Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.S(=O)(=O)(O)O.[Br:19]([O-])(=O)=O.[K+]>O>[Br:19][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=1[O:3][C:2]([F:12])([F:13])[F:1])[C:8]#[N:9]
Reactant: N#Cc1ccc(OC(F)(F)F)cc1
Reactant: [O-][Br+2]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: N#Cc1ccc(OC(F)(F)F)c(Br)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
4-(Trifluoromethoxy)benzonitrile (5.57 g, 29.8 mmol) was added to 50% aqueous sulfuric acid (60 ml) and the mixture was warmed to 80° C. Potassium bromate (5.97 g, 35.7 mmol) was added in portions over 2 hours and the mixture was stirred at 80° C. for a further 2 hours. The mixture was cooled to room temperature and poured into water (200 ml). The mixture was extracted with ethyl acetate (3×200 ml) and the combined organic layers were dried (MgSO4) and evaporated under reduced pressure to give the title compound as an orange oil (6.0 g) which contained 4-trifluoromethoxy)benzonitrile (ca. 30%) as determined by 1H NMR. 1H NMR (250 MHz, CDCl3) δ 7.97 (1H, d, J=2.0 Hz), 7.68 (1H, dd, J=8.5, 2.0 Hz), and 7.42 (1H, dq, J=8.5, 1.5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:21]1[N:29]=[C:28]([F:30])[CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24]>C1COCC1>[F:30][C:28]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[C:21]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=2[F:1])[N:29]=1
Reactant: O=C(O)c1ccc(F)nc1F
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(F)nc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To solution of 2-fluoro-4-iodoaniline (0.82 g, 3.46 mmol) in THF (10 mL) at −78° C. LiHMDS (6.00 mL, 6.60 mmol) was added. After stirring for 15 min, 2,6-difluoronicotinic acid (0.50 g, 3.14 mmol) was added to the mixture. The mixture was allowed to warm to room temperature until completion. The mixture was washed with NaOH (1 N) and extracted with ether. The aqueous layer was acidified with concentrated HCl and back-extracted with ethyl acetate. The organic layer was concentrated to afford product. Second crop of product was obtained by purifying the THF/ether layer with silica gel chromatography. LC/MS [Method B: rt. 9.09 min, m/z 377 (M+1)].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[S:8][CH:7]1[CH3:16].[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[C:25]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:24][S:23][C:22]=2[CH:32]=1.[Na+].[I-]>C(#N)C>[ClH:17].[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[C:25]([N:26]3[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]4[C:10](=[O:11])[C:9]5([CH2:15][CH2:14][CH2:13][CH2:12]5)[S:8][CH:7]4[CH3:16])[CH2:30][CH2:31]3)=[CH:24][S:23][C:22]=2[CH:32]=1
Reactant: Clc1ccc2c(N3CCNCC3)csc2c1
Reactant: CC1SC2(CCCC2)C(=O)N1CCCCBr
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC1SC2(CCCC2)C(=O)N1CCCCN1CCN(c2csc3cc(Cl)ccc23)CC1
Product: Cl
Temperature: 85 °C
Yield: 27.5 %

Procedure:
A mixture of 3-(4-bromobutyl)-2-methyl-1-thia-3-azaspiro[4.4]nonan-4-one (5.00 g), 6-chloro-3-piperazinylbenzo[b]thiophene (5.10 g), K2 CO3 (8.00 g) and NaI (400 mg) in acetonitrile (250 ml) was heated at 85° C. for 15.5 hours and the product was processed in substantially the same manner as in Example 10 to afford 1.43 g of crystalline solid, m.p. 211°-214° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH3:23])[CH2:11][CH2:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][NH:19][OH:20])=[CH:16][CH:15]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH3:23])[CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][N:19]([OH:20])[C:24](=[O:26])[CH3:25])=[CH:21][CH:22]=1
Reactant: CC(=O)OC(C)=O
Reactant: CN(CCOc1ccc(CNO)cc1)c1nc2ccccc2o1
Solvent: C1CCOC1
Product: CC(=O)N(O)Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a mixture of N-[4-[2-(benzoxazol-2-yl-methyl-amino)-ethoxy]-benzyl]-hydroxylamine (1.5 g, 4.78 mmol) in THF (5 mL) was added acetic anhydride (0.49 g, 4.78 mmol). The mixture was stirred for 1 hour and the volatiles were removed in vacuo. Crystallization from EtOAc/hexane, gave a white solid (1.3 g, 77% yield, m.p. 135°-136° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][CH3:13])=[C:6](B(O)O)[CH:7]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([C@H:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=1>O.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][CH3:13])=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([C@H:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=2)[CH:7]=1
Reactant: C[C@@H](N)c1ccc(Br)cc1
Reactant: CCOc1ccc(Cl)cc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: O
Product: CCOc1ccc(Cl)cc1-c1ccc([C@@H](C)N)cc1
Temperature: 200 °C
Yield: 80 %

Procedure:
A suspension of 5-chloro-2-ethoxyphenylboronic acid (601 mg, 3.0 mmol), palladium (II) acetate (33 mg, 0.15 mmol) and (R)-1-(4-bromophenyl)ethylamine (295 mg, 1.5 mmol) in water (4 ml) was heated for 5 min at 200° C. in a Smithcreator microwave oven. The reaction mixture was diluted with dichloromethane and purified on a Strata™ 5 g/20 ml SCX column (eluted with 2M ammonia in methanol) to give (R)-1-(5′-chloro-2′-ethoxy-biphenyl-4-yl)-ethylamine (341 mg, 1.2 mmol, 82%). To a solution of 1-(5′-chloro-2′-ethoxy-biphenyl-4-yl)-ethylamine (30 mg, 0.1 mmol) in dichloromethane (0.75 ml) was added triethylamine (36 mg, 0.35 mmol) and 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride (30 mg, 0.13 mmol) in dichloromethane (0.5 ml). The reaction mixture was then agitated at room temperature for 16 h and quenched with acetic acid (200 μl). Purification by preparatory LCMS and removal of solvent under reduced pressure gave the title compound (21 mg, 0.04 mmol, 40%): 1H NMR (400 MHz, DMSO-d6): δ 8.25 (d, 1H), 7.32-7.37 (m, 3H), 7.21-7.24 (m, 3H), 7.10 (d, 1H), 4.35 (m, 1H), 4.05 (m, 2H), 2.20 (s, 3H), 1.26-1.35 (m, 6H) ppm; MS (ESI) m/z: value [M+H]+.
Reaction SMILES: BrC1C=[CH:6][C:5](/[CH:8]=[C:9](\C)/[CH2:10][O:11][CH2:12][CH2:13]O)=CC=1.[O:16]1C=C[CH2:19][CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=[O:30])=CC=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[O:16]1[CH2:17][CH2:18][CH2:19][CH2:13][CH:12]1[O:11][CH:10]1[CH2:9][CH2:8][CH2:5][CH2:6][O:30]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C1=COCCC1
Reactant: C/C(=C\c1ccc(Br)cc1)COCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C1CCC(OC2CCCCO2)OC1
Yield: 93 %

Procedure:
In 20 ml of methylene chloride were dissolved 2.13 g of 2-[(E)-3-(4-bromophenyl)-2-methylallyloxy]ethanol and 1.43 ml of 3,4-dihydro-2H-pyran and 20 mg of p-toluenesulfonic acid monohydrate was added to the resulting solution with ice-cooling, after which the resulting mixture was subjected to reaction at room temperature for 3 hours. Subsequently, 30 ml of methylene chloride and 20 ml of a saturated aqueous sodium hydrogen-carbonate solution were added to the reaction mixture, and the organic layer was separated, washed successively with 20 ml of water and 20 ml of a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: toluene:ethyl acetate (20:1 by volume)] to obtain 2.6 g (yield 93%) of oily tetrahydropyranyl ether of 2-[(E)-3-(4-bromophenyl)-2-methylallyloxy]ethanol.
Reaction SMILES: N1C=CC=C(C)C=1.[CH2:8]([O:10][N:11]=[C:12]([C:16]1[C:17](=[O:35])[CH2:18][CH:19]([C:23]2[C:24]([O:33][CH3:34])=[N:25][C:26]([S:31][CH3:32])=[N:27][C:28]=2[O:29][CH3:30])[CH2:20][C:21]=1[OH:22])[CH2:13][CH2:14][CH3:15])[CH3:9].[CH3:36][C:37]([CH3:42])([CH3:41])[C:38](Cl)=[O:39]>ClCCl>[CH3:36][C:37]([CH3:42])([CH3:41])[C:38]([O:22][C:21]1[CH2:20][CH:19]([C:23]2[C:28]([O:29][CH3:30])=[N:27][C:26]([S:31][CH3:32])=[N:25][C:24]=2[O:33][CH3:34])[CH2:18][C:17](=[O:35])[C:16]=1[C:12](=[N:11][O:10][CH2:8][CH3:9])[CH2:13][CH2:14][CH3:15])=[O:39]
Reactant: CCCC(=NOCC)C1=C(O)CC(c2c(OC)nc(SC)nc2OC)CC1=O
Reactant: CC(C)(C)C(=O)Cl
Solvent: Cc1cccnc1
Solvent: ClCCl
Product: CCCC(=NOCC)C1=C(OC(=O)C(C)(C)C)CC(c2c(OC)nc(SC)nc2OC)CC1=O
Temperature: 25 °C

Procedure:
A solution of 3-picoline (40 mg) and 2-[1-ethoxyimino)butyl]-5-(4,6-dimethoxy-2-methylthio-5-pyrimidyl)cyclohex-2-en-1-one (2) (80 mg) in dichloromethane (10 ml) was treated with trimethylacetyl chloride with stirring at room temperature. After 2 hours the solution was washed with dilute hydrochloric acid (1M, 20 ml), separated, dried over anhydrous magnesium sulphate and evaporated under reduced pressure to give 3-trimethylacetyloxy-2-[1-(ethoxyimino)butyl]-5-(4,6-dimethoxy-2-methylthio-5-pyrimidyl)cyclohex-2-en-1-one (7) as a pale brown oil (100 mg) which was characterized by nuclear magnetic resonance spectroscopy.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C@H:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@:22]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[C:45]([CH2:50][C:51]3[S:52][C:53]([C:56]4[CH:61]=[CH:60][C:59]([F:62])=[CH:58][CH:57]=4)=[CH:54][CH:55]=3)[CH:44]=2)([O:41][CH3:42])[O:21][C@@H:20]1[CH2:63][OH:64])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C@H:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@:22]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[C:45]([CH2:50][C:51]3[S:52][C:53]([C:56]4[CH:57]=[CH:58][C:59]([F:62])=[CH:60][CH:61]=4)=[CH:54][CH:55]=3)[CH:44]=2)([O:41][CH3:42])[O:21][C@@H:20]1[CH:63]=[O:64])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CO[C@@]1(c2ccc(C)c(Cc3ccc(-c4ccc(F)cc4)s3)c2)O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CO[C@@]1(c2ccc(C)c(Cc3ccc(-c4ccc(F)cc4)s3)c2)O[C@H](C=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
Oxalyl chloride (0.27 mL, 3.12 mmol) was dissolved in 8 mL dichloromethane and cooled to −78° C. The reaction mixture was stirred for 15 minutes before 4 mL solution of dimethyl sulfoxide (0.36 mL, 5.04 mmol) in dichloromethane were added. Then 8 mL solution of [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 9g (1.8 g, 2.4 mmol) in dichloromethane were dropwise added. The reaction mixture was stirred for 30 minutes. Then triethylamine (1.66 mL, 12 mmol) was added before the reaction mixture was warmed to room temperature and stirred for 1 hour. Thereafter, the reaction mixture was partitioned after 12 mL 1 M hydrochloric acid were added, the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 9h (1.8 g, yellow grease), which was used directly in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:17]I>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2([O:14][CH3:17])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: Nc1cccc(C2(O)CCOCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2cccc(N)c2)CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a solution of 4-(3-aminophenyl)-4-hydroxytetrahydropyran (630 mg, 3.26 mmol), prepared as in step 3, in dry DMF (13 mL) was added sodium hydride (326 mg of a 60% oil dispersion). The reaction was stirred at ambient temperature for 1 hour and then methyl iodide (0.24 mL, 3.19 mmol) was added neat. The resulting solution was stirred at ambient temperature for 0.5 hour and quenched with saturated aqueous ammonium chloride. The biphasic solution was extracted with ethyl acetate. The organic layer was washed (1x, saturated aqueous ammonium chloride; 2x, brine), dried (MgSO4), and concentrated in vacuo to provide an oil. Chromatography on silica gel with 20% ethyl acetate/hexanes as the eluant provided 4-(3-aminophenyl)-4-methoxytetrahydropyran as a beige solid (510 mg, 76%). mp 99.0°-100.5° C. 1H NMR (300 MHz, CDCl3) δ7.17 (1H, t, J=9 Hz), 6.73-6.82 (2H, m), 6.62 (1H, ddd, J=9, 2, 1 Hz), 3.85 (2H, td, J=10.5, 10.5, 2.5 Hz), 3.81 (2H, ddd, J=10.5, 9, 3 Hz), 2.99 (3H, s), 1.87-2.07 (4H, m). MS m/e 207 (M)+, 225 (M+NH4)+.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[N:29][CH:28]=[N:27]3)=[C:22]([OH:31])[CH:21]=2)[CH2:15][CH2:14]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH2:34][CH2:35][N:36]([CH3:38])[CH3:37].O>CN(C)C=O>[CH3:3][N:4]([CH:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[N:29][CH:28]=[N:27]3)=[C:22]([O:31][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH:21]=2)[CH2:15][CH2:14]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(CCc1ccccc1)C1CCN(C(=O)c2ccc(-n3cncn3)c(O)c2)CC1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCOc1cc(C(=O)N2CCC(N(C)CCc3ccccc3)CC2)ccc1-n1cncn1
Reaction time: 1 h
Yield: 42.5 %

Procedure:
120 mg of sodium hydride was added, under ice-cooling, to a solution of 1.0 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-[3-hydroxy-4-(1,2,4-triazol-1-yl)benzoyl]piperidine in 10 ml of dimethylformamide. The mixture was stirred for 1 hour. Thereto was dropwise added 320 mg of (2-chloroethyl)dimethylamine. The mixture was stirred at room temperature for 2 hours and then at 50° C. for 2 hours. The reaction mixture was poured into 50 ml of water. The mixture was extracted with three 50-ml portions of ethyl acetate. The extract was washed with 50 ml of a saturated aqueous sodium chloride solution, dried with magnesium sulfate, and subjected to distillation to remove the solvent. The residue was purified by a silica gel column chromatography (eluant: dichloromethane/methanol=10/1 to dichloromethane/methanol/ammonia water=100/10/1). The product was recrystallized from ethyl acetate-n-hexane to obtain 500 mg of 4-[N-methyl-N-(2-phenylethyl)amino]-1-[3-(2-dimethylaminoethoxy)-4-(1,2,4-triazol-1-yl)benzoyl]piperidine as a white powder.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:27])=[N:13][C:14]2[N:15]([N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:20]=2)[C:16]=1Cl)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH2:28]1[C:32]2([CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:31][CH2:30][NH:29]1.C(N(CC)C(C)C)(C)C.[OH-].[Li+]>CN1C(=O)CCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:27])=[N:13][C:14]2[N:15]([N:18]=[C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:20]=2)[C:16]=1[N:29]1[CH2:30][CH2:31][C:32]2([CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:28]1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: C1CCC2(C1)CCNC2
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3ccccc3)nn2c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1nc2cc(-c3ccccc3)nn2c(N2CCC3(CCCC3)C2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 27 %

Procedure:
(S)-methyl 2-(tert-butoxy)-2-(7-chloro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)acetate was dissolved in NMP (1 mL) and combined with 2-azaspiro[4.4]nonane (8.72 mg, 0.070 mmol) and N,N-diisopropylethylamine (27 mg, 0.21 mmol). This mixture was stirred at rt for 24 h. A 1M lithium hydroxide solution (0.348 mL, 0.348 mmol) was added to the reaction mixture and it was heated at 50° C. for 4 h to complete the ester hydrolysis. The reaction mixture was concentrated in vacuo and purified by Biotage (4 g column, 0-10% MeOH/CH2Cl2 ramp) to give 11.1 mg (27% yield) of S)-2-(tert-butoxy)-2-(5-methyl-2-phenyl-7-(2-azaspiro[4.4]nonan-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetic (1:1 solvate with NMP) as a yellow waxy solid.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].C(N(CC)CC)C.[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[CH:17]=O.O>CS(C)=O>[Cl:14][C:15]1[C:16]2[CH:17]=[C:2]([C:1]([O:5][CH3:6])=[O:4])[S:3][C:19]=2[CH:20]=[CH:21][CH:22]=1
Reactant: O=Cc1c(F)cccc1Cl
Reactant: COC(=O)CS
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)c1cc2c(Cl)cccc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl thioglycolate (11.3 ml) was added under nitrogen to a stirred solution of triethylamine (45 ml) in dimethyl sulphoxide (160 ml), then the mixture was stirred at ambient temperature for 30 minutes. A solution of 2-chloro-6-fluorobenzaldehyde (20 g) in dimethyl sulphoxide (80 ml) was added then the mixture was stirred at 95° C. for 4.66 hours, allowed to stand at ambient temperature for 18 hours and poured into water (1600 ml). The resulting solid was collected by filtration, washed with water (3×100 ml), and dried in vacuo to give methyl 4-chlorobenzo[b]thiophene-2-carboxylate (22.4 g) as an off-white solid, m.p. 84-86° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9]([CH3:12])([CH3:11])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.Br[C:17]1[CH:18]=[C:19]([C:22]#[N:23])[S:20][CH:21]=1>>[CH3:11][C:9]1([CH3:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]2[CH:15]=[C:2]([C:17]3[CH:18]=[C:19]([C:22]#[N:23])[S:20][CH:21]=3)[CH:3]=[CH:4][C:5]=2[NH:10]1
Reactant: CC1(C)Nc2ccc(Br)cc2C(C)(C)O1
Reactant: N#Cc1cc(Br)cs1
Product: CC1(C)Nc2ccc(-c3csc(C#N)c3)cc2C(C)(C)O1

Procedure:
Prepared using the coupling procedure for Example 13 starting with 6-bromo-2,2,4,4-tetramethyl-1,4-dihydro-2H-3,1-benzoxazine and 4-bromo-2-cyanothiophene. An amorphous orange solid: 1H-NMR (DMSO-d6) δ 8.4 (d, 1H, J=1.69 Hz), 8.14 (d, 1H, J=1.69 Hz), 7.49 (d, 1H, J=2.20 Hz), 7.38 (dd, 1H, J=8.43, 2.02 Hz), 6.61 (d, 1H, J=8.43 Hz), 6.26 (s, 1H), 1.49 (s, 6H), 1.32 (s, 6H); MS (ES) m/z 299 ([M+H]+).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:48])[N:20]([C:39]2[CH:40]=[CH:41][C:42]3[O:46][CH2:45][CH2:44][C:43]=3[CH:47]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:48])[N:20]([C:39]2[CH:40]=[CH:41][C:42]3[O:46][CH2:45][CH2:44][C:43]=3[CH:47]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1nc(C)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
A mixture of hydroxylammonium chloride (1.4 g), sodium hydrogen carbonate (2.1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.20 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.56 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.47 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.74 g, 55%).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:31][C@H:30]([CH2:32][N:33]5[CH:37]=[C:36]([CH3:38])[N:35]=[N:34]5)[O:29][C:28]4=[O:39])=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1.C(OCC)(=O)C>[OH:8][CH2:9][CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:22]=[CH:23][C:24]([N:27]4[CH2:31][C@H:30]([CH2:32][N:33]5[CH:37]=[C:36]([CH3:38])[N:35]=[N:34]5)[O:29][C:28]4=[O:39])=[CH:25][CH:26]=3)=[CH:19][CH:20]=2)[CH2:11]1
Reactant: Cc1cn(C[C@H]2CN(c3ccc(-c4ccc(C5=NOC(CO[Si](C)(C)C(C)(C)C)C5)cc4)cc3)C(=O)O2)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cn(C[C@H]2CN(c3ccc(-c4ccc(C5=NOC(CO)C5)cc4)cc3)C(=O)O2)nn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 15.6 %

Procedure:
(5R)-3-{4′-[5-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-4,5-dihydroisoxazol-3-yl]-1,1′-biphenyl-4-yl}-5-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]-1,3-oxazolidin-2-one (0.2 g, 0.37 mmol) was dissolved in THF (5 ml) at 25° C. Tetrabutylammoniumfluoride.3H2O (0.11 g, 0.40 mmol) was added as a solid and the reaction was stirred at 25° C. for 1.5 hours. The mixture was then diluted with ethyl acetate (50 ml) and poured into water. The layers were separated and the aqueous layer was extracted three times with ethyl acetate (3×50 ml). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo. The resulting yellow oil was purified by silica flash chromatography with 5-10% methanol in dichloromethane as eluent, giving 0.025 g desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1.[H][H]>C(O)C.[Ni]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH2:9])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Cc1cc(Cl)ncc1N
Yield: 79.1 %

Procedure:
2-Chloro-4-methyl-5-nitropyridine (173 mg) was dissolved in ethanol (5 mL). To the solution, a catalytic amount of Raney nickel was added, and the resultant mixture was stirred in a hydrogen atmosphere at room temperature for 9 hours. The catalyst was removed through filtration, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2), to thereby give the title compound (113 mg).
Reaction SMILES: C[C:2]1([CH:15]=O)[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.[ClH:17].Cl.[NH2:19][C:20]1[C:29]([NH2:30])=[C:28]2[C:23]([CH:24]=[C:25]([C:32]([OH:34])=[O:33])[CH:26]=[C:27]2[OH:31])=[CH:22][CH:21]=1.S(=O)(O)[O-].[Na+].[CH3:40]CO>O>[ClH:17].[CH3:15][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:40]3[NH:19][C:20]4[CH:21]=[CH:22][C:23]5[C:28](=[C:27]([OH:31])[CH:26]=[C:25]([C:32]([OH:34])=[O:33])[CH:24]=5)[C:29]=4[N:30]=3)[CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Nc1ccc2cc(C(=O)O)cc(O)c2c1N
Reactant: CCO
Reactant: CC1=CC=C(c2ccccc2)CC1(C)C=O
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(-c2cccc(-c3nc4c(ccc5cc(C(=O)O)cc(O)c54)[nH]3)c2)cc1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
To an agitated solution of 3,4-dimethylbiphenyl-3-carbaldehyde (0.019 g, 0.09 mmol) in EtOH (0.80 mL) was added 7,8-Diamino-1-hydroxy-3-naphthoic acid dihydrochloride (0.024 g, 0.08 mmol) and sodium bisulfite (0.02 g) in water (0.20 mL). The solution was heated to 60° C. and agitated overnight. The solution was cooled to room temperature and concentrated under reduced pressure. The tan residue was subjected to HPLC (ODS-A, gradient 10-90% CH3CN/water 0.1% TFA) to provide the title compound (0.015 g, 33%) MS(ES) m/z 409 [M+H].