O)(O)O>O1CCCC1>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:38]([C:35]2[CH:34]=[C:33]([Si:32]([CH3:41])([CH3:40])[CH3:31])[O:37][CH:36]=2)[OH:39])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Br[Mg]CCCCCC1CCCCC1
Reactant: C[Si](C)(C)c1cc(C=O)co1
Agent: BrCCCCCC1CCCCC1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc(C(O)CCCCCC2CCCCC2)co1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-cyclohexylpentyl-magnesium bromide (1.32 mmol, prepared from 0.31 g., 1.32 mmol 1-bromo-5-cyclohexylpentane and 2.88 mmol magnesium, with a catalytic amount of 1,2-dibromoethane as initiator), in 2.5 ml anhydrous tetrahydrofuran at 0° under argon was added dropwise 5-trimethylsilyl-3-furaldehyde (0.23 g., 1.40 mmol) in 2.5 ml tetrahydrofuran. This solution was allowed to warm to room temperature, stirred for one hour, and then poured over crushed ice containing several drops of concentrated sulfuric acid. The resulting mixture was partitioned between ethyl ether and 5% sodium bicarbonate. The organic portion was washed with water, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give a colorless oil (0.173 g.). This material was purified by flash chromatography (silica, 90% petroleum ether/ethyl ether) to give the desired alcohol.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=1.[Cl:22][C:23]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:24]=1C(OC)=O>C1COCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([C:30]2[CH:29]=[CH:24][C:23]([Cl:22])=[CH:32][C:31]=2[Cl:33])=[O:21])=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(Cl)cc1Cl
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Temperature: -60 °C
Reaction time: 1.5 h

Procedure:
A 5 L round bottom flask equipped with an addition funnel, N2 inlet, thermometer and a mechanical stirrer was charged with 387 mL of 1M sodium bis-trimethylsilylamide in TBF and cooled to −60° C. A solution of 230 g (1.35 mol) of 4-chlorophenylacetic acid in 300 mL of THF was added keeping the temperature below −40° C. After stirring the mixture for 90 min at −70° C., 264 g (1.29 mol) of methyl 2,4-dichlorobenzoate was added over 20 min. The solution was stirred for 40 min at −70° C., the cooling bath was removed and the mixture was allowed to warm to 0° C. Reaction was quenched by pouring into 4 L of 2N HCl and ice and extracted with ether. Each ether layer was washed with saturated NaHCO3, brine, dried with MgSO4 and filtered through a 2″ plug of silica gel. The filtrate was concentrated to ca. 1 lit of a slushy liquid which was diluted with 1 L of hexane and cooled in a refrigerator. The solid formed was filtered, washed with hexane and dried. A second crop was isolated by concentrating the mother liquors. The two crops of crystals were combined.
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.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[C:24]=1[F:32])#[N:16]>>[F:32][C:24]1[C:25]([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:26][CH:27]=[CH:28][C:23]=1[C:18]1[C:17]([C:15]#[N:16])=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1ccccc1-c1cccc(B(O)O)c1F
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Product: N#Cc1ccccc1-c1cccc(-c2cnc3nc(C(F)(F)F)ccn23)c1F
Yield: 18 %

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 2′-cyano-2-fluorobiphenyl-3-boronic acid as described in Example 1 to give 2′-fluoro-3′-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile as an off-white solid (70 mg, 18%): δH (400 MHz, DMSO) 7.60-7.64 (2H, m), 7.70 (1H, d, J 1), 7.76 (1H, d, J 2), 7.83 (1H, s), 7.87-7.91 (2H, m), 8.05 (1H, dd, J 7 and 1), 8.35 (1H, s), 9.13 (1H, dd, J 7 and 3); m/z (ES+) 383 (M++H).