Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH:5]([N:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([Cl:17])[C:11]=3[C:10]3=[N:18][O:19][C:20]([CH3:21])=[C:9]3[C:8]2=[O:22])[CH:4]=[CH:3]1.[O:23]=[C:24]([C:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=1)[C:25](Cl)=[O:26]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:17][C:12]1[C:11]2[C:10]3[C:9](=[C:20]([CH3:21])[O:19][N:18]=3)[C:8](=[O:22])[N:7]([CH:5]3[CH2:6][CH:2]([NH:1][C:25](=[O:26])[C:24](=[O:23])[C:28]4[CH:29]=[C:30]([O:38][CH3:39])[C:31]([O:36][CH3:37])=[C:32]([O:34][CH3:35])[CH:33]=4)[CH:3]=[CH:4]3)[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1onc2c1c(=O)n(C1C=CC(N)C1)c1cccc(Cl)c21
Reactant: COc1cc(C(=O)C(=O)Cl)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(C(=O)C(=O)NC2C=CC(n3c(=O)c4c(C)onc4c4c(Cl)cccc43)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.4 %

Procedure:
To a stirred solution of 5-(4-amino-cyclopent-2-enyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one (50 mg, 0.216 mmol) in CH2Cl2 (2 mL) was added oxo-(3,4,5-trimethoxy-phenyl)acetyl chloride (80 mg, 0.33 mmol, prepared from its acid and oxalyl chloride) and DMAP (catalytic amount) and stirred at r.t. for 18 hours. The mixture was diluted with CH2Cl2, washed (brine), dried (Na2SO4), filtered and concentrated. Column chromatography (silica gel, hexanes/ethyl acetate, gradient) gave the title compound (33 mg, 38%). Mass Spectrum (FIA) (m/z) 538A 4 (A+1). 1H NMR (CDCl3): δ 7.80 (d, 1H); 7.50 (t, 1H); 7.35 (d, 1H); 6.00 (m, 2H); 5.40 (m, 1H); 5.21 (m, 111); 3.80-3.90 (m, 1H); 2.95 (s, 3H); 2.30 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]([CH3:12])[C:5]2=[O:13].[Cl-].[C:15]([O:19][C:20](=[O:23])[CH2:21][Zn+])([CH3:18])([CH3:17])[CH3:16].C(OCC)C>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2]>[CH3:12][N:6]1[C:5](=[O:13])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH2:21][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:23])[CH:3]=2)[N:8]=[CH:7]1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: Cn1cnc2ccc(Br)cc2c1=O
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cn1cnc2ccc(CC(=O)OC(C)(C)C)cc2c1=O
Temperature: 50 °C

Procedure:
To a solution of 6-bromo-3-methylquinazolin-4(3H)-one (0.485 g, 2.0 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.19 g, 0.20 mmol) and Q-phos (0.20 g) in 40 mL of THF was added 2-tert-butoxy-2-oxoethylzinc chloride 0.5 M in diethyl ether (8.1 ml, 4.1 mmol). The reaction was heated at 50° C. for 16 hours and was quenched with 40 mL of satd. NH4Cl. The mixture was diluted with 60 mL of EtOAc. The organic phase was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo to give red solid. The residue was purified by a silica gel column chromatography (5% EtOAc/Hex to EtOAC) to provide a red solid. MS (ESI pos. ion) m/z: 275 (MH+). Calc'd exact mass for C15H18N2O3: 274.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7](Cl)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([Cl:13])[N:4]=1)[CH3:2].[CH:14]([NH2:17])([CH3:16])[CH3:15]>>[CH2:1]([C:3]1[N:4]=[C:5]([Cl:13])[C:6]([N+:10]([O-:12])=[O:11])=[C:7]([NH:17][CH:14]([CH3:16])[CH3:15])[N:8]=1)[CH3:2]
Reactant: CCc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: CC(C)N
Product: CCc1nc(Cl)c([N+](=O)[O-])c(NC(C)C)n1
Yield: 79.3 %

Procedure:
111 g (0.5 mole) of 2-ethyl-4,6-dichloro-5-nitro-pyrimidine are reacted with 59.1 g (1.0 mole) of isopropylamine. To yield 97 g of 2-ethyl-6-isopropylamino-5-nitro-4-chloro-pyrimidine of m.p. 51°-52° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH3:20])[C:10](=[O:21])[C:9]=2[CH2:22][CH2:23][CH2:24][OH:25])[CH:5]=[CH:6][CH:7]=1.[CH3:26]C(C)([O-])C.[Na+].CI.Cl>O.C(O)(C)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH3:20])[C:10](=[O:21])[C:9]=2[CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: CCn1c(=O)c(CCCO)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Agent: Cl
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CI
Solvent: O
Product: CCn1c(=O)c(CCCOC)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Temperature: 60 °C
Yield: 34.6 %

Procedure:
To a 10 ml tert-butanol solution containing 500 mg of 4-(3-chlorophenyl)-1-ethyl-3-(3-hydroxypropyl)-7-methyl-1,8-naphthyridin-2(1H)-one were added 300 mg of sodium tert-butoxide and 0.2 ml of methyl iodide successively, followed by stirring under heating at an oil bath temperature of 60° C. for 2 hours. After the reaction mixture was cooled to room temperature, water and 1M hydrochloric acid were added thereto, and the whole was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by a silica gel column chromatography (hexane-ethyl acetate) and then recrystallized from diisopropyl ether to obtain 180 mg of 4-(3-chlorophenyl)-1-ethyl-3-(3-methoxypropyl)-7-methyl-1,8-naphthyridin-2(1H)-one as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C(OCC)(=O)C.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>[CH:12]([C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([C:21]3[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=3)[CH:15]=[O:16])[CH:3]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:14])[CH3:13]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CC(C)c1cc(Br)c2ncccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)c1cc(-c2cccc(C=O)c2)c2ncccc2c1
Temperature: 70 °C

Procedure:
A mixture of 8-bromo-6-isopropyl-quinoline (9.79 g, 39 mmol, described in International Patent Publication WO 94/22852), 3-(formyl)-phenyl-boronic acid (11.7 g, 78 mmol), sodium carbonate (78 mL, 2M, H2O), Pd(Ph3P)4 (2.7 g, 2.3 mmol) in DME (200 mL) was heated at 70° C. for 18 h. The reaction mixture was cooled to 21° C. then diluted with water and ethyl acetate. The organic extracts were washed (H2O, brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with hexane/ethyl acetate, 80:20) provided the title compound.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][S:17][C:18]#[N:19])=[CH:11][CH:10]=1.[Cl-].[CH2:22]([O:24][C:25]([C:27]1([NH3+:30])[CH2:29][CH2:28]1)=[O:26])[CH3:23]>C(O)C>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]=[C:18]([NH:30][C:27]3([C:25]([O:24][CH2:22][CH3:23])=[O:26])[CH2:29][CH2:28]3)[S:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: N#CSCC(=O)c1ccc(Br)cc1
Reactant: CCOC(=O)C1([NH3+])CC1
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(Nc2nc(-c3ccc(Br)cc3)cs2)CC1
Temperature: 65 °C
Reaction time: 96 h
Yield: 35.7 %

Procedure:
Triethylamine (3.1 mL, 22.3 mmol) was added under nitrogen to a mixture of 2-(4-bromophenyl)-2-oxoethyl thiocyanate (5.2024 g, 20.3 mmol), prepared in step 1 of Example 1, and 1-ethoxycarbonyl-cyclopropyl-ammonium chloride (3.7001 g, 22.3 mmol), prepared in the previous step, in 400 mL of absolute ethanol. After the addition, the reaction was stirred at 65° C. for 4 days. The reaction was concentrated under reduced pressure to remove the ethanol. The residue was taken up in methylene chloride, applied to a Biotage FLASH 25+™ cartridge and the methylene chloride allowed to evaporate. Purification of the residue on the samplet on a Horizon™ Flash Collector (the Biotage FLASH 25+™ cartridge) using a linear gradient of 5% ethyl acetate-hexane to 100% ethyl acetate gave ethyl 1-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}cyclopropane carboxylate (2.66 g, 36%) as a light yellow solid, mp 152-154° C.; MS m/z 367.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C.O.[CH2:36]([OH:40])[CH2:37][CH2:38][CH3:39]>>[CH2:36]([O:40][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Reactant: CCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCOc1nc(-c2ccc(S(C)(=O)=O)cc2)cc(C(F)(F)F)n1
Temperature: 50 °C

Procedure:
A suspension of 2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (525 g) in n-butanol (5.25 L) was treated with potassium carbonate (210 g) at 20±5° C. The mixture was heated to 50±5° C. overnight until the reaction was complete by HPLC. Acetic acid (1.57 L) was added dropwise, to control any gas evolution, keeping the temperature at 50±5° C. Water (3.67 L) was then added over 30 min keeping the temperature at 50±5° C. to allow full crystallisation to occur. The slurry was then cooled to 20-25° C. and aged for at least 1 hour. The resulting product was then filtered under vacuum and washed with a mixture of n-butanol (787 mL), acetic acid (236 mL), and water (551 mL) followed by water (2×1.57 L). The product was then dried at up to ca50° C. under vacuum to yield the title compound. Yield, 457 g, 88.4% of theory. The title compound was found to be identical to that of Example 10.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2([CH3:13])[CH3:12])=[CH:5][CH:4]=1.C(O)(=[O:16])C>C(O)(=O)C.O.[O-2].[O-2].[O-2].[Cr+6]>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6](=[CH:5][CH:4]=1)[C:7](=[O:16])[CH2:8][C:9]2([CH3:13])[CH3:12]
Reactant: COc1ccc2c(c1)C(C)(C)CC2
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Product: COc1ccc2c(c1)C(C)(C)CC2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 6-methoxy-1,1-dimethyl-indan (1 g, 5.67 mmol) in acetic acid (5 mL) is cooled to 0° C. and treated with a solution of chromium trioxide (1.3 g, 13 mmol) in acetic acid/H2O (5 mL/4 mL). Then the reaction mixture is allowed to warm to ambient temperature and stirred for 3 h. The reaction mixture is diluted and extracted with ethyl acetate (3×20 mL). The combined organic phases are washed with saturated aqueous NaHCO3 and brine and dried over Na2SO4. Evaporation of solvent affords 5-methoxy-3,3-dimethyl-indan-1-one as a yellow oil: ESMS m/z 191.1 (M+H+).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:17][CH3:18])[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=[C:8]([C:19](O)=[O:20])[C:7]2=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:28]=[CH:27][NH:26][N:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[NH:26]1[CH:27]=[CH:28][C:24]([NH:23][C:19]([C:8]2[C:7](=[O:22])[N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[C:11]3[N:12]=[C:13]([NH:17][CH3:18])[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=2)=[O:20])=[N:25]1
Reactant: Nc1cc[nH]n1
Reactant: CNc1nc(C)c2cc(C(=O)O)c(=O)n(C3CCCC3)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNc1nc(C)c2cc(C(=O)Nc3cc[nH]n3)c(=O)n(C3CCCC3)c2n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To 110 μL of 0.1 M solution of example 89 in DMF in a test tube (10×95 mm) was added 100 μL of 0.1 M solution of 3-aminopyrazole in DMF followed by 110 μL each of 0.1 M solution of HATU and triethylamine, respectively. The reaction mixture was stirred at 80° C. for 8 h. After the removal of the solvent in vacuo, the residue was reconstituted in 1.2 mL of DMSO and subjected to HPLC purification to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:17]4[CH2:18][CH:14]([CH2:15][CH2:16]4)[CH:13]2[CH2:12][N:11](C)[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:17]4[CH2:18][CH:14]([CH2:15][CH2:16]4)[CH:13]2[CH2:12][N:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)Cl
Reactant: CN1CC2C3CCC(C3)C2(c2ccc(Cl)c(Cl)c2)C1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2C3CCC(C3)C2(c2ccc(Cl)c(Cl)c2)C1

Procedure:
By the method of Example 26, (-)-3a-(3,4-dichlorophenyl)octahydro-2-methyl-4,7-methano-1H-isoindole is reacted with ethyl chloroformate in toluene to give the corresponding 3a-(3,4-dichlorophenyl)octahydro-4,7-methano-2H-isoindole-2-carboxylic acid, ethyl ester. This urethane is hydrolyzed with hydrochloric acid and the solution is evaporated to give (-)-3a-(3,4-dichlorophenyl)octahydro-4,7-methano-1H-isoindole hydrochloride as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[C:17]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:16][C:11]=3[C:12]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[C:17]([O:23][CH:24]([CH3:25])[CH3:26])=[CH:16][C:11]=3[C:12]=2[C:13]([NH:27][CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CC(C)Oc1cc2c(C(=O)O)c(-c3ccc(F)cc3)oc2cc1[N+](=O)[O-]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc2c(C(=O)NCCNC(=O)OC(C)(C)C)c(-c3ccc(F)cc3)oc2cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-(4-fluorophenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylic acid (1.3 g, 3.62 mmol), tert-butyl (2-aminoethyl)carbamate (0.696 g, 4.34 mmol) in DMF (50 mL) at room temperature was added N,N-diisopropylethylamine (DIPEA) (2.53 mL, 14.47 mmol). The mixture was cooled to 0° C., added with (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (2.40 g, 5.43 mmol), and then stirred at room temperature (rt) overnight. The reaction mixture was diluted with water, stirred for 5 min. The solid was filtered and dried under suction to obtain the title compound as a yellow solid. Yield: 1.6 g, (88%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.61 (t, J=5.65 Hz, 1H) 8.32 (s, 1H) 7.90-8.09 (m, 2H) 7.50 (s, 1H) 7.28-7.46 (m, 2H) 6.91 (t, J=5.65 Hz, 1H) 4.87 (dt, J=12.17, 5.96 Hz, 1H) 3.35-3.49 (m, 2H) 3.06-3.23 (m, 2H) 1.09-1.47 (m, 15H). LCMS: (ES+) m/z=502.34 (M+H)+; Column—ACQUITY UPLC BEH C8 (50×2.1 mm; 1.7 nm); M phase A: 5 mM Ammonium Acetate: MeCN (95:5); M phase B: 5 mM Ammonium Acetate:MeCN (5:95)
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][S:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16].[OH:18]O>C(O)(=O)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][S:10]([CH2:11][C:12]([OH:14])=[O:13])=[O:18])=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16]
Reactant: OO
Reactant: COc1ncc(CSCC(=O)O)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: COc1ncc(CS(=O)CC(=O)O)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
Treatment of 2-((6-methoxy-5-nitropyridin-3-yl)methylthio)acetic acid (1.0 mmol, 0.26 g) in acetic acid (30 mL) with hydrogen peroxide 35% (1.0 mmol, 0.05 mL) and the mixture was stirred at room temperature for 1.5 hr followed by 60° C. for 30 minutes. The mixture was evaporated in vacuo to yield the title compound. 1H-NMR (D2O) δ: 1.97 (s, 2H, CH2), 4.23 (d, 1H, J=14.0 Hz, CH), 4.44 (d, 1H, J=14.0 Hz, CH), 4.14 (s, 3H, OCH3), 8.43 (s, 1H, Py-H), 8.52 (s, 1H, Py-H); HR-MS (ESL) m/z: 273.0146 [M−H]−, C9H10N2O6S requires 274.0260.
Reaction SMILES: [NH2:1][C@@H:2]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:3]([N:5]1[C@H:14]([C:15](=[O:27])[NH:16][C@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:28]([O:30][CH3:31])=[O:29])=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[C:36]([O:40][C:41]([N:43]([CH3:49])[C@@H:44]([CH3:48])[C:45](O)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[C:36]([O:40][C:41]([N:43]([CH3:49])[C@@H:44]([CH3:48])[C:45]([NH:1][C@@H:2]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:3]([N:5]1[C@H:14]([C:15](=[O:27])[NH:16][C@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:28]([O:30][CH3:31])=[O:29])=[CH:10][CH:11]=2)[CH2:6]1)=[O:4])=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc2c(c1)CN(C(=O)[C@@H](N)C(C)(C)C)[C@H](C(=O)N[C@@H]1CCCc3ccccc31)C2
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: COC(=O)c1ccc2c(c1)CN(C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)(C)C)[C@H](C(=O)N[C@@H]1CCCc3ccccc31)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a 0° C. solution of (S)-methyl 2-((S)-2-amino-3,3-dimethylbutanoyl)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (966 mg, 2.02 mmol) and (S)-2-((tert-butoxycarbonyl)(methyl)amino)propanoic acid (Advanced ChemTech, 411 mg, 2.02 mmol) in DMF (20 mL) was added EDC (465 mg, 2.43 mmol), followed by HOAt (330 mg, 2.43 mmol). NMM (667 μl, 6.07 mmol) was then added, and the resulting reaction mixture was stirred at 0° C. for 30 min, then warmed to room temperature and stirred for 4 h. The reaction mixture was then poured into a separatory funnel containing EtOAc and sat. aq. NaHCO3 solution. The aqueous layer was extracted with EtOAc (3×). The combined organic extracts were washed with 1N HCl (2×) and 10% LiCl, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (1.34 g, 2.02 mmol, 100%) as a light yellow foam, which was used without further purification. MS (ESI+) m/z 663.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:7]=1[CH2:8]Cl)=[O:4].[OH:15][C:16]1[C:17]2[N:18]([C:22]([CH3:26])=[C:23]([CH3:25])[N:24]=2)[CH:19]=[CH:20][CH:21]=1.[F-].[K+]>C(#N)C>[CH3:1][O:2][C:3]([NH:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:7]=1[CH2:8][O:15][C:16]1[C:17]2[N:18]([C:22]([CH3:26])=[C:23]([CH3:25])[N:24]=2)[CH:19]=[CH:20][CH:21]=1)=[O:4]
Reactant: COC(=O)Nc1cccc(C)c1CCl
Reactant: Cc1nc2c(O)cccn2c1C
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Nc1cccc(C)c1COc1cccn2c(C)c(C)nc12
Temperature: 70 °C

Procedure:
A solution of 9.5 g of 2-methoxycarbonylamino-6-methylbenzyl chloride in 150 ml of dry acetonitrile is added dropwise at RT to a suspension of 7.2 g of 8-hydroxy-2,3-dimethylimidazo[1,2-a]pyridine in 130 ml of dry acetonitrile, to which 8 g of commercial potassium fluoride (50% by weight) in kieselguhr (for example Celite®) has been added. The mixture is heated at 70° C. for 9 h. After cooling to RT, the mixture is poured into 1 l of ice-water and extracted three times with ethyl acetate. The collected organic phases are washed with distilled water and dried over sodium sulfate. After stripping off the organic solvent in vacuo, the precipitating residue is filtered off, washed with a little ethyl acetate and ether and dried. After recrystallization from isopropanol, 2.2 g of the title compound of m.p. 176°-177° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[C:5]([CH2:7][OH:8])[N:6]=1.[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[S:17]([NH:20][C:21]1[C:26](Cl)=[N:25][C:24]([Cl:28])=[CH:23][N:22]=1)(=[O:19])=[O:18]>>[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[S:17]([NH:20][C:21]1[C:26]([O:8][CH2:7][C:5]2[N:6]=[C:2]([CH3:1])[O:3][CH:4]=2)=[N:25][C:24]([Cl:28])=[CH:23][N:22]=1)(=[O:19])=[O:18]
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Reactant: Cc1nc(CO)co1
Product: Cc1nc(COc2nc(Cl)cnc2NS(=O)(=O)c2cccc(Cl)c2Cl)co1

Procedure:
Prepared by the method of Example 31b using (2-methyl-4-oxazolyl)methanol (0.08 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.26 g).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:13])[CH2:8]2
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Reactant: C1COCCN1
Product: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1N1CCOCC1

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 88 mg; 0.30 mmol) and morpholine (0.26 mL; 3.0 mmol) under microwave irradiation for 4 hr according to the procedure described for Example 14 provided after purification by reverse phase HPLC, 1-methyl-5-morpholin-4-yl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (76 mg, 74%) as an off-white powder. ES-HRMS m/e calcd for C19H28N4O2 (M+H+) 345.2285, found 345.2282.
Reaction SMILES: [CH2:1]([C@@:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:39]>C(Cl)Cl>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@@:4]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)([CH2:1][CH:2]3[CH2:3][O:39]3)[O:9][C:8]2=[O:10])[CH3:12])=[CH:18][CH:17]=1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CC2CO2)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (900 mg, 2.0 mmol) in dry CH2Cl2 (30 mL) was added dropwise 3-chlorobenzoperoxoic acid (690 mg, 4.0 mmol) by portion at 0° C. Then the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was quenched by 10% Na2SO3 solution. The organic phase was dried over Na2SO4, filtered and concentrated to afford the residue, which was purified by TLC to give (6S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(oxiran-2-ylmethyl)-1,3-oxazinan-2-one (470 mg, 50%). 1H NMR (CDCl3): 1.54 (m, 3H), 1.71 (m, 3H), 2.01 (m, 1H), 2.15 (m, 3H), 2.48 (m, 2H), 2.67 (m, 1H), 3.00 (m, 1H), 5.67 (m, 1H), 6.84 (m, 4H), 7.02 (m, 2H), 7.21 (m, 4H), 7.31 (m, 1H).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].C(OCC)C.O.Br[CH2:13][C:14]([CH3:28])=[CH:15][C:16]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:17]>>[C:1]([O:4][CH2:13][C:14]([CH3:28])=[CH:15][C:16]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=CC(=O)OCCOc1ccccc1)CBr
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(=O)OCC(C)=CC(=O)OCCOc1ccccc1

Procedure:
β-phenoxyethyl 4-bromo-3-methyl-2-butenoate (15g) obtained in Example 7 was refluxed with anhydrous sodium acetate (5.32g) in glacial acetic acid (15g) for 8 hours. Ethylether (300ml) and water (20ml) were added to the reaction mixture and the ether layer was washed with water, dried, and concentrated, giving a crude product (11.7g). The crude product on fractionation gave a fractionation gave a fraction (6.1g), b.p. 165°-168° C./0.6mmHg. Structural assignment for this compound was made from its infrared absorption spectrum; 1738, 1710, 1658, 1600, 1590, 1500, 1240, 1215, 1145, 1055, 1040, 755, and 690cm-1.