Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([CH2:12][CH2:13][OH:14])=[C:7]([CH3:15])[C:6]=2[CH:16]=1.[H-].[Na+].Br[CH:22]([CH3:24])[CH3:23]>CN(C=O)C>[OH:14][CH2:13][CH2:12][C:8]1[C:9](=[O:11])[O:10][C:5]2[CH:4]=[C:3]([O:17][CH3:18])[C:2]([O:1][CH:22]([CH3:24])[CH3:23])=[CH:16][C:6]=2[C:7]=1[CH3:15]
Reactant: COc1cc2oc(=O)c(CCO)c(C)c2cc1O
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2oc(=O)c(CCO)c(C)c2cc1OC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
67 g (268 mmol) of 6-hydroxy-3-(2-hydroxyethyl)-7-methoxy-4-methyl-2H-1-benzopyran-2-one (Example 41) is carefully added, using an ice bath for cooling, to 11.8 g (295 mmol) of sodium hydride (60% in white oil) in 300 ml of DMF. The mixture is stirred for 1 hour at room temperature, and then 49.5 g (402 mmol) of 2-bromopropane is added dropwise and the mixture is stirred for 24 hours at 60° C. under nitrogen. After adding a further 3.33 g (83 mmol) of sodium hydride and 52.4 g (426 mmol) of 2-bromopropane, the mixture is stirred for a further 24 hours at 60° C. The solution is evaporated, extracted with ethyl acetate, and the organic phase is washed with water, dried with Na2SO4 and re-evaporated. The product is purified by column chromatography over silica gel 60 (eluent: ethyl acetate). Yield 53.3 g (68%); m.p. 110°-112° C. (from acetone/PE).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[C:24]([O:28][C:29](=[O:34])[C@@H:30]([NH2:33])[CH2:31][CH3:32])([CH3:27])([CH3:26])[CH3:25]>N1C=CC=CC=1.O>[C:24]([O:28][C:29](=[O:34])[C@@H:30]([NH:33][C:8]([C:3]1[C:2]([NH2:1])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:10])[CH2:31][CH3:32])([CH3:26])([CH3:25])[CH3:27]
Reactant: CC[C@H](N)C(=O)OC(C)(C)C
Reactant: Nc1cccnc1C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: c1ccncc1
Product: CC[C@H](NC(=O)c1ncccc1N)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
To a solution of 276 mg of 3-aminopyridine-2-carboxylic acid in pyridine (3.0 mL) is added 324 mg of 1,1′-carbonyldiimidazole. The mixture is stirred at room temperature for 2 h. Then 391 mg of (S)-2-amino-butyric acid tert-butyl ester hydrochloride is added and the mixture is stirred for 16 h at room temperature. Then the reaction mixture is diluted with water (1 mL) and concentrated. The residue is diluted with additional 5 mL water and the product is extracted with ethyl acetate (3×5 mL). The combined organic layers are washed with brine, dried (sodium sulfate) and concentrated. The residue is purified by flash chromatography on silica gel to give 218 mg (39%) of (S)-2-[(3-amino-pyridine-2-carbonyl)-amino]-butyric acid tert-butyl ester.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:11]=[C:12]([CH:35]=[CH:36][CH:37]=1)[C:13]([NH:15][C:16]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:17]=1[C:18]([O:20]C(C)(C)C)=[O:19])=[O:14])#[N:9]>C(Cl)Cl>[C:8]([C:10]1[CH:11]=[C:12]([CH:35]=[CH:36][CH:37]=1)[C:13]([NH:15][C:16]1[CH:28]=[C:27]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:26]=[CH:25][C:17]=1[C:18]([OH:20])=[O:19])=[O:14])#[N:9]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cccc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
0.5 mL of trifluoroacetic acid was added to 0.5 mL of methylene chloride solution containing 10 mg of tert-butyl 2-(3-cyanobenzamido)-4-phenylbenzoate and stirred at room temperature for 1 hour and 30 minutes. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 7.6 mg of 2-(3-cyanobenzamido)-4-phenylbenzoic acid as white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@@H:17]([NH2:19])[CH3:18])=[C:8]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:9]=2)[CH:4]=[CH:3]1.[NH2:20][C:21]1[N:26]=[C:25]([NH2:27])[C:24]([C:28]#[N:29])=[C:23](Cl)[N:22]=1.CCN(CC)CC>CN(C=O)C>[NH2:20][C:21]1[N:26]=[C:25]([NH2:27])[C:24]([C:28]#[N:29])=[C:23]([NH:19][C@H:17]([C:7]2[N:6]=[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:10]3=[CH:9][C:8]=2[CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH3:18])[N:22]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1C1CCOCC1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1C1CCOCC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 28.9 %

Procedure:
To a 20 mL vial were added (S)-1-(1-methyl-6-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (336 mg, 1.296 mmol), 2,4-diamino-6-chloropyrimidine-5-carbonitrile (242 mg, 1.425 mmol) and Et3N (1.8 mL, 13 mmol) in DMF (7 mL). The resulting yellow solution was heated to 90° C. and stirred overnight. The crude product was purified by preparative HPLC eluting with 25-50% ACN in water (with 0.05% ammonium bicarbonate). The fractions containing the desired product were combined and lyophilized to give the title compound as a white solid (147 mg, 28%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37-1.51 (m, 3 H), 1.58-1.87 (m, 3 H), 1.91-2.07 (m, 1 H), 3.04-3.18 (m, 1 H), 3.43-3.60 (m, 3 H), 3.77-3.88 (m, 3 H), 3.90-4.08 (m, 2 H), 5.64-5.80 (m, 1H), 6.39-6.54 (m, 3 H), 6.56-6.67 (m, 2 H), 6.82-6.96 (m, 1 H), 7.54-7.66 (m, 1 H), 7.81-7.96 (m, 1 H),); ESI-MS m/z [M+H]+ calc'd for C20H24N8O, 393; found 393.
Reaction SMILES: [ClH:1].[NH2:2][C:3](=[O:32])[CH2:4][N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)C(=O)OC(C)(C)C>>[ClH:1].[C:30]([C:27]1[CH:26]=[CH:25][C:24]([CH2:23][O:22][C:19]2[CH:20]=[CH:21][C:16]([C@@H:14]3[CH2:15][C@H:13]3[NH:5][CH2:4][C:3]([NH2:2])=[O:32])=[CH:17][CH:18]=2)=[CH:29][CH:28]=1)#[N:31]
Reactant: CC(C)(C)OC(=O)N(CC(N)=O)[C@@H]1C[C@H]1c1ccc(OCc2ccc(C#N)cc2)cc1
Agent: Cl
Product: N#Cc1ccc(COc2ccc([C@@H]3C[C@H]3NCC(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
HCl (2 M ethereal solution, 1 mL, 2 mmol) was added to a flask containing tert-butyl 2-amino-2-oxoethyl[(trans)-2-{4-[(4-cyanobenzyl)oxy]phenyl}cyclopropyl]carbamate (36 mg, 0.09 mmol) and the mixture was stirred at room temperature for 24 h. After removal of the solvent, the solid was washed with Et2O (2×2 mL) and vacuum dried, rendering 29 mg of 2-[((trans)-2-{4-[(4-cyanobenzyl)oxy]phenyl}cyclopropyl)amino]acetamide hydrochloride salt (white solid, 100% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:37])[CH2:27][CH2:28][NH:29]C(=O)OC(C)(C)C)[CH2:22][CH2:21]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:29][CH2:28][CH2:27][C:26]([N:23]1[CH2:22][CH2:21][N:20]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[C:4]=23)[CH2:25][CH2:24]1)=[O:37]
Reactant: CC(C)(C)OC(=O)NCCC(=O)N1CCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCC(=O)N1CCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
tert-Butyl 3-(4-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropylcarbamate (0.020 g, 0.035 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.5 mL) was then added and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness, dissolved in minimal DCM, and added to a stirring solution of 1M HCl in ether. The resulting solid product was filtered, washed with ether and dried to give the product N-(4-(4-(3-aminopropanoyl)piperazin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyri din-3-yl)nicotinamide (0.015 g, 74% yield) as the trihydrochloride salt. MS APCI (+) m/z 473 detected.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[O:19][C:20]([CH3:30])=[C:21]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:31][CH2:32][CH2:33][CH3:34])=O)C1C=CC=CC=1>[Pd].CO>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[O:19][C:20]([CH3:30])=[C:21]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OCCC)C2)oc1C
Agent: [Pd]
Solvent: CO
Product: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OCCC)C2)oc1C
Yield: 94 %

Procedure:
The same operation as in Example (95b) was performed using butyl cis(±)-2-(4-{[(benzyloxy)carbonyl]amino}-3-propoxypiperidin-1-yl)-5-methyl-1,3-oxazole-4-carboxylate obtained in Example (114a) (0.98 g, 2.1 mmol), 10% Pd/C (0.25 g) and methanol (15 mL), to obtain 0.67 g of the title compound as a light yellow oily substance (95%).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[N:17]=[CH:16][C:15]([OH:18])=[CH:14][N:13]=3)[CH:10]=2)[CH:5]=[C:4]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:3]=1.[H-].[Na+].[CH2:30](Br)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].O>CN(C=O)C>[CH2:30]([O:18][C:15]1[CH:14]=[N:13][C:12]([C:9]2[CH:10]=[C:11]3[C:6]([CH:5]=[C:4]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:3]=[C:2]3[F:1])=[CH:7][CH:8]=2)=[N:17][CH:16]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCOc1cc2ccc(-c3ncc(O)cn3)cc2c(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1cnc(-c2ccc3cc(OCCCCCCCC)nc(F)c3c2)nc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
10 mmol of 1-fluoro-7-(5-hydroxypyrimidin-2-yl)-3-octyloxyisoquinoline are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo, and the residue is chromatographed on silica gel, giving 9 mmol of 7-[5-(octyloxy)pyrimidin-2-yl]-1-fluoro-3-octyloxyisoquinoline. 1-Fluoro-7-(5-hydroxypyrimidin-2-yl)-3-alkyloxyisoquinolines can for example be reacted analogously to Example 3 with 2-fluoroalkyl sulfonates, 2,3-difluoroalkyl sulfonates, 3-alkyloxirane-2-methyl sulfonates, (ω-bromoalkyl)cyclopropanes or 1-bromodimethylsilanylalkanes.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]([CH3:16])([CH3:15])[C:10](=[O:14])[CH2:11][C:12]#[N:13].[Cl:17][C:18]1[CH:26]=[C:25]([S:27][CH3:28])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].CC(C)(O)C#N>ClCCl>[Cl:17][C:18]1[CH:26]=[C:25]([S:27][CH3:28])[CH:24]=[CH:23][C:19]=1[C:20](=[O:21])[CH:11]([C:12]#[N:13])[C:10](=[O:14])[C:9]([CH3:16])([CH3:15])[CH3:8]
Reactant: CSc1ccc(C(=O)Cl)c(Cl)c1
Reactant: CC(C)(C)C(=O)CC#N
Agent: CC(C)(O)C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ccc(C(=O)C(C#N)C(=O)C(C)(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.8 %

Procedure:
Triethylamine (1.78 g) was added to a stirred solution of 4,4-dimethyl-3-oxopentanenitrile (2.0 g) in dichloromethane and the mixture was stirred at room temperature for 2 hours. A solution of 2-chloro-4-methylsulphenylbenzoyl chloride (3.02 g) in dichloromethane was added and the mixture stirred at room temperature overnight. Acetone cyanohydrin (1.36 g) was added and the mixture stirred for 4 days, then filtered. The filtrate was washed with hydrochloric acid (2M), water, aqueous sodium bicarbonate solution, water, then dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue purified by column chromatography (hexane, ethyl acetate and acetic acid). The main fraction was washed with aqueous sodium hydroxide (2M), water, dried and evaporated to dryness to give 1-(2-chloro-4-methylsulphenylphenyl)-2-cyano-4,4-dimethylpentan-1,3-dione (COMPOUND 664, 0.16 g) as a white solid, m.p. 97°-99° C.
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:6]([SH:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C(N(CC)CC)C>[CH2:6]([S:18][CH:3]([CH3:4])[CH2:2][CH:1]=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: C/C=C/C=O
Reactant: CCCCCCCCCCCCS
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCSC(C)CC=O
Reaction time: 1.5 h

Procedure:
14.02 Grams of crotonaldehyde (0.20 mole) is added dropwise over a 40-minute period at 60° to 65° C. to a solution of 41.2 grams of n-dodecyl mercaptan (0.20 moles) and 0.66 grams of triethylamine after which heating and stirring are continued at 85° C. for 1.5 hours. Analysis of the reaction mixture indicates that the reaction is then substantially complete. The product is isolated as a light yellow liquid by stripping off the volatiles.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:39]1(=[O:49])[NH:43][C:42](=[O:44])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][N:43]2[C:39](=[O:49])[C:40]3[C:41](=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:42]2=[O:44])=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccc(Br)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Br)cc1)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 57 %

Procedure:
To a solution of 1,1-dimethylethyl [(1S)-2-(4-bromophenyl)-1-(hydroxymethyl)ethyl]carbamate (70.6 mmol), tripheylphosphine (84.7 mmol), and phthalimide (84.7 mmol) in anhydrous tetrahydrofuran (550 mL) at 0° C. was added dropwise diisopropyl azodicarboxylate (84.7 mmol) over 10 minutes. The reaction continued to stir allowing to warm to RT over 5 h. The reaction was then concentrated in vacuo and product was triturated out of solution using ethyl acetate (500 mL). The precipitate was filtered, washed with ethyl acetate (3×100 mL), and dried to afford the title product as a white solid (57%). ESMS [M+H]+: 460.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH2:24])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C.[CH3:32][C:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH:24][C:39]([C:33]2([CH3:32])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:40])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:11][CH2:10]1
Reactant: CC1(C(=O)Cl)CCCCC1
Reactant: COc1ccccc1N1CCN(C[C@H](N)Cc2ccccn2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(C[C@@H](Cc2ccccn2)NC(=O)C2(C)CCCCC2)CC1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
To a solution of (1R)-2-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-1-pyridin-2-ylmethyl-ethylamine (1.06.; 3.2 mmol, from Example 13) in dichloromethane (40 mL) at 0° C. was added triethylamine (0.90 mL; 6.5 mmol) and a solution of 1-methyl-1-cyclohexanecarbonyl chloride (520 mg.; 3.2 mmol) in dichloromethane (6 mL). The reaction mixture was stirred while allowing to warm to ambient temperature over 1 hour, washed sequentially with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered, and the solvent removed in vacuo. The crude residue was purified by flash chromatography on silica gel (2% methanol/chloroform) to yield the free base of the title compound as a clear oil (1.0 g.; 70%). Treatment with an equimolar amount of fumaric acid in ethanol afforded the fumarate salt as a white amorphous solid, m.p. 135–139° C.; MS (+) FAB [M+H]+ @ m/z 451; 1H NMR, 400 MHz, DMSO-d6. Analysis for C27H38N4O2.C4H4O4 Calculated: C, 65.70; H, 7.47; N, 9.89 Found: C, 65.29; H, 7.69; N, 9.77
Reaction SMILES: [CH2:1]([N:8]([CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:9][C:10](O)([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:29])CC>ClCCl>[CH2:1]([N:8]([CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:9][C:10]([F:29])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(O)CN(Cc1ccccc1)C1CCCC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(C)(F)CN(Cc1ccccc1)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
To ethyl 3-(benzyl(cyclopentyl)amino)-2-hydroxy-2-methylpropanoate (4.2 g, 14 mmol) in 50 ml of dichlormethane at −78° C., was added DAST (2.7 ml, 21 mmol) dropwise. The reaction mixture was gradually warmed up to room temperature and stirred for 2 h. It was then diluted to dichloromethane, washed by NaHCO3, brine and water. Organic extract dried and concentrated to a residue, which was purified on silica gel column chromatographically (Hex/EtOAc=40:1 to 20:1) to give 3.5 g product (83%) as light yellow liquid. [M+H] calc'd for C18H26FNO2, 308; found 308.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH2:9])=[O:8])=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>>[Cl:10][CH2:11][C:12]1[N:9]=[C:7]([C:5]2[O:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[O:8][CH:14]=1
Reactant: O=C(CCl)CCl
Reactant: Cc1ccc(C(N)=O)o1
Product: Cc1ccc(-c2nc(CCl)co2)o1
Yield: 38 %

Procedure:
In substantially the same manner as in Reference Example 47, 5-methyl-2-furancarboxamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(5-methyl-2-furyl)oxazole. The yield was 38%. Recrystallization from diethyl ether-hexane gave. Colorless needles, mp 93-94° C.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2].[Cl:13][CH2:14][Si:15](Cl)([CH3:17])[CH3:16]>>[CH2:1]([NH:3][C:4](=[O:12])[C:5]1[C:10]([Si:15]([CH2:14][Cl:13])([CH3:17])[CH3:16])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2]
Reactant: CCNC(=O)c1ccccc1Cl
Reactant: C[Si](C)(Cl)CCl
Product: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)CCl

Procedure:
The title compound was prepared from the compound of Example f and 2.0 eq (chloromethyl)dimethylsilyl chloride according to General Method C. Recrystallization from ethyl acetate gave 3.0 g of the desired compound as a white solid, a 52% yield. m.p. 88-89° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[C:28]1[N:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:34]([C:31]1[CH:30]=[N:29][C:28]([N:23]2[CH2:24][CH2:25][CH:20]([C@@:18]3([CH3:26])[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:21][CH2:22]2)=[N:33][CH:32]=1)[CH3:35]
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(-c3ccc(S(C)(=O)=O)cc3)ncc2O1
Reactant: CCc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCc1cnc(N2CCC([C@]3(C)Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ncc4O3)CC2)nc1

Procedure:
The title compound is prepared from (S)-5-(4-methanesulfonyl-phenyl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 32; the configuration of the stereocenter is arbitrarily assigned) and 2-chloro-5-ethylpyrimidine in dimethylsulfoxide at 105° C. in the presence of potassium carbonate. LC (method 4): tR=1.09 min; Mass spectrum (ESI+): m/z=479 [M+H]+.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]1([NH2:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.F[C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27].[NH4+].[Cl-]>C1COCC1>[F:25][C:23]1[CH:22]=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[C:19]([NH:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:24]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1Nc1ccccc1
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
LiHMDS (1.0M in THF, 12.57 mL) was added dropwise to a stirred solution of phenylamine (600 μL, 6.60 mmol) in ahydrous THF (10 mL) under a nitrogen atmosphere at −78° C. After 30 min, a solution of 2,4-difluoro-1-nitrobenzene (690 μL, 6.29 mmol) in THF (10 mL) was added and stirring was continued for 1 h. The solution was poured into an aqueous solution of NH4Cl (100 mL) and extracted with EtOAc (×3). The combined organic layers were dried and concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane) affording (5-Fluoro-2-nitrophenyl)phenylamine as a yellow/orange solid (1.37 g, 94%). 1H NMR (CDCl3, 400 MHz): δ 9.66 (1H, s), 8.28 (1H, dd, J=9.48, 6.01 Hz), 7.47 (2H, t, J=7.63 Hz), 7.36-7.24 (3H, m), 6.82 (1H, dd, J=11.38, 2.61 Hz), 6.53-6.44 (1H, m).
Reaction SMILES: N.[C:2]1([CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH3:28])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[C:9]#[N:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(OC)(O[CH3:33])(=O)=O>[N+]([O-])([O-])=O.[Fe+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>[C:2]1([C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH3:28])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)([CH3:33])[C:9]#[N:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCC(c2ccc(OC(C#N)c3ccccc3)cc2)c2ccccc21
Reactant: COS(=O)(=O)OC
Agent: [Fe+3]
Agent: N
Agent: O=[N+]([O-])[O-]
Product: CN1CCC(c2ccc(OC(C)(C#N)c3ccccc3)cc2)c2ccccc21
Reaction time: 2 h

Procedure:
At -40°, 50 mg. of iron (III) nitrate and then, under agitation, 2.3 g. of Na are dissolved in 100 ml. of liquid ammonia. After two hours of agitation, 3.54 g. of 2-phenyl-2-[4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxy]-acetonitrile is added thereto, the mixture stirred for 30 minutes, and then 19.2 ml. of dimethyl sulfate is added dropwise within one hour. The mixture is further agitated overnight at -35° and then combined dropwise with another 10 ml. of dimethyl sulfate. After the ammonia has been evaporated, the residue is combined with water and extracted with ether. The crude 2-phenyl-2-[4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxy]-propionitrile obtained after the evaporation of the ether is refluxed for 40 hours with 3 g. of KOH in 30 ml. of ethanol and 3 ml. of water. The mixture is concentrated by evaporation, mixed with water, extracted with ether, hydrochloric acid is added to pH 5, and the acid Ih is thus produced.
Reaction SMILES: [CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]C)=[O:24])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH2:27][CH3:28])[CH2:7][CH2:6]1)([CH3:3])[CH3:2].[OH-].[Na+].O.CC#N>C(O)C.O1CCCC1>[CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH2:27][CH3:28])[CH2:7][CH2:6]1)([CH3:3])[CH3:2]
Reactant: CCc1cc(C#Cc2ccc(CC(=O)OC)cc2)ccc1C1(OC(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC#N
Solvent: O
Product: CCc1cc(C#Cc2ccc(CC(=O)O)cc2)ccc1C1(OC(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
Using General Procedure I; a solution of methyl {4-[4-(1-isopropoxycyclopropyl)-3-ethyl-phenylethynyl]-phenyl}-acetate (Compound 96, 156.0 mg, 0.41 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up and isolation by HPLC (partisil 10-pac, 10% H2O/CH3CN) afforded 85.0 mg (57%) of the title compound.