Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][N:10]([CH:15]([CH3:18])[CH2:16][OH:17])[C:11](=[O:14])[CH2:12]Br)=[CH:7][CH:6]=1>O1CCCC1>[CH3:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][N:10]2[CH:15]([CH3:18])[CH2:16][O:17][CH2:12][C:11]2=[O:14])=[CH:7][CH:6]=1
Reactant: COc1ccc(CN(C(=O)CBr)C(C)CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)COCC2C)cc1
Temperature: 25 °C

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of sodium hydride (3.46 g, 100.92 mmol, 2.00 equiv, 70%) in tetrahydrofuran (200 mL). This was followed by the dropwise addition of a solution of N-(4-methoxybenzyl)-2-bromo-N-(1-hydroxypropan-2-yl)acetamide (16 g, 50.47 mmol, 1.00 equiv) in tetrahydrofuran (100 mL) with stirring at 25° C. The resulting solution was stirred overnight at 25° C. in an oil bath. The reaction was then quenched by the addition of 200 g of water/ice. The resulting solution was extracted with 5×200 mL of dichloromethane and the organic layers combined. The organic layers were washed with 3×50 mL of H2O. Dried over anhydrous magnesium sulfate and concentrated under vacuum. This resulted in 11.9 g (crude) of 4-(4-methoxybenzyl)-5-methylmorpholin-3-one as yellow oil.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1.[ClH:15].N([O-])=O.[Na+].[OH-].[Na+]>O>[Cl:15][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1
Reactant: Nc1ccc(Sc2ccccc2)cn1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1ccc(Sc2ccccc2)cn1
Temperature: -5 °C

Procedure:
Alternatively, 2-amino-5-(phenylthio) pyridine (30 g., 0.15 moles) is added portionwise to 30 ml. of concentrated hydrochloric acid at 0°. The resultant suspension is cooled to -15° C and 20.7 g. of sodium nitrite in 40 ml. of water is added dropwise while keeping the temperature at -15° to -10° C. After stirring for an additional hour at -5° C, an aqueous 30% sodium hydroxide solution is slowly added to pH7 while not allowing the temperature to exceed 0° C. The resultant mixture is extracted with methylene chloride and the combined extracts are washed with water, dried and evaporated in vacuo to yield 2-chloro-5-(phenylthio) pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:18][C:19]1[C:20]([CH3:34])=[C:21]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:22]=[CH:23][CH:24]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.N1C=CC=CC=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([NH:18][C:19]2[C:20]([CH3:34])=[C:21]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH:22]=[CH:23][CH:24]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1c(N)cccc1CCC(=O)OC(C)(C)C
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1c(CCC(=O)OC(C)(C)C)cccc1NC(=O)[C@H](c1ccc(Cl)cc1)[C@@H](C)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 100 mg (0.38 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid, 88 mg (0.38 mmol) of tert-butyl 3-(3-amino-2-methylphenyl)propanoate, 213 mg (0.56 mmol) of 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and 1 ml of pyridine in 4 ml of DMF was stirred at room temperature overnight. After the reaction had ended, the reaction mixture was directly, without further work-up, separated into its components by preparative HPLC (mobile phase acetonitrile/water). This gave 151 mg (83% of theory) of the title compound as a colourless oil.
Reaction SMILES: [CH3:1][C@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][CH2:12][OH:13]>ClCCl>[OH:13][CH2:12][CH2:11][NH:9][C@@H:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: OCCBr
Solvent: ClCCl
Product: C[C@H](NCCO)c1ccccc1
Temperature: 51 °C
Reaction time: 52 h
Yield: 78683.9 %

Procedure:
108.23 g (0.903 mmole) of (S)-(−)-α-methylbenzylamine was dissolved in 140 ml of dichloromethane and 144.0 g (1.071 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51° C. for 52 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and the residue was subjected to fractional distillation to obtain 117.4 g of the title compound, which had a pale yellow color.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:9][C:10]([CH2:13][CH3:14])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH3:33])[CH2:28][CH2:27][C:26]([N+:34]([O-:36])=[O:35])=[CH:25]2>C1COCC1>[C:1]([NH:5][C:6]([C:8]1[S:9][C:10]([CH2:13][CH3:14])=[CH:11][C:12]=1[C@@H:25]1[C:24]2[C:29](=[CH:30][C:31]([O:32][CH3:33])=[C:22]([O:21][CH3:20])[CH:23]=2)[CH2:28][CH2:27][C@H:26]1[N+:34]([O-:36])=[O:35])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1ccc(C(=O)NC(C)(C)C)s1
Reactant: COc1cc2c(cc1OC)CCC([N+](=O)[O-])=C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc([C@@H]2c3cc(OC)c(OC)cc3CC[C@H]2[N+](=O)[O-])c(C(=O)NC(C)(C)C)s1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 50.1 %

Procedure:
To a solution of 5.4 g (25.5 mmol) of 5-ethyl-2-thiophenecarboxylic acid, N-t-butyl amide, from step 3b above, in 80 mL of THF cooled to -78° C. was added 20.4 mL (51.1 mmol) of n-butyllithium (2.5M in hexane). The solution was then stirred at 0° for 40 min, then re-cooled to -78° C., and a solution of 6.0 g of 1,2-dihydro-6,7-dimethoxy-3-nitronaphthalene, from Example 1 b above, in 100 mL of THF cooled to -78° C. was added via cannula. The solution was stirred at -78° C. for 1 hour and at 0° C. for 1 hour. The reaction was quenched with saturated NH4Cl, diluted with water, and extracted with methylene chloride. The extract was washed with brine, dried and concentrated. The residue was dissolved in 30 mL of acetonitrile, 1 mL of triethylamine was added, and the reaction was stirred for 16 hours. The solvent was evaporated, and the residue was purified by flash chromatography, eluting with 6:1 hexane:ethyl acetate to afford 5.7 g of the title product. MS 447 (M+H)+, 464 (M+NH4)+. NMR (CDCl3), δ:6.48 (s, 1H), 6.37 (s, 1H), 6.30 (s, 1H), 5.70 (bs, 1H, 5.47 (d, 1H, J=8 Hz), 5.05 (m, 1H), 3.85 (s, 3H) 3.69 (s, 3H), 3.2-2.88 (m, 2H), 2.72 (q, 2H, J=7 Hz), 2.5-2.35 (m, 2H), 1.42 (s, 3H), 1.23 (t, 3H, J=7 Hz).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]3[N:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][CH3:28])=[O:26])[CH2:21][CH2:20]4)[N:17]=[CH:18][C:10]=13)[CH2:2]2.[NH2:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1>C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:13]2[N:12]=[C:11]3[N:16]([CH:19]4[CH2:20][CH2:21][N:22]([C:25]([O:27][CH3:28])=[O:26])[CH2:23][CH2:24]4)[N:17]=[CH:18][C:10]3=[C:9]([N:3]3[CH2:2][CH:1]4[O:8][CH:5]([CH2:6][CH2:7]4)[CH2:4]3)[N:14]=2)=[CH:32][CH:31]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: COC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(Cl)nc32)CC1
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: CCO
Solvent: Cc1ccccc1
Product: COC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(N)cc4)nc32)CC1
Temperature: 120 °C

Procedure:
A suspension of methyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (2.3 mmol), 4-aminophenylboronic acid pinacol ester (0.76 g, 3.5 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.27 g, 10 mol %) in toluene/ethanol (1:1, 12 mL) and 2 M aqueous sodium carbonate solution (2.5 mL) was heated in a 10-20 mL Smith process vial in the microwave reactor for one hour at 120° C. The cooled mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude residue was purified via reverse-phase high performance liquid chromatography using a Phenomenex Gemini column, running a gradient elution of 20% acetonitrile/80% of 0.07% aqueous ammonium hydroxide to 95% acetonitrile over 10 minutes. After the concentration of fractions under reduced pressure, methyl 4-(6-(4-aminophenyl)-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate was obtained. MS (ES+): 464.6 (M+H)+
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(C=CC=2)N)C=CN=1.[Cl:23][C:24]1[N:29]=[C:28]([C:30]2[O:34][C:33]([C:35]([CH3:38])([CH3:37])[CH3:36])=[N:32][C:31]=2[C:39]2[C:40]([F:52])=[C:41]([NH:45]C(=O)OCC=C)[CH:42]=[CH:43][CH:44]=2)[CH:27]=[CH:26][N:25]=1.C([SnH](CCCC)CCCC)CCC>>[Cl:23][C:24]1[N:29]=[C:28]([C:30]2[O:34][C:33]([C:35]([CH3:38])([CH3:37])[CH3:36])=[N:32][C:31]=2[C:39]2[C:40]([F:52])=[C:41]([CH:42]=[CH:43][CH:44]=2)[NH2:45])[CH:27]=[CH:26][N:25]=1
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(C(C)(C)C)oc2-c2ccnc(Cl)n2)c1F
Agent: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Agent: CCCC[SnH](CCCC)CCCC
Product: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)o1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 13 using 2-propen-1-yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-oxazol-4-yl]-2-fluorophenyl}carbamate (1.2 g, 2.78 mmol) and tri-n-butyltin hydride (1.21 g, 4.17 mmol), the title compound was obtained as a yellow solid (530 mg, 55%). MS (ESI): 347 [M+H]+.
Reaction SMILES: [OH-].[Na+:2].C(O)C.[CH3:6][CH:7]([CH3:42])[CH2:8][C@H:9]([NH:31][C:32]([C@@H:34]1[O:36][C@H:35]1[C:37]([O:39]CC)=[O:38])=[O:33])[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[C:20]=2[O:29][CH3:30])[CH2:14][CH2:13]1)=[O:11]>C(O)C>[CH3:6][CH:7]([CH3:42])[CH2:8][C@H:9]([NH:31][C:32]([C@@H:34]1[O:36][C@H:35]1[C:37]([O-:39])=[O:38])=[O:33])[C:10]([N:12]1[CH2:13][CH2:14][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[C:20]=2[O:29][CH3:30])[CH2:16][CH2:17]1)=[O:11].[Na+:2]
Reactant: CCOC(=O)[C@@H]1O[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N1CCN(Cc2ccc(OC)c(OC)c2OC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CN2CCN(C(=O)[C@H](CC(C)C)NC(=O)[C@@H]3O[C@H]3C(=O)[O-])CC2)c(OC)c1OC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98 %

Procedure:
Under cooling with ice, a 0.48N sodium hydroxide-ethanol solution (9.48 ml) was added to an ethanol solution (20 ml) of ethyl trans-3-[(s)-3-methyl-1-{4-(2,3,4-trimethoxyphenylmethyl)piperazine-1-yl carbonyl}butylcarbamoyl]-oxirane-2-carboxylate (2.38 g) obtained above, and the mixture was stirred at room temperature for 2.5 hours. After removal of ethanol by distillation under reduced pressure, water was added, and any insoluble matters were removed by filtration using sellaite. The filtrate was concentrated and dried under reduced pressure to yield 2.31 g of sodium trans-3-[(s)-3-methyl-1-{4-(2,3,4-trimethoxyphenylmethyl)piperazine-1-yl carbonyl}butylcarbamoyl]oxirane-2-carboxylate as a light yellow powder (yield: 98%).
Reaction SMILES: C(Cl)Cl.[OH:4][C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:10][C:9]2[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=[CH:23][C:8]=2[NH:7][C:6]1=[O:28].[C:29]1(=[O:39])[O:34][C:32](=[O:33])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12>CN(C1C=CN=CC=1)C.C(N(CC)CC)C>[C:32]([C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=1[C:29]([O:4][C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:10][C:9]2[C:20]([C:24]([F:25])([F:26])[F:27])=[CH:21][CH:22]=[CH:23][C:8]=2[NH:7][C:6]1=[O:28])=[O:39])([OH:34])=[O:33]
Reactant: COc1ccc([C@H]2Cc3c(cccc3C(F)(F)F)NC(=O)[C@H]2O)cc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc([C@H]2Cc3c(cccc3C(F)(F)F)NC(=O)[C@H]2OC(=O)c2ccccc2C(=O)O)cc1
Temperature: 15 °C

Procedure:
Under argon, to dry methylene chloride (800 ml) and triethylamine (38 ml) was added DMAP (2.17 g) and (cis)-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin -2-one (62.51 g). After stirring, the so-formed suspension was cooled to about 15° C. and phthalic anhydride (39.53 g) was added. The resulting solution was warmed to room temperature and stirred for 4 hours. Upon quenching with 500 ml of dilute hydrochloric acid the layers were separated and the crystallized product from the methylene chloride layer was filtered and washed and dried in vacuo to give 84.8 g (95.4%) of the title A compound as a white crystalline solid, m.p. 161°-162° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]=[C:4]([CH2:12][N:13]2[C:17](=[O:18])[CH2:16][CH2:15][C:14]2=[O:19])[NH:3]1.[NH2:20][C:21]1[S:25][C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[C:22]=1[C:30](O)=[O:31].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[NH2:20][C:21]1[S:25][C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[C:22]=1[C:30]([N:9]1[CH2:8][CH2:7][C:6]2([N:5]=[C:4]([CH2:12][N:13]3[C:14](=[O:19])[CH2:15][CH2:16][C:17]3=[O:18])[NH:3][C:2]2=[O:1])[CH2:11][CH2:10]1)=[O:31]
Reactant: Nc1sc2ccccc2c1C(=O)O
Reactant: O=C1CCC(=O)N1CC1=NC2(CCNCC2)C(=O)N1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Nc1sc2ccccc2c1C(=O)N1CCC2(CC1)N=C(CN1C(=O)CCC1=O)NC2=O

Procedure:
5A (1.0 equivalent) in DMF (0.12 M) along with a 2-aminobenzo[b]thiophene-3-carboxylic acid (1.0 equivalent) was treated with EDC (1.0 equivalent), HOBt (1.0 equivalent) and Et3N (2.0 equivalents) at rt. The reaction mixture was stirred until the reaction was complete as determined by LCMS analysis and then partitioned between ethyl acetate and water. Organic layers were washed with brine and dried over Na2SO4, and volatiles removed under reduced pressure. Residue purified by LCMS to afford 1-((8-(2-aminobenzo[b]thiophene-3-carbonyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-2-yl)methyl)pyrrolidine-2,5-dione (5B).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Cl[CH2:45][C:46]1[CH:51]=[N:50][CH:49]=[CH:48][N:47]=1.BrCC1OC(C(F)(F)F)=CC=1>>[N:47]1[CH:48]=[CH:49][N:50]=[CH:51][C:46]=1[CH2:45][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21]
Reactant: ClCc1cnccn1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2cnccn2)c2ccccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1H)-one, and 2-(chloromethyl)pyrazine to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1′-(pyrazin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (27%) as a colorless solid: mp 143-144° C.; 1H NMR (300 MHz, CDCl3) δ8.64 (br s, 1H), 8.58-8.59 (m, 2H), 7.24-7.17 (m, 2H), 7.09-7.02 (m, 1H), 6.91-6.86 (m, 1H), 6.54 (s, 1H), 6.43 (s, 1H), 5.14 (ABq, 2H), 4.85 (ABq, 2H), 4.59-4.50 (m, 2H), 3.10-2.91 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.9, 161.9, 161.3, 151.4, 144.2, 143.9, 143.8, 141.6, 132.7, 128.8, 124.0, 123.8, 120.0, 119.9, 119.0, 109.1, 93.2, 80.6, 72.4, 57.8, 43.8, 29.0; MS (ES+) m/z 372.3 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH2:6][C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1.C(N(CC)CC)C>O1CCCC1>[C:1]([NH:5][CH2:6][C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)(=[O:3])[CH3:2]
Reactant: NCc1ncccc1OCc1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCc1ncccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Add dropwise with stirring a solution of 3.5 ml acetyl chloride in 50 ml THF (tetrahydrofuran) to a cooled solution of 10 gm of 2-aminomethyl-3-phenylmethoxypyridine and 7.1 ml triethylamine in 125 ml THF. Warm to room temperature and stir an additional hour. Remove triethylamine hydrochloride by filtration and evaporate the filtrate under reduced pressure. Recrystallize the residue from toluene to obtain 2-acetamidomethyl-3-(phenylmethoxy)pyridine, mp 94°-96°.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:53])[CH:15]([C:38]1[CH:43]=[CH:42][C:41]([S:44]([CH:47]2[CH2:49][CH2:48]2)(=[O:46])=[O:45])=[C:40]([CH:50]2[CH2:52][CH2:51]2)[CH:39]=1)[CH2:16][C@H:17]1[CH2:37][CH2:36][C:19]2(O[C@H](C3C=CC=CC=3)[C@@H](C3C=CC=CC=3)[O:20]2)[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CC(C)=O.C(=O)([O-])O.[Na+]>O>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:53])[C@@H:15]([C:38]1[CH:43]=[CH:42][C:41]([S:44]([CH:47]2[CH2:49][CH2:48]2)(=[O:46])=[O:45])=[C:40]([CH:50]2[CH2:52][CH2:51]2)[CH:39]=1)[CH2:16][C@H:17]1[CH2:37][CH2:36][C:19](=[O:20])[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)C(C[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C1CC[C@H](C[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)C1
Temperature: 25 °C
Yield: 41 %

Procedure:
A mixture of (4R)-4-benzyl-3-{2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]propanoyl}-1,3-oxazolidin-2-one (70 g), 4 M hydrochloric acid (140 mL), and acetone (560 mL) was stirred under heating and reflux for 2 hours. After leaving it to be cooled at room temperature, saturated aqueous sodium hydrogen carbonate solution/water (1/1, 200 mL) was added thereto, and the organic solvent was evaporated under reduced pressure, followed by extraction with ethyl acetate (200 mL×2). The organic layer was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70→50:50) to obtain (4R)-4-benzyl-3-{(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanoyl}-1,3-oxazolidin-2-one (21 g) as a colorless amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([O:13][CH3:14])=[C:4](Cl)[N:3]=1.[NH3:16]>CS(C)=O.O>[NH2:16][C:4]1[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]=1[O:13][CH3:14]
Reactant: COc1c(Cl)nc(Cl)nc1-c1ccco1
Reactant: N
Solvent: CS(C)=O
Solvent: O
Product: COc1c(N)nc(Cl)nc1-c1ccco1
Temperature: 60 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
2,6-Dichloro-5-methoxy-4-furan-2-yl pyrimidine (500 mg, 2.0 mmol) (see Example 5 for the preparation of 2,6-dicholor-5-methoxy-4-furan-2-yl pyrimidine) was dissolved in dry DMSO (10 mL) and heated to 60° C. This mixture was treated with a gentle stream of ammonia. After approximately 2 h, conversion was complete to about a 95:5 ratio of mono-amino isomers (having a molar weight of 225 g/mol). This mixture was cooled and diluted with water (50 mL), and the product extracted with ethyl acetate (2×50 mL). Then, the product was washed with ethyl acetate, twice with water (25 mL), and once with saturated sodium chloride (25 mL). The result was dried and concentrated. The product was purified by column chromatography using silica with a 5 to 20% ramp of ethyl acetate/hexane to give the title compound (400 mg, 89% yield). The various isomers were not separated.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.Cl.[C:12]1([C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:12]1([C:18]2[CH2:23][CH2:22][N:21]([C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=3)[CH2:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1=C(c2ccccc2)CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CC=C(c3ccccc3)CC2)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 1-fluoro-4-nitrobenzene (2.71 ml), 1,2,3,6-tetrahydro-4-phenylpyridine hydrochloride (5 g) and potassium carbonate (8.83 g) in dimethylsulfoxide (50 ml) was stirred for 1 hour at 100° C. The reaction mixture was pulverized with water. The precipitate was collected by filtration, and dried under reduced pressure to give 4-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)nitrobenzene.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH2:23]([CH:26]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=2[F:40])[CH2:29][NH:28][C:27]1=O)[CH:24]=[CH2:25]>C1(C)C=CC=CC=1>[CH2:23]([CH:26]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=2[F:40])[CH2:29][NH:28][C:27]1=[S:10])[CH:24]=[CH2:25]
Reactant: C=CCC1CCC(c2cccc(F)c2F)CNC1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: C=CCC1CCC(c2cccc(F)c2F)CNC1=S
Temperature: 45 °C
Reaction time: 3 h
Yield: 56.7 %

Procedure:
Lawesson's reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] (649 mg, 1.61 mmol) was added to a suspension 3-allyl-6-(2,3-difluorophenyl)azepan-2-one (426 mg, 1.61 mmol) in toluene (10 mL). After 3 h, the reaction mixture was heated to 45° C. After 30 min, the mixture was concentrated in a cold water bath. Purification by silica gel chromatography (100% hexanes→70% hexanes/ethyl acetate) gave the title compound (257 mg). MS 282.1 (M+1).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:18])([CH3:17])[C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH:11]=O)([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[NH2:24][OH:25].Cl.CC(O)=O>CC#N.CCCC[N+](CCCC)(CCCC)CCCC.[Cl-].O>[C:1]([SiH2:5][O:6][C:7]([CH3:18])([CH3:17])[C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH:11]=[N:24][OH:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(C=O)ccc1Cl
Reactant: NO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])O
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(C=NO)ccc1Cl
Reaction time: 0.08 h
Yield: 112.9 %

Procedure:
3-(tert-Butyl-dimethyl-silanyloxymethyl)-4-chloro-benzaldehyde (12.7 g, 44.6 mmol) was dissolved in CH3CN (53 mL). To this sol. was added NaHCO3 (11.2 g, 134 mmol), and the mixture was stirred vigorously for 5 min. Water (96 mL) was added and the mixture was stirred for 10 min. NH2OH—HCl (6.20 g, 89.2 mmol) was added dropwise, followed by TBAC (622 mg, 2.24 mmol). The mixture was stirred at rt for 1 h, and AcOH (4.00 mL) was added dropwise to pH 6-7. The mixture was diluted with water (100 mL), and this mixture was extracted with Et2O (3×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the crude title compound (15.1 g, 98%) that was used further without purification. LC-MS: tR=1.09 min; ES+: 341.13.