Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]1[CH2:14][N:13](C(OCC2C=CC=CC=2)=O)[CH2:12]1.[H][H]>CO.[Pd]>[NH:13]1[CH2:14][CH:11]([C:3]2[N:2]([CH3:1])[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[N:4]=2)[CH2:12]1
Reactant: [H][H]
Reactant: Cn1c(C2CN(C(=O)OCc3ccccc3)C2)nc2ccccc21
Agent: [Pd]
Solvent: CO
Product: Cn1c(C2CNC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-3 (3.32 g, 10.33 mmol) in MeOH (52 mL) was subjected to 2 cycles of the evacuation/backfilling with nitrogen and then treated with 10% Pd/C (1.1 g). The evacuation/backfilling with nitrogen procedure was repeated two times and then the nitrogen atmosphere was exchanged for a hydrogen atmosphere by evacuation/backfilling with a balloon of hydrogen. After stirring for 3 h under hydrogen at room temperature, the reaction mixture was filtered through celite, and washed with additional MeOH (20 mL). The filtrate was concentrated to yield Intermediate 1 as brown solid. MS: m/z=188.2 (M+H).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:32])([F:31])[C:9]1[C:13]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[N+:23]([O-:25])=[O:24])[OH:15])=[C:12]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[NH:11][N:10]=1>ClCCl.[O-2].[Cr+6].[O-2].[O-2]>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]([C:13]2[C:9]([C:8]([F:31])([F:7])[F:32])=[N:10][NH:11][C:12]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:15])=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=1
Reactant: CCOC(=O)c1[nH]nc(C(F)(F)F)c1C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1[nH]nc(C(F)(F)F)c1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.4 %

Procedure:
Chromium(VI) oxide (CrO3, 2.828 g, 28.28 mmol) was added to a solution of pyridine (4.58 mL, 56.63 mmol) in dichloromethane (70 mL) and the mixture was stirred at room temperature for 15 minutes. To the resulting burgundy-colored solution was added a solution of ethyl 3-trifluoromethyl-4-[(4-chloro-2-nitro-phenyl)(hydroxy)methyl]-1H-pyrazole-5-carboxylate (1.64 g, 4.17 mmol) in dichloromethane (15 mL). The resulting mixture was stirred at room temperature for 4 days. The dichloromethane solution was decanted from the dark viscous residue, which was washed with diethyl ether (3×100 mL). The dichloromethane and diethyl ether extracts were combined, washed successively with 1 N aqueous hydrochloric acid (2×100 mL) and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated by rotary evaporation to afford 1.33 g (82%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:15])[F:14])[NH:6]2.Cl.Cl[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:14])[F:15])[N:6]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1Cl
Reactant: ClCc1ccccn1
Agent: Cl
Product: N#Cc1ccc2c(cc(C(F)F)n2Cc2ccccn2)c1Cl

Procedure:
Synthesized as described in Example 39 from 4-chloro-2-(difluoromethyl)-1H-indole-5-carbonitrile and 2-(chloromethyl)pyridine hydrochloride. MS (ESI) m/z 318.07 (M+1).
Reaction SMILES: [C:1]([I:20])([C:4]([C:7]([C:10]([C:13]([C:16]([F:19])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[C:21](=O)([O-:25])[O:22]CC.C(C(OCC)=O)(C(C(C(C(C(F)(F)F)(F)F)(F)F)(F)F)(F)F)(F)F.C(C(O)=O)(C(C(C(C(C(F)(F)F)(F)F)(F)F)(F)F)(F)F)(F)F>[Cu].[Zn].CS(C)=O>[C:1]([I:20])([C:4]([C:7]([C:10]([C:13]([C:16]([F:17])([F:18])[F:19])([F:14])[F:15])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[C:21](=[O:25])=[O:22]
Reactant: CCOC(=O)[O-]
Agent: [Cu]
Agent: CCOC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Solvent: CS(C)=O
Product: O=C=O
Reaction time: 3 h

Procedure:
44.6 g. of C6F13I and 12 g. of ethyl carbonate are dissolved in 30 ml. of DMSO and added slowly to a dispersion of 18 g. of zinc-copper couple in 40 ml. of DMSO. At the end of the addition, which lasts 3 hours, the reaction mixture is centrifuged and by decanting a yellow liquid is obtained and identified by comparison of NMR and infrared spectra with that of a sample of C6F13COOC2H5 prepared by esterification of the acid, C6F13COOH, obtained by reaction of C6F13I and of CO2.
Reaction SMILES: [OH:1][CH:2]([C:4]([CH3:18])([CH:16]=[CH2:17])[C:5]([N:7]1[C@@H:11]([CH:12]([CH3:14])[CH3:13])[CH2:10][O:9][C:8]1=[O:15])=[O:6])[CH3:3].[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].N1C=CN=C1>CN(C)C=O>[C:22]([Si:19]([CH3:21])([CH3:20])[O:1][CH:2]([C:4]([CH3:18])([CH:16]=[CH2:17])[C:5]([N:7]1[C@@H:11]([CH:12]([CH3:13])[CH3:14])[CH2:10][O:9][C:8]1=[O:15])=[O:6])[CH3:3])([CH3:25])([CH3:24])[CH3:23]
Reactant: C=CC(C)(C(=O)N1C(=O)OC[C@@H]1C(C)C)C(C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CC(C)(C(=O)N1C(=O)OC[C@@H]1C(C)C)C(C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 68.7 %

Procedure:
A solution of (S)-3-[2-(1-hydroxy-ethyl)-2-methyl-but-3-enoyl]-4-isopropyl-oxazolidin-2-one (1.742 g, 6.809 mmol) and tert-butyldimethylsilyl chloride (1.231 g, 8.17 mmol) in anhydrous N,N-dimethylformamide (10 mL) was treated with imidazole (927 mg, 13.618 mmol). After stirring at room temperature for 6 h, tert-butyldimethylsilyl chloride (1.1 g, 7.3 mmol) and imidazole (950 mg, 13.954 mmol) were added. After stirring at room temperature for 12 days, the reaction was quenched with a saturated solution of ammonium chloride. The aqueous layer was extracted with diethyl ether (2×). The organics were combined, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/diethyl ether 1:0 to 1:1 to afford the title compound (1.729 g, 69%) as an undetermined mixture of diastereoisomers and as a yellow oil. LCMS (m/z) 370.1 [M+H], Tr=3.96 min and 370.1 [M+H], Tr=4.22 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([CH2:18][OH:19])[CH:14]=1)=[C:5]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC(O)=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([C:18]([OH:28])=[O:19])[CH:14]=1)=[C:5]2[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)c1-c1cc(CO)no1
Reactant: CC(=O)O
Product: O=C(O)c1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)on1
Temperature: 50 °C
Reaction time: 3 h
Yield: 21 %

Procedure:
To a solution of 6-chloro-3-(3-hydroxymethyl-isoxazol-5-yl)-4-phenyl-1H-quinolin-2-one (example 21) (353 mg, 1 mmol) in HOAc (1 mL), CrO3 (100 mg, 1 mmol) was added. The resulting mixture was stirred at 50° C. for 3 h. The reaction mixture was allowed to cool to RT and HOAc was removed. The residue was subjected to reversed phase HPLC to obtain the title compound. Yield 21%.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](O)=[O:4].ClC(Cl)(Cl)C([O-])=O.[Na+].[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:30]=[CH:29][C:26](C=O)=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>CN(C)C=O>[Cl:1][C:2]([Cl:7])([Cl:6])[CH:3]([C:26]1[CH:25]=[CH:24][C:23]([N:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)=[CH:30][CH:29]=1)[OH:4]
Reactant: O=C(O)C(Cl)(Cl)Cl
Reactant: CN1CCN(c2ccc(C=O)cc2)CC1
Agent: O=C([O-])C(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(C(O)C(Cl)(Cl)Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
1.0 ml (10.00 mmol) of trichloroacetic acid and, in small portions, 1.854 g. (10 mmol) of sodium 2,2,2-trichloroacetate are added at room temperature to a solution of 1.362 g (6.67 mmol) of 4-(4-methylpiperazine-1-yl)benzaldehyde in 13.5 ml of dimethylformamide. The reaction mixture is stirred for 3 hours at room temperature. The solvent is concentrated and the crude reaction product extracted with ethyl acetate. The organic phase is washed using saturated sodium bicarbonate solution. The organic phases are combined, dried on magnesium sulfate and then concentrated to yield 1.760 g (yield=82%) of 2,2,2-trichloro-1-(4-(4-methylpiperazine-1-yl)phenyl)ethanol in the form of a white solid.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:19]=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[Li]CCCC.[CH:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[C:33]1([CH:32]([C:4]2[CH:3]=[CH:2][CH:10]=[C:9]3[C:5]=2[C:6]([CH:19]=[CH:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:7][N:8]3[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:18])[CH3:16])[OH:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=Cc1ccccc1
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(I)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2c(C(O)c3ccccc3)cccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of 6-iodo-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole, prepared in Example 14, step (i), (143 mg, 0.3 mmol) in THF (1 mL) cooled to −78° C. under an atmosphere of argon was added n-BuLi (0.2 mL, 0.315 mmol) dropwise. The resulting mixture was stirred at −78° C. for 30 min, then a solution of benzaldehyde (0.035 mL, 0.33 mmol) in THF (0.5 mL) was added rapidly via a cannula. After 0.5 h the reaction was quenched with saturated NH4Cl (aq) and diluted with EtOAc (10 mL) and H2O (3 mL). The phases were separated and the aqueous was extracted 2×10 mL EtOAc. The pooled EtOAc was washed with brine (5 mL), dried with Na2SO4, decanted and concentrated under reduced pressure. The crude mixture was purified by silica gel chromatography (eluting with hexane:EtOAc 4:1) to give phenyl-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-yl}-methanol (68 mg, 50% yield). Rf sm=0.72; Rf p=0.39 (7:3 hexane:EtOAc); FTIR (thin film) 3368, 2952, 2893, 1621, 1478, 1449, 1374, 1307, 1249, 1216, 1078, 960, 859, 835 cm−1. MS (ESI) [M+H]/z Calc'd 457, found 457.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH2:4][C@H:5]([C:13]([OH:15])=[O:14])[NH:6][CH2:7]2.S(=O)(=O)(O)O.[CH3:21]O>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH2:4][C@H:5]([C:13]([O:15][CH3:21])=[O:14])[NH:6][CH2:7]2
Reactant: O=C(O)[C@H]1Cc2c(Br)ccc(O)c2CN1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)[C@H]1Cc2c(Br)ccc(O)c2CN1
Temperature: 85 °C
Yield: 98 %

Procedure:
Slurry the 5-bromo-8-hydroxy-1,2,3,4-tetrahydroisoquinoline-3(R)-carboxylic acid (1.538 g, 0.005652 mol) in methanol (60 mL). Add sulfuric acid (305 uL, 0.00572 mol). Heat at 85° C. for 2.5 days. Cool the solution to room temperature and concentrate under reduced pressure to a volume of ˜5 mL. Add ethyl acetate (100 mL) and neutralize with 10% aqueous potassium carbonate. Separate the layers and extract the aqueous layer with ethyl acetate (1×100 mL). Combine the organic layers and dry over magnesium sulfate. Concentrate the filtrate to give the desired product (1.65 g, 98%) as a light pink solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[C:28]([Cl:29])=[CH:27][C:26](I)=[CH:25][C:24]=3[Cl:31])=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[Li+].[CH2:35]([Zn]CC)[CH3:36].CCCCCCC.[NH4+].[Cl-]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6](=[O:32])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[C:28]([Cl:29])=[CH:27][C:26]([CH2:35][CH3:36])=[CH:25][C:24]=3[Cl:31])=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(OCc3c(Cl)cc(I)cc3Cl)cc2)C1
Reactant: CC[Zn]CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CCc1cc(Cl)c(COc2ccc(C3CN(CCC(=O)OC(C)(C)C)CCO3)cc2)c(Cl)c1
Temperature: 0 °C

Procedure:
3-{2-[4-(2,6-Dichloro-4-iodo-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acid tert-butyl ester (0.34 g; 0.57 mmol), and Pd(dppf)Cl2 (14.70 mg; 0.02 mmol) were added to a solution of lithium chloride (4.59 ml; 0.50 mol/l; 2.30 mmol) in THF; 0.04 eq.). The resulting mixture was cooled to 0° C. and a solution of diethylzinc in n-heptane (1.15 ml; 1.00 mol/l; 1.15 mmol) was added dropwise. The mixture was heated to 60° C. overnight. After cooling to RT saturated aqueous NH4Cl was added. The mixture was extracted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, EtOAc:hexanes 1:1) to afford 3-{2-[4-(2,6-dichloro-4-ethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acid tert-butyl ester (115.00 mg)
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:11]([CH:12]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:13][O:14][Si](C(C)(C)C)(C)C)=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7].O.O.O.[F-].C([NH3+])(C)(C)C.O>O1CCCC1>[CH3:1][C:2]1[O:3][C:4]2[C:11]([CH:12]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:13][OH:14])=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7]
Reactant: CCN(CC)C(CO[Si](C)(C)C(C)(C)C)c1cccc2c(C)c(C)oc12
Agent: CC(C)(C)[NH3+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C(CO)c1cccc2c(C)c(C)oc12
Temperature: 0 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
2.77 g (7.68 mmol) of 2,3-dimethyl-7-(1-diethylamino-2-[tert-butyldimethylsilyloxy]ethyl)benzofuran and 30 ml of tetrahydrofuran are introduced into a 250 ml round-bottomed flask. The reaction mixture is cooled to 0° C. by an ice bath and a solution of 2.9 g (9.21 mmol) of tert-butylammonium fluoride trihydrate in 10 ml of tetrahydrofuran is added. The reaction mixture is stirred at 0° C. for 1 hour and at room temperature for 16 hours. 150 ml of water are added and extraction is carried out with ethyl ether (3×200 ml). The organic phases are combined, dried over magnesium sulphate and concentrated under vacuum. The residue is purified by chromatography on a silica column (elution solvent: 5% methanol in dichloromethane). 1.6 g (Yield: 80%) of 2,3-dimethyl-7-(1-diethylamino-2-hydroxyethyl)benzofuran are obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[OH:22].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[OH:22]
Reactant: Oc1ccc2ccccc2c1Br
Reactant: OB(O)c1ccccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CCO
Product: Oc1ccc2ccccc2c1-c1ccccc1F
Temperature: 80 °C
Yield: 69 %

Procedure:
Into a 200 mL three-neck flask were placed 1.4 g (10 mmol) of 2-fluorophenylboronic acid, 2.2 g (10 mmol) of 1-bromo-2-naphthol, 153 mg (0.50 mmol) of tri(ortho-tolyl)phosphine, 25 mL of toluene, 25 mL of ethanol, and 5.0 mL of a 2M aqueous solution of potassium carbonate. This mixture was degassed under reduced pressure, and the air in the system was replaced with nitrogen. This mixture was stirred at 80° C., 23 mg (0.10 mmol) of palladium(II) acetate was added thereto, and the mixture was refluxed at about 100° C. for 6.5 hours. After the reflux, this mixture was washed with water, and the aqueous layer was subjected to extraction with ethyl acetate. The obtained solution of the extract and the organic layer were combined and washed with saturated brine. The obtained organic layer was dried over magnesium sulfate. This mixture was gravity-filtered, and the obtained filtrate was concentrated to give a brown oily substance. This oily substance was purified by silica gel column chromatography (developing solvent: toluene), so that 1.6 g of a brown oily substance of the object of the synthesis was obtained in 69% yield. The above-described synthesis, scheme is illustrated in the following scheme (B-1).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[O:10]=[C:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH:18]=2)[C:13](=O)[O:12]1.O>CN(C=O)C>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[N:4]1[C:13](=[O:12])[C:14]2[C:19](=[CH:18][CH:17]=[C:16]([C:20]([OH:22])=[O:21])[CH:15]=2)[C:11]1=[O:10]
Reactant: Cc1cccc(C)c1N
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1N1C(=O)c2ccc(C(=O)O)cc2C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,6-dimethylaniline (1.21 g) in DMF (15 mL) was added 1,3-dioxo-1,3-dihydroisobenzofuran-5-carboxylic acid (1.92 g) and the mixture was stirred at room temperature for 18 h. The mixture was poured into water and the resulting precipitate was filtered, washed with water and dried under reduced pressure. The solid was suspended in HOAc (25 mL) and the mixture was heated at 110° C. for 4 h. The resulting solution was cooled and the solvent was removed under reduced pressure to give 2-(2,6-dimethylphenyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid as an off-white solid, mp=210-213° C.; MS (m/z) 294 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C@@:8]2([CH3:26])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[O:23][CH3:24])[C:12](=[O:25])[CH2:11]S[CH2:9]2)[CH:7]=1.O[O:29][S:30]([O-:32])=O.[K+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C@@:8]2([CH3:26])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[O:23][CH3:24])[C:12](=[O:25])[CH2:11][S:30](=[O:32])(=[O:29])[CH2:9]2)[CH:7]=1
Reactant: O=S([O-])OO
Reactant: COc1ccc(CN2C(=O)CSC[C@@]2(C)c2cc(Br)ccc2F)c(OC)c1
Agent: [K+]
Solvent: CO
Product: COc1ccc(CN2C(=O)CS(=O)(=O)C[C@@]2(C)c2cc(Br)ccc2F)c(OC)c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of (R)-5-(5-bromo-2-fluorophenyl)-4-(2,4-dimethoxybenzyl)-5-methylthiomorpholin-3-one (2.95 g, 6.49 mmol, Eq: 1.00) in methanol (100 ml) was added at 23° C. Oxone® (7.98 g, 13.0 mmol, Eq: 2.00). The reaction mixture was stirred at 23° C. for 16 hours. The reaction mixture was carefully quenched by addition of water at 0° C., then 10 ml of a diluted NaHSO3-solution, sat. NaHCO3-solution and ethyl acetate were added. Vigorous stirring was continued for 10 min. The organic layer was separated and washed with water, then dried over Na2SO4, filtered and evaporated to give a yellow oil which was chromatographed on 20 g silica gel with 0-50% ethyl acetate in heptane to give (R)-5-(5-bromo-2-fluoro-phenyl)-4-(2,4-dimethoxy-benzyl)-5-methyl-1,1-dioxo-1λ6-thiomorpholin-3-one (3 g, 6.17 mmol, 95.0% yield) as a white foam. MS (ISP): m/z=486.2 [M+H]+ and 488.1 [M+2+H]+.
Reaction SMILES: C([O:3][C:4](=[O:15])[CH:5]([C:13]#[N:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[C:13]([CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:15])=[O:3])#[N:14]
Reactant: CCOC(=O)C(C#N)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#CC(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
To a solution of 406 mg of 2-cyano-3-phenylpropionic acid ethyl ester in 10 ml of ethanol were added 1.1 ml of a 2N-aqueous sodium hydroxide solution, and then the mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water and washed with diethyl ether. The aqueous solution was adjusted to a pH of 2 by adding a 2N-hydrochloric acid and extracted with diethyl ether. The ethereal layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 324 mg of 2-cyano-3-phenylpropionic acid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[CH2:24][CH3:25]>CN(C=O)C>[CH2:24]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:18]=1[CH2:17][S:8][C:6]1[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=1)[CH3:25]
Reactant: Cc1cc(O)nc(S)n1
Reactant: CCc1cnccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cnccc1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 7 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (686 mg, 4.8 mmol) was dissolved in anhydrous DMF (30 mL), and then potassium carbonate (2.0 g, 14.5 mmol) and 4-(bromomethyl)-3-ethylpyridine (5.8 mmol) in DMF (10 mL) were added. The mixture was stirred for 2.5 hours at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 3-12% DCM/MeOH to afford 2-{[(3-ethylpyridin-4-yl)methyl]sulfanyl)-6-methylpyrimidin-4-ol (88 mg, 6% yield for 3 steps).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]2[O:6][CH2:7][C:8]3([CH2:22][O:23][C:4]=2[CH:3]=1)[O:12][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[N:10]([CH:19]([CH3:21])[CH3:20])[CH2:9]3.N12CCN(CC1)CC2.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>CCOCC>[CH:19]([N:10]1[CH2:9][C:8]2([CH2:7][O:6][C:5]3[CH:24]=[CH:25][C:2]([NH:1][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:3][C:4]=3[O:23][CH2:22]2)[O:12][CH:11]1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([CH3:20])[CH3:21]
Reactant: CC(C)N1CC2(COc3ccc(N)cc3OC2)OC1c1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: C1CN2CCN1CC2
Solvent: CCOCC
Product: CC(C)N1CC2(COc3ccc(NS(C)(=O)=O)cc3OC2)OC1c1ccccc1

Procedure:
The crude 7-amino-3'-isopropyl-2'-phenyl-3,4-dihydro-2H-1,5-benzodioxepin-3-spiro-5'-oxazolidine (352 mg.) is dissolved in dry ether (23 ml.) and 1,4-diazabicyclo[2,2,2]-octane (118 mg.; 1.065 mmole) is added. Methane sulphonyl chloride (105 mg.; 1.065 mmole) dissolved in dry ether (5 ml.) is added dropwise with stirring and the reaction mixture then is stirred at room temperature for 1 hour. The solid is filtered off and discarded: evaporation of the mother liquors affords 387.2 mg. (91%) of crude product.
Reaction SMILES: [Cl:1][C:2]1[O:25][C:5]2=[C:6]([N:10](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.Cl.O1CCOCC1>C(Cl)Cl>[Cl:1][C:2]1[O:25][C:5]2=[C:6]([NH2:10])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(Cl)oc12
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1nccc2cc(Cl)oc12
Temperature: 55 °C
Yield: 99.1 %

Procedure:
Di-tert-butyl (2-chlorofuro[2,3-c]pyridin-7-yl)imidodicarbonate (18.0 g, 49.1 mmol) in DCM (100 mL) was cooled in an ice bath and treated with 4 N HCl in 1,4-dioxane (75 mL, 300 mmol) added slowly over several minutes. The reaction was removed from the cooling bath and heated at 55° C. for 16 h. The mixture was concentrated in vacuo. The residue was suspended in DCM and treated with saturated NaHCO3 until the pH reached ˜8.5. The organic layer was washed with water and brine and then dried over anhydrous Na2SO4. The material was purified by flash chromatography (50% EtOAc:DCM) to provide 8.2 g (100%) of the title compound as a white solid. 1H NMR (CDCl3, 400 MHz): δ 4.75 (br s, 2H), 6.54 (s, 1H), 6.85 (d, J=5.3 Hz, 1H), 7.86 (d, J=5.3 Hz, 1H); MS (ESI): 169.12 [M+H]+.