Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C@@H:3]([OH:5])[CH3:4].Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:10].CN(C)CCO.Cl>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:9](=[O:10])([O:5][C@@H:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])[O:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: C[C@H](O)C(F)(F)F
Agent: CN(C)CCO
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Temperature: 60 °C

Procedure:
To a solution of (S)-(−)-1,1,1-trifluoro-2-propanol (1.95 g) in CHCl3 (30 mL) was added 4-nitrophenyl chloroformate (5.16 g) and pyridine (1.35 g) at room temperature. After 1-hour stirring at 60° C., the resulting mixture was cooled to room temperature. To the resulting mixture was added 2-(dimethylamino)ethanol (1.52 g) and was stirred at room temperature for 1 hour. The mixture was poured into 1M aqueous solution of HCl and extracted with CHCl3. The extract was washed with water and then dried over Na2SO4 and concentrated. The residue was purified with silica gel column chromatography (eluent: hexane/EtOAc=1/0˜50/50) to give 4-nitrophenyl (2S)-1,1,1-trifluoropropan-2-yl carbonate as a pale yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[C:18]([OH:20])=[O:19])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:27]([N:32]([CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:33](Cl)=[O:34])[CH2:28][CH2:29][CH2:30][CH3:31].C(N(CC)CC)C.Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:33](=[O:34])[N:32]([CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:14][C@H:13]2[C:18]([OH:20])=[O:19])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCCCCN(CCCCC)C(=O)Cl
Reactant: O=C(O)[C@@H]1CNCCN1C(=O)N(c1ccccc1)c1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2cc(Cl)cc(Cl)c2)[C@H](C(=O)O)C1
Temperature: 55 °C
Reaction time: 24 h
Yield: 54.4 %

Procedure:
A mixture of 470 mg (1.19 mmole) of (S)-1-[N-(3,5-dichlorophenyl)-N-phenylcarbamoyl]piperazine-2-carboxylic acid (from Step E above), 393 mg (1.79 mmole) of N,N-di-n-pentylcarbamoyl chloride (from Example 1, Step C-2) and 578 mg (4.17 mmole) of triethylamine in 15 mL of THF and 8 mL of water was stirred at 55° C. for 24 hours. The mixture was cooled and treated with 16 mL of 0.5N aqueous hydrochloric acid, and the aqueous layer was extracted with 3×55 mL of ethyl acetate. The combined organic extracts piperazine-2-carboxylic acid (from Step E above), 393 mg (1.79 mmole) of N,N-di-n-pentylcarbamoyl chloride (from Example 1, Step C-2) and 578 mg (4.17 mmole) of triethylamine in 15 mL of THF and 8 mL of water was stirred at 55° C. for 24 hours. The mixture was cooled and treated with 16 mL of 0.5N aqueous hydrochloric acid, and the aqueous layer was extracted with 3×55 mL of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on 120 g of silica eluting with 1 L of 100:3 methylene chloride:methanol then 1 L of 100:4.5:0.15 methylene chloride:methanol: acetic acid to give 374 mg (54%) of an oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[C:6]([OH:14])[CH:5]=1.[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22](F)=[C:21]([Cl:26])[CH:20]=1)(=[O:18])=[O:17]>CN(C=O)C>[Cl:26][C:21]1[CH:20]=[C:19]([S:16]([CH3:15])(=[O:18])=[O:17])[CH:24]=[CH:23][C:22]=1[O:14][C:6]1[CH:5]=[C:4]([F:3])[CH:9]=[CH:8][C:7]=1[CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C(O)Cc1ccc(F)cc1O
Reactant: CS(=O)(=O)c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2cc(F)ccc2CC(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% wt. disp. oil, 0.176 g) was added to a solution of the product from step (vi) (0.34 g) in dry DMF (10 ml) and stirred at RT for 1 h before adding the product from example 3 step (vii) (0.416 g). The mixture was heated at 80° C. for 1 h, then partitioned between 2M hydrochloric acid/ethyl acetate. The organics were dried, evaporated under reduced pressure and the residue purified by reverse phase HPLC. Yield 0.064 g
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:16])[C@@H:6]([NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH2:7][CH3:8].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1>ClCCl>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[S:27])[NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:16])[C@H:6]([NH:9][C:10](=[O:15])[C:11]([F:14])([F:12])[F:13])[CH2:7][CH3:8])=[CH:21][CH:20]=1
Reactant: COc1ccc(N=C=S)cc1
Reactant: CC[C@H](NC(=O)C(F)(F)F)C(=O)NCCN
Solvent: ClCCl
Product: CC[C@@H](NC(=O)C(F)(F)F)C(=O)NCCNC(=S)Nc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (S)—N-(2-aminoethyl)-2-(2,2,2-trifluoroacetamido)butanamide (276.6 mg, ca, 1.10 mmol) in dichloromethane (10 mL) was added 4-methoxyphenyl isothiocyanate (120 μL, 0.868 mmol). and the resulting mixture was stirred for 72 h at room temperature. The resulting mixture was then concentrated to an oil, which was purified by column chromatography, eluting with 6% methanol in chloroform to yield (R)—N-(2-(3-(4-methoxyphenyl)thioureido)ethyl)-2-(2,2,2-trifluoroacetamido)butanamide as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:12]([CH:14]([O:16]C(=O)C)[CH3:15])=[O:13])[NH:7][C:6](=[O:20])[CH2:5]2.O.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:12](=[O:13])[CH:14]([OH:16])[CH3:15])[NH:7][C:6](=[O:20])[CH2:5]2
Reactant: CC(=O)OC(C)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Yield: 65.6 %

Procedure:
Acetic acid 1-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-ethyl ester 8a (1.86 g, 6.4 mmol) was dissolved in 20 ml of methanol under stirring, and added with 10 ml of water and sodium hydroxide solution (10 ml, 0.7 mol/L) to the solution and stirred for 4 hours at room temperature. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was neutralized with hydrochloride acid (1 mol/L) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and dried to obtain N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-propionamide 8b (1.0 g, yield 70%) as a white solid.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19]2[N:28]=[C:27]([N:29]([CH3:31])[CH3:30])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[CH2:14][CH2:13]1)C1C=CC=CC=1>CO.[Pd]>[NH2:10][CH2:11][CH:12]1[CH2:13][CH2:14][CH:15]([NH:18][C:19]2[N:28]=[C:27]([N:29]([CH3:31])[CH3:30])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[CH2:16][CH2:17]1
Reactant: CN(C)c1nc(N[C@H]2CC[C@@H](CNC(=O)OCc3ccccc3)CC2)nc2ccccc12
Agent: [Pd]
Solvent: CO
Product: CN(C)c1nc(NC2CCC(CN)CC2)nc2ccccc12
Temperature: 50 °C
Reaction time: 19 h
Yield: 82.6 %

Procedure:
To a solution of cis-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-carbamic acid benzyl ester obtained in step B of example 24 (12.1 g, 27.9 mmol) in MeOH (120 mL) was added 10% Pd/C (1.21 g). The mixture was stirred at 50° C. under hydrogen atmosphere for 19 hr, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 66% EtOAc in hexane to 15% MeOH in chloroform) to give N2-(4-aminomethyl-cyclohexyl)-N4,N4-dimethyl-quinazoline-2,4-diamine (6.9 g, 83%) as a yellow solid.
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.C1COCC1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:31]=[C:30]([CH2:32][OH:33])[O:29][N:28]=2)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:31]=[C:30]([CH2:32][O:33][C:6](=[O:7])[NH2:5])[O:29][N:28]=2)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: OCc1cc(-c2ccc(OCc3ccccc3)cc2)no1
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)OCc1cc(-c2ccc(OCc3ccccc3)cc2)no1
Reaction time: 1 h
Yield: 84.6 %

Procedure:
4-Benzyloxybenzaldehyde (4.24 g, 20 mmol) was dissolved in a solvent mixture of ethanol and water (3:1, 100 ml) in the concentration of 0.2 M while stirring. NH2OH—HCl (2.78 g, 40 mmol) and sodium acetate (2.46 g, 30 mmol) were added thereto, which was then stirred for about 30 min at room temperature. The completion of reaction was confirmed by liquid chromatography, and water and ethanol were distilled off under reduced pressure to give a pale yellow solid compound. This solid compound was extracted three times with water and ethyl acetate, and the organic solvent layer was subjected to the condition of reduced pressure. The crude compound was recrystallized from hexane/ethyl acetate (10:1) to give a compound as a white solid. Thus obtained solid 4-benzyloxy-benzaldehydeoxime (2.27 g, 10 mmol; a compound of 92% purity) was dissolved in methylene chloride (40 ml, 0.25 M), and propargyl alcohol (1.77 ml, 30 mmol) was added thereto. To this solution was very slowly added in drops 10% NaOCl (13.7 ml, 20 mmol) at 0° C. by using a dropping funnel. After all NaOCl was added, the mixture was stirred for about 5 h during which the temperature was slowly raised to room temperature. After the completion of reaction was confirmed by liquid chromatography, the reaction mixture was distilled under reduced pressure to evaporate methylene chloride. Water (200 ml) was added to the residue, and the resulting solid was filtered. The compound thus filtered was washed with excess water and then finally washed with diethyl ether. The solid compound thus obtained was recrystallized from ethyl acetate/hexane (1:2) to give [3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methanol as a white solid (Yield: 2.5 g). Chlorosulfonyl isocyanate (1.04 ml, 12 mmol) was slowly added to the THF solution (50 ml, 0.2 M) containing [3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methanol (2.813 g, 10 mmol) in a 250 ml flask at −78° C. After disappearance of all the starting materials was confirmed by liquid chromatography, water was added to the reaction solution. After 1 h, distillation under reduced pressure was carried out to evaporate THF. Water (100 ml) was added thereto, and the resulting solid was filtered. Thus filtered solid was washed with 100 me of water and ethyl acetate/hexane (1:2) solution, and dried to give 3.4 g of the crude product (Purity: 95.9%). This crude product was recrystallized from ethyl acetate/hexane/methylene chloride (1:4:1) solution containing 1% methanol to give 2.743 g of carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester (CBI) in the purity of 99%.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17].[C:21](Cl)(=[O:26])[CH2:22][C:23](Cl)=[O:24]>O1CCCC1>[C:16]([C:15]1[CH:14]=[C:13]([N:12]2[C:23](=[O:24])[CH2:22][C:21](=[O:26])[NH:1][C:2]3[C:11]4[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=4[CH:5]=[CH:4][C:3]2=3)[CH:20]=[CH:19][CH:18]=1)#[N:17]
Reactant: N#Cc1cccc(Nc2ccc3c(c2N)CCCC3)c1
Reactant: O=C(Cl)CC(=O)Cl
Solvent: C1CCOC1
Product: N#Cc1cccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCCC2)c1
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
To an anhydrous tetrahydrofuran (30 mL) solution of 3-(1-amino-5,6,7,8-tetrahydronaphthalen-2-ylamino)benzonitrile (747 mg, 2.84 mmol) was added an anhydrous tetrahydrofuran (5 mL) solution of malonyl chloride (276 μL, 2.84 mmol) under cooling in ice-bath. The mixture was stirred for 30 minutes under cooling in ice-bath, and for 2 hours at room temperature. To the mixture was added purified water. The mixture was extracted with ethyl acetate, washed with purified water, and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=1/1) to give the titled compound as white powder (333 mg, yield 35%).
Reaction SMILES: O[C:2]1([C:23]2[C:32]([OH:33])=[CH:31][C:26]3[O:27][CH2:28][CH2:29][O:30][C:25]=3[CH:24]=2)[C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][C:9]=2[O:11][CH3:12])[N:4]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:3]1=[O:22].ClC1C=CC=C2C=1C(O)(C1C(O)=CC3OCCC=3C=1)C(=O)N2C(C1C=CC=CC=1)C1C=CC=CC=1>>[OH:33][C:32]1[C:23]([CH:2]2[C:10]3[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][C:9]=3[O:11][CH3:12])[N:4]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:3]2=[O:22])=[CH:24][C:25]2[O:30][CH2:29][CH2:28][O:27][C:26]=2[CH:31]=1
Reactant: COCCOCCN1C(=O)C(O)(c2cc3c(cc2O)OCCO3)c2c(OC)ccc(OC)c21
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCC2
Product: COCCOCCN1C(=O)C(c2cc3c(cc2O)OCCO3)c2c(OC)ccc(OC)c21

Procedure:
Following the procedure as described in PREPARATION 4C, and making non-critical variations using 3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,7-dimethoxy-1-[2-(2-methoxyethoxy)ethyl]-1,3-dihydro-2H-indol-2-one to replace 4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, 3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,7-dimethoxy-1-[2-(2-methoxyethoxy)ethyl]-1,3-dihydro-2H-indol-2-one was obtained (89%) as a yellow solid: MS (ES+) m/z 446.0 (M+1).
Reaction SMILES: Cl.[CH2:2]([NH2:5])[CH2:3][CH3:4].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH2:14][C:13](=O)[CH2:12][CH2:11]2.C([BH3-])#N.[Na+].Cl.[OH-].[Na+]>CO>[CH2:2]([NH:5][CH:13]1[CH2:12][CH2:11][C:10]2[C:15](=[CH:16][CH:17]=[C:8]([O:7][CH3:6])[CH:9]=2)[CH2:14]1)[CH2:3][CH3:4]
Reactant: COc1ccc2c(c1)CCC(=O)C2
Reactant: CCCN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCNC1CCc2cc(OC)ccc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
Propylamine hydrochloride (169 g, 1.8 mol) was dissolved in methanol (370 mL) and 6-methoxy-2-tetralone (50 g, 0.28 mol) was added. Thereafter, sodium cyanoborohydride (44.2 g, 0.7 mol) was added portionwise with cooling. During the latter addition, the temperature of the reaction mixture was kept at 20° C. to minimize foaming. The resulting suspension was stirred at room temperature (25° C.) for 18 hr. Excess hydrochloric acid (1:1) was added and the white suspension was cooled in ice. The solid was collected on a filter and washed with methanol (3×200 mL) to give 92 g of crude product. The crude product was treated with 10% (w/v) sodium hydroxide and extracted with benzene. The organic extract was dried and evaporated to give a pale yellow oil (31.93 g) of N-propyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine, NMR (CDCl3) δ 0.90 (t, 3H), 1.15 (s, 1H), 1.50 (m, 2H), 3.70 (s, 3H), 6.55 (s, 1H), 6.60 (d, 1H) and 6.90 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12].[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([F:10])[CH:3]=1
Reactant: CC(C)(C)N
Reactant: O=Cc1ccc(Br)cc1F
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)N=Cc1ccc(Br)cc1F
Reaction time: 48 h
Yield: 97.6 %

Procedure:
To a CH2Cl2 (900 mL) solution of 4-bromo-2-fluoro-benzaldehyde (50.0 g, 246 mmol) was added tert-butylamine (42.3 mL, 29.3 g, 400 mmol) and MgSO4 (60.0 g, 499 mmol). After 48 h, the solution was filtered and concentrated to give 62.0 g (98%) of the title compound as a yellow liquid. 1H NMR (CDCl3): 8.48 (s, 1H), 7.89 (t, J=8.1 Hz, 1H), 7.32-7.25 (m, 2H), 1.29 (s, 9H).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[CH:13][CH:14]=2)[O:9]1)[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[CH:13][CH:14]=2)[O:9]1
Reactant: CC=CCC1CC(=O)c2ccc(OC)cc2O1
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(c1)OC(CC=O)CC2=O
Reaction time: 1 h
Yield: 49 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted while stirring for 1 hour through a solution, cooled to -70°, of 6.25 g of (RS)-2-(2-buten-1-yl)-7-methoxy-4-chromanone in 90 ml of anhydrous dichloromethane and 30 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 15 minutes. After the addition of 3 ml of dimethyl sulfide, the mixture was stirred at room temperature for 16 hours. The reaction mixture was subsequently evaporated in a vacuum. The residue was treated with 60 ml of dichloromethane and, after the addition of 15 ml of water and 15 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 100 ml of water and neutralized while stirring by the spatula-wise addition of sodium hydrogen carbonate. An additional 70 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 100 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 2.9 g (49%) of 2-(2-oxoethyl)-7-methoxy-4-chromanone were obtained as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]([CH3:18])[C:16](=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[C:4]([CH3:20])[CH:3]=1.O[CH:22]1[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)(=O)C.O>[CH3:18][N:17]1[C:16](=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([O:1][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:3][C:4]=1[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1cc(O)ccc1-c1nc2ccccc2c(=O)n1C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(OC2CCNCC2)ccc1-c1nc2ccccc2c(=O)n1C
Temperature: 0 °C
Yield: 93.4 %

Procedure:
2-(4-Hydroxy-2-methylphenyl)-3-methyl-4(3H)-quinazolinone (200 mg, 0.751 mmol), tert-butyl 4-hydroxytetrahydro-1(2H)-pyridinecarboxylate (227 mg, 1.12 mmol) and triphenyl phosphine (295 mg, 1.12 mmol) were dissolved in THF (2.0 mL), and with stirring at 0° C., diisopropyl azodicarboxylate (228 mg, 1.12 mmol) was added thereto and stirred for 24 hours. The reaction solution was diluted with ethyl acetate, poured into saturated saline water, extracted with ethyl acetate, and the organic layer was dried with magnesium sulfate. The solvent was evaporated off, and the resulting residue was dissolved in chloroform (3 mL), trifluoroacetic acid (2 mL) was added thereto, and stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed with aqueous 1 N sodium hydroxide solution and saturated saline water, and the organic layer was dried with magnesium sulfate. The solvent was evaporated off, and the residue was purified through silica gel column chromatography (chloroform/methanol=1/1) to obtain the intended compound (245 mg, 93%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].Br[CH:39]([CH2:41][CH3:42])[CH3:40]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH:39]([CH2:41][CH3:42])[CH3:40])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: CCC(C)Br
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Product: CCC(C)Oc1cc2c(cc1OC)CCN(CC(=O)NC1CCc3ccccc31)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 2-bromo-butane
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:23]2[CH:24]=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=2)=[C:8]([NH:13][C:14]([CH:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[C:9]=1[CH:10]([CH3:12])[CH3:11])=[O:4].O[Li].O>C1COCC1.CO.O>[CH:10]([C:9]1[C:8]([NH:13][C:14]([CH:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])=[C:7]([C:23]2[CH:24]=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])([CH3:11])[CH3:12]
Reactant: COC(=O)c1sc(-c2cccc(C)c2)c(NC(=O)C2CCC(C)CC2)c1C(C)C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cccc(-c2sc(C(=O)O)c(C(C)C)c2NC(=O)C2CCC(C)CC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.4 %

Procedure:
3-Isopropyl-[(4-methyl-cyclohexanecarbonyl)-amino]-5-m-tolyl-thiophene-2-carboxylic acid methyl ester (30 mg, 0.073 mmol) was taken in a mixture of THF:MeOH:H2O (3:2:1, 3 mL) and then added 1N aqueous solution of LiOH.H2O (0.44 mL, 0.438 mmol). The reaction mixture was stirred at room temperature for 12 h. Solvents were removed and the residue was partitioned between water and ethyl acetate. The aqueous layer was acidified using 10% KHSO4 solution. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by preparative TLC using chloroform:methanol:acetic acid (9:1:0.1) to obtain 3-Isopropyl-[(4-methyl-cyclohexanecarbonyl)-amino]-5-m-tolyl-thiophene-2-carboxylic acid (15 mg, 52%) as a white solid. 1H NMR (CDCl3, 400 MHz): (s, 2H), 7.38 (t, 1H), 7.24 (m, 1H), 7.08 (s, 1H), 5.01 (s, 1H), 2.42 (s, 3H), 2.10-0.62 (m, 20H). ESI− (M-H): 398.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32].[CH3:33][N:34](C=O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[C-]#N.[Zn+2].[C-]#N>[C:33]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32])#[N:34]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(Br)c(OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C-]#N
Product: COC(=O)c1ccc(C#N)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
Triphenylphosphine polymer bound (50 mg; 0.15 mmol; 0.15 eq.), palladium (II) acetate (15.04 mg; 0.07 mmol; 0.07 eq.) and DMF (3 mL) were first mixed, purged with N2 and let stirring at RT for 2 h. The vial was then opened, zinc cyanide (117.43 mg; 1 mmol; 1 eq.) and methyl 4-bromo-3-methoxybenzoate (COMBI-BLOCKS; CA-4192; 245.07 mg; 1 mmol; 1 eq.) were added and the resulting mixture was purged once more before heating at 140° C. for 50 min. The reaction mixture was then filtrated through a glass frit and the resin was washed with Et2O (3×10 mL). The combined organic solutions were washed with water (3×5 mL), once with NaCl sat. solution (10 mL) and then dried over magnesium sulfate. Evaporation of the solvent gave the title compound as a white solid (137 mg; 72%). 1H NMR (DMSO-d6, 300 MHz) δ 7.91 (d, J=7.9 Hz, 1H), 7.66-7.62 (m, 2H), 4 (s, 3H), 3.90 (s, 3H). LC/MS (Method A): 232.8 (M+ACN)+. GC/MS: 191. HPLC (Method A), Rt 3.14 min (purity: 99.3%).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][S:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8])C.O.[OH-].[Na+].Cl>CO>[CH2:13]([CH:5]([CH2:6][S:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8])[C:4]([OH:20])=[O:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)S(=O)CC(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.2 g of 2-benzyl-3-tert.-butylsulphinyl-propionic acid ethyl ester are dissolved in 30 ml of methanol, and 30 ml of water and 10.8 ml of 1N sodium hydroxide solution are added thereto. The mixture is stirred at room temperature for 16 hours, neutralised with 10.8 ml of 1N hydrochloric acid and concentrated in vacuo. The residue is purified by flash chromatography on 150 g of silica gel 60 (eluant J). Rf (J)=0.38.