Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:14][C:13]2(O)[NH:15][C:16]([CH3:33])=[C:17]([C:27]([O:29][CH2:30][CH2:31][OH:32])=[O:28])[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[Cl:26])[CH:12]2[S:11](=[O:36])(=[O:35])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:37](OC(=O)C)(=[O:39])[CH3:38]>N1C=CC=CC=1>[Cl:26][C:20]1[C:21]([Cl:25])=[CH:22][CH:23]=[CH:24][C:19]=1[CH:18]1[C:12]2[S:11](=[O:35])(=[O:36])[CH2:10][CH2:9][NH:8][CH2:14][C:13]=2[NH:15][C:16]([CH3:33])=[C:17]1[C:27]([O:29][CH2:30][CH2:31][O:32][C:37](=[O:39])[CH3:38])=[O:28]
Reactant: CC(=O)OC(C)=O
Reactant: CC1=C(C(=O)OCCO)C(c2cccc(Cl)c2Cl)C2C(O)(CN(C(=O)OC(C)(C)C)CCS2(=O)=O)N1
Solvent: c1ccncc1
Product: CC(=O)OCCOC(=O)C1=C(C)NC2=C(C1c1cccc(Cl)c1Cl)S(=O)(=O)CCNC2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
2-Hydroxyethyl 4-t-butyloxycarbonyl-9-(2,3-dichlorophenyl)-1,1-dioxo-5a-hydroxy-2,3,4,5,5a,6,9,9a-octahydro-7-methylpyrido[2,3-f][1,4]thiazepine-8-carboxylate (0.500 g, 0.97 mmole) from Example 18, was dissolved in 5 mL of pyridine and 5mL of acetic anhydride, and stirred for 2 hours. The solvents were removed under reduced pressure, and the residue was slurried in 25 mL of ethyl acetate and cooled to 0° C., after which the mixture was saturated with gaseous HCl. After 90 minutes, the reaction was poured into 30 mL of 4N NaOH. The ethyl acetate layer was separated and dried with brine, and the aqueous layer was extracted with 2×30 mL of chloroform. The combined organic extracts were dried with sodium sulfate and evaporated, and the residue was chromatographed (2% methanol, 0.1% ammonia in chloroform, silica gel) to give the product as a white solid (0.351 g, 89% yield).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[CH3:12][CH:13](O)[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>COC(OC)(C)C.C1(C)C=CC=CC=1>[CH2:12]([CH:2]1[CH2:3][C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:1]1)[CH:13]=[CH:14][CH3:15]
Reactant: C=CC(C)O
Reactant: O=C1CCOc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: Cc1ccccc1
Product: CC=CCC1CC(=O)c2ccccc2O1
Yield: 38 %

Procedure:
A solution of 48 g of 4-chromanone, 67 ml of 3-buten-2-ol and 500 mg of p-toluenesulfonic acid in 67 ml of 2,2-dimethoxypropane and 500 ml of anhydrous toluene was boiled under reflux for 46 hours. The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 4:1). 24.7 g (38%) of (RS)-2-(2-buten-1-yl)-4-chromanone were obtained as a yellow oil.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][C:15](O)=[O:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>O1CCCC1.B.O1CCCC1>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][OH:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Oc2ccccc2)c1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: OCCc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3-phenoxyphenyl)acetic acid (1.157 g) in tetrahydrofuran (23 ml), 6.5 ml of borane-tetrahydrofuran complex (1.17M tetrahydrofuran solution) was added, and the reaction solution was stirred at room temperature for 2 hours. To the reaction solution was added water, and the mixture was extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (10:90-80/20)) to afford the title compound as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]1=2.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl.CCOC(C)=O>[CH3:32][S:33]([O:1][CH2:2][CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]1=2)(=[O:35])=[O:34]
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCO)c3ccccc23)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCOS(C)(=O)=O)c3ccccc23)CC1
Reaction time: 0.5 h

Procedure:
tert-Butyl 6-(2-hydroxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.181 g, 0.549 mmol) and triethylamine (0.115 mL, 0.0833 g, 0.824 mmol, 1.5 equiv.) were dissolved in CH2Cl2 at -10° C. under N2. MsCl (0.0510 mL, 0.0755g, 0.659 mmol, 1.2 equiv.) was added and the reaction mixture was stirred for 30 min. The reaction mixture was taken up in EtOAc (25 mL) and was washed sequentially with 10% citric acid (10 mL), 5% NaHCO3 (10 mL), and brine (10 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The crude tert-butyl 6-{2-[(methylsulfonyl)oxy]ethyl}-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate was used directly in the next reaction.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([O:28][CH3:29])=[CH:20][C:16]=2[C:17]([OH:19])=[O:18])=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:37][CH3:38]>CN(C=O)C>[CH2:37]([O:18][C:17](=[O:19])[C:16]1[CH:20]=[C:21]([O:28][CH3:29])[C:22]([C:24]([CH3:26])([CH3:25])[CH3:27])=[CH:23][C:15]=1[C:14]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:38]
Reactant: COc1cc(C(=O)O)c(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OC)c(C(C)(C)C)cc1-c1cccnc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
step 1—To a solution of 76 (100 mg, 0.26 mmol) in DMF (3 mL) were added Cs2CO3 (101 mg, 0.31 mmol) and iodoethane (25 μL, 0.31 mmol). The reaction mixture was stirred at RT overnight then quenched with H2O and thrice extracted with EtOAc. The combined organics were washed with H2O (3×), dried (MgSO4), filtered and concentrated under reduced pressure to afford 109 mg (99%) of 2-(2-benzyloxypyridin-3-yl)-4-tert-butyl-5-methoxybenzoic acid ethyl ester (78) as a pale yellow foam.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9](NC)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH2:17]([N:19](CC)CC)C>C1(C)C=CC=CC=1.ClCCl>[CH3:14][O:13][C:11]1[CH:10]=[C:9]([CH2:17][NH:19][C:1]([Cl:4])=[O:2])[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=1
Reactant: O=C(Cl)Cl
Reactant: CCN(CC)CC
Reactant: CNc1cc(OC)cc(OC)c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc(CNC(=O)Cl)cc(OC)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of phosgene (11.6 mmol) in toluene (6 ml) is diluted with dichloromethane (15 ml) and cooled to 0° C. To this is added a solution of (3,5-Dimethoxy-phenyl)-methyl-amine (1.67 g, 10 mmol) and triethylamine (1.78 ml, 14.0 mmol) in dichloromethane (5 ml) slowly over 30 minutes, and the reaction mixture allowed to warm to ambient temperature with stirring over 2 hours. After stirring at ambient temperature for a further 2 hours, the reaction mixture is partitioned between ether and 1M hydrochloric acid solution. The ether phase is washed with brine, dried over magnesium sulphate and evaporated to afford (3,5-Dimethoxy-phenyl)methyl-carbamoyl chloride as a white solid.
Reaction SMILES: [H-].[Na+].[NH2:3][CH:4]([C:7]1([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)[CH2:5][CH3:6].[CH2:20]([O:27][C:28]1[C:37]2[C:32](=[CH:33][C:34](F)=[C:35]([Cl:38])[CH:36]=2)[CH:31]=[CH:30][N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(N(C)C)=O>[CH2:20]([O:27][C:28]1[C:37]2[C:32](=[CH:33][C:34]([O:13][CH:10]3[CH2:11][CH2:12][C:7]([CH:4]([NH2:3])[CH2:5][CH3:6])([CH:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:8][CH2:9]3)=[C:35]([Cl:38])[CH:36]=2)[CH:31]=[CH:30][N:29]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Fc1cc2ccnc(OCc3ccccc3)c2cc1Cl
Reactant: CCC(N)C1(C2CCOCC2)CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCC(N)C1(C2CCOCC2)CCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CC1
Yield: 23.5 %

Procedure:
To a suspension of sodium hydride (60%, 167 mg, 4.17 mmol, 3 eq.) in dimethyl acetamide (8 mL) was added a solution of 4-(1-aminopropyl)-4-(tetrahydropyran-4-yl)-cyclohexanol (7,369 mg, 1.53 mmol, 1.1 eq.) in dimethyl acetamide (8 mL). After stirring for 60 min at room temperature a solution of 1-benzyloxy-7-chloro-6-fluoro-isoquinoline (1,400 mg, 1.39 mmol) in dimethyl acetamide (8 mL) was added and stirring was continued first at room temperature, then at 50° C. until the reaction went to completion. The reaction was quenched by addition of water (30 mL) and the reaction mixture was extracted three times with a mixture of dichloromethane and 2-propanol (3:1). The combined organic layers were evaporated, and the obtained crude product was purified by flash chromatography (SiO2, 0%→30% methanol in dichloromethane) to yield 83 mg (earlier eluting isomer 1, 8) and 48 mg (later eluting isomer 2, 9) of the pure diastereoisomers as racemates respectively. The relative stereochemistry was not assigned. Additionally, 166 mg of the product as a diastereomeric mixture could be isolated. Rt=0.92 min (8), 0.93 min (9) (Method B). Detected mass: 419.4 (M+H+).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1.[C:35]([N:42]1[CH2:47][CH2:46][CH:45]([C:48]([OH:50])=O)[CH2:44][CH2:43]1)([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>CN(C=O)C.CCOC(C)=O>[CH3:5][O:4][N:3]([CH3:2])[C:48]([CH:45]1[CH2:44][CH2:43][N:42]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:47][CH2:46]1)=[O:50]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Add N,O-dimethylhydroxylamine hydrochloride (2.52 g, 26 mmol), 1-hydroxybenzotriazole (HOBt) (2.8 g, 20.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl)(4 g, 20.8 mmol) and 4-methylmorpholine (5.28 g, 52 mmol) at 0° C. to the solution of N-Boc-piperidine-4-carboxylic acid (4 g, 17.4 mmol) in DMF (50 mL), stir the mixture overnight at room temperature. TLC (PE:EtOAc=1:1) shows the reaction is complete. Partition between ethyl acetate and water, collect the organic layer and wash with brine, dry over anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure to give the crude product (4.5 g, 95%) which is used in next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:24])[CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH:7]=1.CN([CH:28]=[O:29])C>>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:8]2[CH:7]=[C:6]([NH:5][CH2:4][CH:3]3[O:24][C:28](=[O:29])[NH:1][CH2:2]3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(-c2cc(NCC(O)CN)c3ccccc3n2)cc1
Reactant: CN(C)C=O
Product: COc1ccc(-c2cc(NCC3CNC(=O)O3)c3ccccc3n2)cc1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 73 %

Procedure:
To a 0° C. solution of (RS)-1-amino-3-[2-(4-methoxy-phenyl)-quinolin-4-ylamino]-propan-2-ol (0.139 g) 0.429 mmol) in DMF (2.5 ml) was added dropwise a solution of 1,1-carbonyldiimidazole (0.076 g, 0.472 mmol) in DMF (1 ml). After 20 min. at 0° C., and 1.5 hours at 60° C., the reaction mixture was cooled to room temperature and concentrated. Addition of H2O provided (RS)-5-{[2-(4-methoxy-phenyl)-quinolin-4-ylamino]-methyl}-oxazolidin-2-one (0.110 g, 73%) as yellowish solid, MS: m/e=349 (M+).
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:3][CH2:4][OH:5].C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:3][CH2:4][OH:5]
Reactant: [H][H]
Reactant: CC(=CCO)CCCC(C)CCCC(C)CCCC(C)C
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Yield: 82.6 %

Procedure:
To a solution of 50.0 g (169 mmol) of 3,7,11,15-tetramethyl-2-hexadecen-1-ol in 200 mL of ethanol were added 0.3 g (3 mmol) of triethylamine and 500 mg of 5% Pd on carbon. The mixture was maintained under 50 psi (345 kPa) of hydrogen on a Parr hydrogenator for 24 h. The mixture was filtered and concentrated, and distillation afforded 41.7 g (83%) of 3,7,11,15-tetramethyl-1-hexadecanol as a clear, colorless liquid, bp 150-155° C. at 0.05 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([OH:35])[C:17]2[C:12](=[CH:13][C:14](C#N)=[CH:15][C:16]=2[C:18]([F:21])([F:20])[F:19])[N:11]([CH2:24][C@H:25]2[CH2:28][C@H:27]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:26]2)[C:10]1=[O:34].Cl.C([N:39]([CH2:42]C)CC)C.[N-:44]=[N+:45]=[N-:46].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([OH:35])[C:17]2[C:12](=[CH:13][C:14]([N:45]3[N:46]=[N:39][CH:42]=[N:44]3)=[CH:15][C:16]=2[C:18]([F:21])([F:20])[F:19])[N:11]([CH2:24][C@H:25]2[CH2:28][C@H:27]([N:29]([CH2:30][CH3:31])[CH2:32][CH3:33])[CH2:26]2)[C:10]1=[O:34]
Reactant: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3ccc(Cl)cc3Cl)c3c2cc(C#N)cc3C(F)(F)F)C1
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3ccc(Cl)cc3Cl)c3c2cc(-n2ncnn2)cc3C(F)(F)F)C1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the compound of Example 1-3 (40 mg, 0.076 mmol) in toluene (2 mL) were added triethylamine hydrochloride (10.8 mg, 0.076 mmol) and sodium azide (10.0 mg, 0.154 mmol) under nitrogen, and the mixture was stirred at 100° C. for 5 hours. The reaction solution was concentrated in vacuo and the residue was purified by preparative liquid chromatography to give the titled compound (15 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][CH2:8][NH2:9].P([O-])([O-])([O-])=[O:11].[C:15]1(C)C=[CH:19][CH:18]=[CH:17][CH:16]=1>CCOCC>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][CH2:8][N:9]1[CH2:15][CH2:16][CH2:17][CH2:18][C:19]1=[O:11]
Reactant: Cn1cccc1CCN
Reactant: O=P([O-])([O-])[O-]
Reactant: Cc1ccccc1
Solvent: CCOCC
Product: Cn1cccc1CCN1CCCCC1=O
Reaction time: 8 h

Procedure:
2-(1-Methylpyrrol-2-yl)ethylamine (4.96g, 0.04m) and triethylamine (5.6mL, 0.04m) were stirred together in toluene (60mL). A solution of ethyl 5-bromopentanoate (7.80g, 0.04m) in toluene (20 mL) was added dropwise over 1 hr at room temperature. The reaction mixture was heated with stirring at 70 degrees overnight. The reaction was worked up by addition of a phosphate buffer until a pH of 5-6 was reached; the reaction mixture was then diluted with ether and the layers were separated. The aqueous layer was exhaustively washed with diethyl ether. The combined organic layers were washed with water, brine and then dried over anhydrous potassium carbonate. The dryinq agent was filtered away, and the filtrate was concentrated to a light yellow solid weighing 5.2g. It was recrystallized from methylene chloride/hexane to give 4.2g (51.2%) of purified title compound.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]([C:6]([O:8][C@@H:9]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[O:7])[CH2:2]1.ClC1C=CC=C(C(OO)=[O:35])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[O:35]=[S:1]1[CH2:5][CH2:4][N:3]([C:6]([O:8][C@@H:9]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])=[O:7])[CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)OC(=O)N1CCSC1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)OC(=O)N1CCS(=O)C1
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a solution of benzyl 2(S)-(3-thiazolidine-carbonyloxy)-3-phenylpropionate (371 mg) in methylene chloride (7 ml), which was cooled to 0° C., was added 80% m-chloroperbenzoic acid (215 mg). The mixture was stirred at same temperature for 30 minutes. Then 10% sodium sulfite aqueous solution and methylene chloride were added thereto, and the mixture was separated. The separated aqueous layer was extracted with methylene chloride (2 times). The combined extract was washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution successively, dried over magnesium sulfate, and concentrated under reduced pressure. Obtained crystals were washed with n-hexane to give benzyl 2(S)-(1-oxo-thiazolidine-3-carbonyloxy)3-phenylpropionate (350 mg).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:4]([O:22][CH3:23])[CH:3]=1.[Cl:24][C:25]1[CH:33]=[C:32]2[C:28]([C:29]([C:34]([O:36][CH3:37])=[O:35])=[CH:30][NH:31]2)=[CH:27][C:26]=1B1[O:43][CH2:42][C:41]([CH3:45])([CH3:44])[CH2:40][O:39]1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:16]([O:15][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@H:8]1[CH2:7][O:6][C:5]1[CH:20]=[CH:21][C:2]([C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][C:25]=2[Cl:24])[NH:31][CH:30]=[C:29]3[C:34]([O:36][CH3:37])=[O:35])=[CH:3][C:4]=1[O:22][CH3:23])=[O:14])([CH3:19])([CH3:18])[CH3:17].[OH:39][CH2:40][C:41]([CH3:45])([CH2:42][OH:43])[CH3:44]
Reactant: COc1cc(Br)ccc1OC[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(CO)CO
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OC[C@@H]4CCCN4C(=O)OC(C)(C)C)c(OC)c3)cc12
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-tert-butyl 2-((4-bromo-2-methoxyphenoxy)methyl)pyrrolidine-1-carboxylate (77 mg, 0.20 mmol) in toluene (1.5 mL) was added methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (77 mg, 0.24 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (6.7 mg, 0.0080 mmol), ethanol (absolute, 0.5 mL), and potassium carbonate (2 M solution in water, 0.4 mL, 0.80 mmol). Nitrogen was bubbled through the mixture for 20 min. The mixture was then sealed and heated to 90° C. After 18 h, the mixture was allowed to cool to 23° C., diluted with ethyl acetate (5 mL), and filtered through Celite. The filtrate was dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography (silica gel, 0-50% ethyl acetate in heptane) afforded the title compound contaminated with neopentyl glycol.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17]([C:27]3[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=3[F:35])[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[OH-].[Na+].Cl.O>O1CCOCC1.ClCCl>[F:35][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:27]=1[C:17]1[O:16][C:12]2[N:13]=[CH:14][N:15]=[C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:36])=[O:2])[C:11]=2[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(-c3c(F)cccc3OC)c(-c3ccc(OC)cc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(-c2c(-c3c(F)cccc3OC)oc3ncnc(NCCCCCC(=O)O)c23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve 42 mg (0.09 mmol) 6-{[6-(2-fluoro-6-methoxyphenyl)-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester in 1.0 ml dioxan and add 0.26 ml 1 N sodium hydroxide solution. Stir for 16 h at RT, then add 0.26 ml 1 N hydrochloric acid and then 2 ml water and 5 ml dichloromethane. Separate the organic phase, dry over sodium sulphate, filter, and concentrate by evaporation. 39 mg (96% of theor.) of the target compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14](O)=[O:15])=[O:9])=[C:4]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:25]=2)(=[O:23])=[O:22])[CH:3]=1.[N:35]1([CH2:40][CH2:41][NH2:42])[CH2:39][CH2:38][CH2:37][CH2:36]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([NH:42][CH2:41][CH2:40][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:15])=[O:9])=[C:4]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([C:31]([F:34])([F:32])[F:33])[CH:25]=2)(=[O:22])=[O:23])[CH:3]=1
Reactant: NCCN1CCCC1
Reactant: O=C(O)c1cccc(CS(=O)c2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NCCN1CCCC1)c1cccc(CS(=O)c2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 18.7 %

Procedure:
Following General Procedure R, the title compound (17 mg, 19%) was prepared from 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)benzoic acid (76 mg, 0.14 mmol), 2-(pyrrolidin-1-yl)ethanamine (26 μl, 0.21 mmol), EDC (53 mg, 0.28 mmol) and DMAP (cat.) in DMF (2 ml).
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][NH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].C(Cl)(Cl)Cl>N1C=CC=CC=1.CCOCC>[C:17]([N:10]1[C:11]2[CH2:12][CH2:13][C:4]3[CH:3]=[C:2]([Cl:1])[C:15]([Cl:16])=[CH:14][C:5]=3[C:6]=2[CH2:7][CH2:8][CH2:9]1)(=[O:19])[CH3:18]
Reactant: Clc1cc2c(cc1Cl)C1=C(CC2)NCCC1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)N1CCCC2=C1CCc1cc(Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
6.17 g (0.024 mol) of 8,9-dichloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline are dissolved in 10 ml of pyridine, 9 ml (0.09 mol) of acetic anhydride are added dropwise thereto and the mixture is stirred at room temperature for 17 hours. Chromatography on silica gel with chloroform yields a product which is suspended in ether and removed by filtration. There is obtained 4-acetyl-8,9-dichloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline with melting point 146°-148°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=[CH2:29].C(O[Na])(C)(C)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:29][CH2:28][C:27]([O:31][CH3:32])=[O:30])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(C(F)(F)F)cc3)c2C1
Reactant: C=CC(=O)OC
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1
Product: COC(=O)CCn1nc(-c2ccc(C(F)(F)F)cc2)c2c1CCN(C(=O)OC(C)(C)C)C2
Temperature: 75 °C
Reaction time: 48 h
Yield: 15 %

Procedure:
3-(4-Trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1.85 g, 5.04 mmol) and methyl acrylate (0.50 mL, 5.6 mmol) were combined in toluene (30 mL) and heated to 75° C. The resulting mixture was treated with t-BuONa (100 mg), and heating continued for 48 h. The mixture was allowed to cool and partitioned between EtOAc (300 mL) and NaHCO3 (75 mL). The aqueous layer was extracted with EtOAc (3×75 mL). The combined extracts were dried over Na2SO4 and concentrated. Column chromatography (silica, 30-60% EtOAc/hexanes) afforded 343 mg (15%) of the title compound. TLC (silica, 50% EtOAc/hexanes): Rf=0.4. MS (electrospray): m/z calculated for C22H27F3N3O4 [M++H] 454.20, found 454.1. 1H NMR (CDCl3, 400 MHz): 7.75 (br d, J=8.1 Hz, 2H), 7.64 (br s, 2H), 4.63 (br s, 2H), 4.30 (t, J=6.6 Hz, 2H), 3.75 (br s, 2H), 3.68 (s, 3H), 2.98 (t, J=6.6 Hz, 2H), 2.79 (br t, J=5.6 Hz, 2H), 1.48 (s, 9H).