Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]2=[O:27])[CH2:10][CH2:9]1)(C)(C)C.NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]2=[O:27])[CH2:10][CH2:9]1
Reactant: Cc1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)CO2
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: Cc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2

Procedure:
tert-Butyl{1-[2-(6-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}-carbamate (Intermediate 92) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was obtained as a colorless solid and used without further purification for the next step (quantitative yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([NH:11][C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=3[F:19])=[C:9]([C:20](O)=[O:21])[CH:8]=[N:7][C:6]=12.Cl.[F:24][C:25]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([NH:11][C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=3[F:19])=[C:9]([C:20]([N:28]3[CH2:29][CH2:30][C:25]([F:24])([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:26][CH2:27]3)=[O:21])[CH:8]=[N:7][C:6]=12
Reactant: FC1(c2ccccc2)CCNCC1
Reactant: Cc1ccc(F)c(Nc2c(C(=O)O)cnc3c(Br)cnn23)c1
Agent: Cl
Product: Cc1ccc(F)c(Nc2c(C(=O)N3CCC(F)(c4ccccc4)CC3)cnc3c(Br)cnn23)c1
Yield: 29 %

Procedure:
In the same manner as in Example 21, step 5 and using 3-bromo-7-(2-fluoro-5-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (333 mg, 0.91 mmol) obtained in step 2 and 4-fluoro-4-phenylpiperidine hydrochloride (296 mg, 1.37 mmol), the title compound (1-39 mg, 29%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:15]C)=[C:6]([S:8]([NH:11][CH2:12][CH2:13][Cl:14])(=[O:10])=[O:9])[CH:7]=1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:15])=[C:6]([S:8]([NH:11][CH2:12][CH2:13][Cl:14])(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(Br)cc1S(=O)(=O)NCCCl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=S(=O)(NCCCl)c1cc(Br)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 29.9 g (91 mmol) of the product obtained in Step B above in 450 ml of CH2Cl2 there are added dropwise, at ambient temperature, 200 mL (200 mmol) of 1M BBr3 solution in CH2Cl2. After stirring for 30 minutes, the solution is poured onto an ice/water mixture, whilst continuing to stir. After separation and extracting once with CH2Cl2, the organic phase is washed with brine, dried over MgSO4 and evaporated. The oily residue is triturated in heptane until crystallisation takes place. The title product is collected by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][CH3:8])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl[C:21]1[S:22][C:23]([CH:27]=[O:28])=[C:24]([Cl:26])[N:25]=1>O1CCCC1>[Cl:26][C:24]1[N:25]=[C:21]([N:7]([CH2:6][C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH3:8])[S:22][C:23]=1[CH:27]=[O:28]
Reactant: CNCc1ccc(Cl)cc1
Reactant: O=Cc1sc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(Cc1ccc(Cl)cc1)c1nc(Cl)c(C=O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 119525.2 %

Procedure:
To a solution of (4-chloro-benzyl)-methyl-amine (550, 2 g, 0.01 mol) and N,N-diisopropylethylamine (4 mL, 0.03 mol) in tetrahydrofuran (50 mL) was added 2,4-dichloro-thiazole-5-carbaldehyde (93, 3 g, 0.01 mmol) in tetrahydrofuran (20 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was collected by filtration and washed with hexanes to provide the desired compound as a light-yellow solid (551, 3.6 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:25][N:26]([CH3:31])[S:27](Cl)(=[O:29])=[O:28]>O1CCCC1>[CH3:25][N:26]([CH3:31])[S:27]([NH:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:29])=[O:28]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCOC(=O)C1=Cc2cccc(N)c2OCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=Cc2cccc(NS(=O)(=O)N(C)C)c2OCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of ethyl 9-amino-2,3-dihydro-1-benzoxepin-4-carboxylate (1.0 g) and triethylamine (4.18 ml) in tetrahydrofuran (10 ml) was added dimethylsulfamoyl chloride (2.30 ml) at 5° C. The reaction mixture was stirred overnight at ambient temperature and partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of n-hexane and ethyl acetate (4:1) to give ethyl 2,3-dihydro-9-dimethylsulfamoylamino-1-benzoxepin-4-carboxylate (0.89 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.I[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=1[N+:18]([O-:20])=[O:19]>C(OCC)(=O)C>[N+:18]([C:8]1[CH:9]=[C:10]([O:13][C:14]([F:15])([F:16])[F:17])[CH:11]=[CH:12][C:7]=1[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1I
Reactant: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1-n1ccnc1
Yield: 69.3 %

Procedure:
1H-imidazole (818 mg, 12 mmol, 4 eq) and 1-iodo-2-nitro-4-(trifloromethoxy)benzene (1.0 g, 3 mmol, 1 eq) under argon are heated with a heat-gun at between 300 and 500° C. for 45 min until 1-iodo-2-nitro-4-(trifluoromethoxy)benzene has completely reacted on TLC monitoring. The crude mixture is cooled to room temperature, diluted in ethyl acetate and washed with a saturated solution of ammonium chloride. The organic phase is dried over sodium sulfate and concentrated under vacuum. Purification on silica gel (95/05 dichloromethane/methanol) afforded the title compound (570 mg, 2.08 mmol, 69%) as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[O:13]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:23](Cl)(=[O:26])[CH2:24][CH3:25].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][C:23](=[O:26])[CH2:24][CH3:25])=[CH:21][C:14]=3[O:13]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1OC
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCC(=O)Oc1ccc2c(c1)OC(=Cc1ccc(OC)c(OC)c1)C2=O
Temperature: 25 °C

Procedure:
After 2-[(3,4-dimethoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.525 g was dissolved in pyridine 5 ml, propionyl chloride 0.218 ml was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml, saturated sodium bicarbonate solution 50 ml, and a saturated sodium chloride solution 50 ml. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for five hours under reduced pressure to obtain the desired compound 311.6 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]/[CH:9]=N/NC(N)=O)=[C:4]([N+:15]([O-])=O)[CH:3]=1>C1COCC1.C1(C)C=CC=CC=1.[Rh]>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:8]=[CH:9][NH:15]2)=[CH:6][CH:7]=1
Reactant: NC(=O)N/N=C/Cc1ccc(F)cc1[N+](=O)[O-]
Agent: [Rh]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Fc1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.8 %

Procedure:
To a stirred suspension of (1E)-(4-fluoro-2-nitrophenyl)ethanal semicarbazone (27.0 g, 0.110 mol) in THF (750 mL) in a 1 L bomb was added Rh/C (5%; 3.5 g, 0.002 mol Rh) slurried in toluene and Fe(OAc)2 (2.9 g, 0.017 mol). The bomb was charged with H2 to 50 atm and stirred at room temperature for 2 days. The reaction mixture was filtered through celite, washing with MeOH (150 mL). The filtrate was concentrated to give a black oil that was partitioned between DCM (500 mL) and water (300 mL). The layers were separated and the aqueous fraction was extracted with DCM (2×200 mL). The combined organic extracts were washed with brine (200 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was dissolved in DCM (100 mL) and treated with flash silica to decolourise the solution. The mixture was filtered concentrated under reduced pressure, giving 12.9 g (87%) of the title compound.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.CCN(CC)CC.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1B(O)O>CN(C)C=O.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[NH:14]1[CH:15]=[CH:16][CH:17]=[C:13]1/[CH:12]=[C:4]1\[C:5](=[O:11])[NH:6][C:7]2[C:3]\1=[C:2]([C:26]1[S:25][CH:29]=[CH:28][CH:27]=1)[CH:10]=[CH:9][CH:8]=2
Reactant: OB(O)c1cccs1
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Nc2cccc(-c3cccs3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (36.9 mg, 0.110 mmol) (Starting Material 1), Et3N (46 μL, 0.329 mmol), tri-o-tolylphosphine (2.1 mg, 0.007 mmol) (Aldrich), Pd(OAc)2 (0.7 mg, 0.003 mmol) (Aldrich), and 2-thiopheneboronic acid (21.1 mg, 0.165 mmol) (Aldrich) in 439 μL of dry N,N-dimethylformamide was heated at 100° C. for 24 h. The reaction mixture was allowed to cool to room temperature, concentrated in vacuo to remove N,N-dimethylformamide, and then directly purified by flash chromatography (Merck Silica gel 60, 70-230 mesh, 10% ethyl acetate-hexanes then 25% ethyl acetate-hexanes elution) to provide pure (Z)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-4-(2-thiophenyl)-2H-indol-2-one (Yield 26.8 mg, 83%) as an orange solid (mp 213-214° C.).
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH:15]=2)[N:10]([CH3:24])[C:9]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:38][C:39]([O:41][CH3:42])=[O:40]>CC(C)=O>[CH3:42][O:41][C:39](=[O:40])[CH2:38][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([CH3:24])[C:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:8]3[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:19]=1
Reactant: Cn1c(-c2ccccc2)c(Cc2ccccc2)c2cc(-c3ccc(O)cc3)ccc21
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(-c2ccccc2)n3C)cc1

Procedure:
The desired product was prepared using a procedure similar to step 1 of example 4. Thus, 4-(3-benzyl-1-methyl-2-phenyl-1H-indol-5-yl)-phenol (0.140 g, 0.359 mmol) was reacted with K2CO3 (0.065 g, 0.467 mmol) and methyl bromoacetate (0.071 g, 0.467 mmol) in acetone (5 ml) to give the product (0.141 g, 0.305 mmol, 85%) as a glass-like solid. 1H NMR (DMSO-d6) δ 3.62 (s, 3H), 3.70 (s, 3H), 4.04 (s, 2H), 4.81 (s, 2H), 6.97 (d, J=8.9 Hz, 2H), 7.07-7.11 (m, 3H), 7.18 (t, J=7.6 Hz, 2H), 7.41-7.57 (m, 10H); [ESI(+)], m/z 462 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:15])[CH:7]=1>>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:15])[C:7]=1[N+:1]([O-:4])=[O:2]
Reactant: Cc1cc(Cl)ccc1C(=O)O
Reactant: O=[N+]([O-])O
Product: Cc1c(C(=O)O)ccc(Cl)c1[N+](=O)[O-]
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To fuming nitric acid (20.4 mL, 410 mmol) was slowly added dropwise 4-chloro-2-methylbenzoic acid (5.0 g, 29.3 mmol) while maintaining the temperature of the reaction mixture at 5-10° C. The reaction solution was stirred at 0-5° C. for 1 hr, and poured into ice. The precipitated solid was recovered, washed with water, and dried under reduced pressure to give 4-chloro-2-methyl-3-nitrobenzoic acid (6.14 g, purity 33%) as a crudely purified product.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[C:11]1[C:10]([OH:17])=[CH:9][C:8]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:7][C:6]=1[O:5]2.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][OH:31].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>CS(C)=O>[OH:17][C:10]1[C:11]2[C:12](=[O:16])[C:13]3[C:4](=[CH:3][C:2]([O:31][CH2:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)=[CH:15][CH:14]=3)[O:5][C:6]=2[CH:7]=[C:8]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:9]=1
Reactant: OCc1ccccn1
Reactant: O=c1c2ccc(F)cc2oc2cc(N3CCOCC3)cc(O)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1c2ccc(OCc3ccccn3)cc2oc2cc(N3CCOCC3)cc(O)c12
Temperature: 80 °C

Procedure:
6-Fluoro-1-hydroxy-3-morpholin-4-yl-xanthen-9-one (15 mg, 0.05 mmol) and 2-pyridylmethanol (8 mg, 0.07 mmol) were dissolved in DMSO (0.25 mL) and KHMDS (0.5 M in toluene, 0.24 mL) was added. The reaction mixture was heated to 80° C. for 16 hours. The reaction was quenched with sat. NH4Cl/water (1:1, 2 mL) and the solids were filtered. The crude solid was purified via flash chromatography eluting with CH2Cl2/MeOH (98:2) to produce 4.9 mg (25%). 1H NMR (CDCl3, 400 MHz) δ: 12.80 (s, 1H), 8.63 (d, 1H), 8.13 (d, 1H), 7.76 (dd, 1H), 7.52 (d, 1H), 7.27-7.24 (m, 1H), 7.02 (d, 1H), 6.88 (s, 1H), 6.27 (s, 1H), 6.23 (s, 1H), 5.31 (s, 2H), 3.86-3.83 (m, 4H), 3.37-3.35 (m, 4H). LRMS (APCI, positive): Da/e 405.1 (m+1).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH2:11][C:8]2([CH2:10][CH2:9]2)[CH:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6][CH:5]=1.[F-].[K+]>CO>[O:3]=[C:4]1[CH2:11][C:8]2([CH2:9][CH2:10]2)[CH:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6][CH2:5]1
Reactant: CCOC(=O)C1CC=C(O[Si](C)(C)C)CC12CC2
Agent: [F-]
Agent: [K+]
Solvent: CO
Product: CCOC(=O)C1CCC(=O)CC12CC2
Temperature: 25 °C
Yield: 20.2 %

Procedure:
The product of Step 1 (1.698 g, 6.33 mmol) was dissolved in methanol (6 ml). Potassium fluoride (0.404 g, 6.96 mmol) was added, and the solution was maintained at room temperature for 1 hour. The solution was concentrated in vacuo. Purification via silica gel column chromatography (0-25% EtOAc:Hexanes) afforded ethyl 7-oxospiro[2.5]octane-4-carboxylate (251 mg, 20%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 4.27-4.14 (m, 2H), 2.90 (d, J=14.9, 1H), 2.66 (ddd, J=5.6, 11.4, 16.8, 1H), 2.42-2.25 (m, 2H), 2.15-2.04 (m, 2H), 1.68 (d, J=14.9, 1H), 1.34-1.26 (m, 3H), 0.76-0.67 (m, 1H), 0.50-0.40 (m, 2H), 0.40-0.31 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[S:17][CH:18]=[C:19]([CH2:21][OH:22])[N:20]=3)[CH:13]=[CH:12][N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(O)(C)(C)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[S:17][CH:18]=[C:19]([CH:21]=[O:22])[N:20]=3)[CH:13]=[CH:12][N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(Nc2nccc(-c3nc(CO)cs3)n2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: Cc1cc(C)cc(Nc2nccc(-c3nc(C=O)cs3)n2)c1
Reaction time: 1 h

Procedure:
To a solution of 7a (100 mg, 0.320 mmol) and 163 uL of t-butanol in 2 mL of DCM was added 163 mg of Dess_Martin periodinane reagent. The reaction mixture was stirred for 1 h after which it was quenched with sodium thiosulfate (1 mL). It was stirred until the two phase became clear. The organic layer was dried (Na2SO4) and concentrated in vacuo to give 35 mg (38%) the crude aldehyde 9a that was used directly for the next step. 1H NMR (CDCl3) δ 10.1 (s, 1H), 8.3 (d, 1H), 8.1 (s, 1H), 7.5 (d, 1H), 7.2 (s, 2H), 6.8 (s, 1H), 2.3 (s, 6H).
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.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>CN1CCCC1=O.O>[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=2)=[CH:28][CH:27]=1
Reactant: NCc1ccc(F)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(NCc3ccc(F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (1 g, 2.629 mmol) in N-methylpyrrolidone (10 ml) was treated with 4-fluorobenzylamine (0.60 ml). The mixture was stirred at room temp for 18 h and was then diluted with water (50 ml). This gave the title compound as a colourless solid which was collected by filtration and dried (0.72 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.[C:10]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([O:8][CH3:10])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(Br)ccc1F
Agent: [K+]
Solvent: CI
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1cc(Br)ccc1F
Temperature: 40 °C
Yield: 77.3 %

Procedure:
To a solution of 7A (3.3 g, 17.3 mmol) and K2CO3 (4.78 g, 34.6 mmol) in DMF (20 mL) was added methyl iodide (1.46 mL, 23.4 mmol) at rt. The mixture was heated at 40° C. for 2.0 h. After cooling to rt, it was diluted with diethyl ether, washed with water and brine, dried over MgSO4. The crude residue was purified by flash column chromatography (EtOAc:hexanes=1:6) to give 2.74 g (77%) of 7B as a viscous oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.89 (s, 3H), 6.95-7.00 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)(Cl)=O.[OH-:18].[Na+]>C(O)C>[CH3:4][C:5]1[N:1]=[C:2]2[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][N:3]2[C:8](=[O:18])[C:6]=1[CH2:7][CH3:2]
Reactant: CCOC(=O)c1ccnc(N)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1ccn2c(=O)c(CC)c(C)nc2c1
Yield: 42 %

Procedure:
0.02 moles of 2-amino-4-ethoxycarbonylpyridine and 0.02 moles of ethyl-2-ethylacetacetate are stirred in a mixture of 10 ml. of phosphorous oxychloride and 2 g. of polyphosphoric acid at 120° C. for 2 hours. The reaction mixture is treated with 20 ml. of ethanol at 70° to 80° C., whereupon it is neutralized with a 10% (w/v) aqueous sodium hydroxide solution with ice cooling. The ethanol is evaporated, the residue is extracted with four 25-ml. portions of chloroform and the combined extracts are dried and evaporated. The evaporation residue is triturated with ether to give crystalline 2-methyl-3-ethyl-8-ethoxycarbonyl-4-oxo-4H-pyrido-(1,2-a)pyrimidine, melting at 95° to 96° C. Yield 42%. The product does not give any melting point depression when admixed with the product of Example 17.
Reaction SMILES: CN(C=O)C.C(Cl)(=O)C(Cl)=O.[O:12]=[C:13]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]([NH2:28])=O)[C:14](=[O:20])[C:15]([CH3:19])([CH3:18])[CH2:16][CH3:17].N1C=CC=CC=1>C(#N)C.O>[O:12]=[C:13]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]#[N:28])[C:14](=[O:20])[C:15]([CH3:18])([CH3:19])[CH2:16][CH3:17]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(N)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C#N
Reaction time: 0.08 h
Yield: 72 %

Procedure:
To a solution of 0.465 mL DMF (6 mmol) in 10 mL acetonitrile at 0° C. was added 0.48 mL (5.5 mmol) of oxalyl chloride. A white precipitate formed immediately and was accompanied by gas evolution. When complete, a solution of 1.2 g (5 mmol) of (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxamide (from Example 2) in 2.5 mL acetonitrile was added. When the mixture became homogeneous, 0.9 mL (11 mmol) pyridine was added. After 5 min., the mixture was diluted into water and extracted by 200 mL ethyl acetate. The organic layer was concentrated and further purified by silica gel to give 0.8 g product as a white solid (72% yield). 1H NMR (CDCl3): δ 0.87 (t, 0.3H, J=7.5); 1.22 (s, 3H); 1.24 (s, 3H); 1.80 (m, 2H); 2.03–2.23 (m, 4H); 3.55 (m, 2H); 4.73 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C@@H:4]([OH:9])[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)([O-:23])=[O:22].O>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C@@H:4]([O:9][S:30]([C:27]1[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:29][CH:28]=1)(=[O:31])=[O:32])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@H](O)c1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@H](OS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1Cl
Yield: 81.7 %

Procedure:
(R)-Methyl o-chloromandelate (98.4 g, 0.49 mol, ee=99%) was dissolved in 500 ml of anhydrous dichloromethane, and then 91 ml of triethylamine (0.65 mol) and a catalytic amount of DMAP were added. 120 g (0.54 mol) of p-nitrophenylsulfonyl chloride was dissolved in 500 ml of anhydrous dichloromethane, which was added dropwise into the reaction solution at 0° C., and reacted for 4-5 hrs at 0° C. Water (500 ml) was added to the reaction solution and the layers were separated. The aqueous phase was extracted with dichloromethane (150 ml×3), and the organic phases were combined and dried, and dichloromethane was evaporated under reduced pressure to afford 206.5 g of a crude product as a dark red oil, which was recrystallized in methanol to obtain 154.5 g of a solid product (II-1). Yield 82%. 1H-NMR (300 MHz, CDCl3) δ 3.57 (s, 3H), 6.39 (s, 1H), 7.21-7.39 (m, 4H), 8.07 (d, 2H, J=8.9 Hz), 8.30 (d, 2H, J=8.9 Hz); ESI-MS m/z 408.0 [M+Na]+.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]2[C:2]=1[CH:3]1[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH:4]1[CH2:5][O:6]2.[H-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23].Cl>CN(C=O)C.O>[CH2:23]([O:11][C:9]1[CH:8]=[C:7]2[C:2]([CH:3]3[O:14][C:13]4[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=4[CH:4]3[CH2:5][O:6]2)=[CH:1][CH:10]=1)[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: Oc1ccc2c(c1)OCC1c3ccccc3OC21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc2c(c1)OCC1c3ccccc3OC21
Yield: 49.3 %

Procedure:
Compound 6a,11a-Dihydro-6H-benzo[4,5]furo[3,2-c]chromen-3-ol (100 mg, 0.42 mmol) was dissolved in DMF (5 ml) and NaH (10 mg, 0.42 mmol) was added to the solution at room temperature, followed by allyl bromide (0.07 ml, 0.84 mmol). The reaction mixture was stirred at room temperature to 6 hours and poured into iced water and neutralized with 10% HCl to get the white precipitate. Precipitate were washed with water and purified by silica gel column chromatography using hexane-chloroform as the eluent to give 3-(allyloxy)-6a,11a-dihydro-6H-benzofuro[3,2-c]chromene (58 mg, 50%) as white solid.