Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]Cl.[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[CH:11][C:6]=2[O:5][CH2:4]1>C(Cl)Cl.C(O)(=O)C>[I:1][C:9]1[C:10]([NH:12][C:13](=[O:15])[CH3:14])=[CH:11][C:6]2[O:5][CH2:4][O:3][C:7]=2[CH:8]=1
Reactant: CC(=O)Nc1ccc2c(c1)OCO2
Reactant: ClI
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)Nc1cc2c(cc1I)OCO2
Reaction time: 8 h
Yield: 22 %

Procedure:
A 1.0 M solution of iodine monochloride in methylene chloride (72.6 mL) was added dropwise to a solution of N-(benzo[d][1,3]dioxol-5-yl)acetamide (10 g, 55.8 mmol) in methylene chloride (66 mL) and acetic acid (11 mL). The mixture was stirred under nitrogen overnight and then washed with saturated sodium thiosulfate (2×150 mL) and brine (150 mL). The methylene chloride solution was dried (MgSO4) and evaporated, and the residue was purified by column chromatography on silica gel (CH2Cl2/petroleum at 20/1) to obtain N-(6-iodobenzo[d][1,3]dioxol-5-yl)acetamide (3.7 g, 22%) as a white solid. LCMS: 306 [M+1]+; 1H NMR (DMSO-d6) δ 2.00 (s, 3H), 6.06 (s, 2H), 6.95 (s, 1H), 7.37 (s, 1H), 9.34 (s, 1H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH:9]1[CH2:21][C:22]([O:24][CH3:25])=[O:23])C1C=CC=CC=1.Cl.[C:27]([O:31][C:32]([O:34]N=C(C1C=CC=CC=1)C#N)=O)([CH3:30])([CH3:29])[CH3:28]>CO>[CH3:25][O:24][C:22]([CH2:21][CH:9]1[NH:8][CH2:13][CH2:12][N:11]([C:32]([O:31][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:34])[CH2:10]1)=[O:23]
Reactant: COC(=O)CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Agent: Cl
Solvent: CO
Product: COC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
The product of example 22A (9.78 g, 28.9 mmol) was combined with 20% Pd(OH)2—C (wet, 1.96 g) in methanol (100 mL) and 12 Maqueous HCl (2.9 mL, 35 mmol). The mixture was stirred under hydrogen (30 psi) at room temperature for 22 hours, then filtered and concentrated under vacuum. The residue was combined with 20% aqueous K2CO3 (40 mL) and ethyl acetate (50 mL), and the mixture stirred with ice-cooling as 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (Aldrich, 7.12 g, 28.9 mmol) was added gradually over 5 minutes. The mixture was stirred with ice cooling for 1 hour, then it was allowed to warm to room temperature for 2 hours. The mixture was extracted with ethyl acetate (2×100 mL) and the combined ethyl acetate washes were extracted with 10% aqueous HCl (40 mL). The aqueous layer was washed with ethyl acetate (30 mL), then made basic (pH˜9) by gradual addition of solid K2CO3 (11.8 g). Ethyl acetate (80 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The aqueous phase was separated, and the organic phase was washed with brine (50 mL), dried (MgSO4) and concentrated under vacuum to leave the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.46 (s, 9H), 2.31-2.49 (m, 2H), 2.50-2.68 (m, 1H), 2.72-2.81 (m, 1H), 2.82-2.98 (m, 2H), 2.98-3.09 (m, 1H), 3.70 (s, 3H), 3.90 (d, J=9.9 Hz, 2H); MS (DCI) m/z 259 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH:4]([OH:7])[CH2:5][OH:6].[Na][Na].[H-].[Na+].CS(O[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH3:31])(=O)=O>O1CCCC1>[CH3:1][N:2]([CH2:3][CH:4]([O:7][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]/[CH:23]=[CH:22]\[CH2:21][CH2:20][CH2:19][CH3:18])[CH2:5][O:6][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH3:31])[CH3:8]
Reactant: CN(C)CC(O)CO
Reactant: CCCC/C=C\CCCCCCCCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Agent: [Na][Na]
Solvent: C1CCOC1
Product: CCCC/C=C\CCCCCCCCOCC(CN(C)C)OCCCCCCCC/C=C\CCCC

Procedure:
Racemic 1-dimethylamino-2,3-propanediol (0.96 g; Janssen Chimica) was converted to the disodium salt in situ by treatment with sodium hydride (60% in oil, 0.8 g) in tetrahydrofuran (70 mL). Condensation with myristoleyl methane sulfonate (5.3 g; NuChek Prep) afforded crude (±)-N,N-dimethyl-(2,3-bis(myristoleyloxy))propylamine (DMOP-DMA). This material was purified to homogeneity by silica gel chromatography employing a step gradient of ether in hexane (from 10% to 50%), and finally neat ether, as the eluents. DMOP-DMA (2.4 g) was then treated with N-(3-bromopropyl)phthalimide (2.5 g) in dimethylformamide (15 mL) at elevated temperature (85° C., overnight) to effect quaternization of the amine. Removal of the dimethylformamide in vacuo followed by silica gel chromatography using a step gradient of methanol/chloroform as the eluent afforded TLC homogenous material. Deprotection of the primary amine was accomplished by treatment of the phthalimide (2.1 g) with anhydrous hydrazine (1.7 mL) in anhydrous ethanol (40 mL) and propargyl alcohol (10 eq.). Filtration, evaporative removal of the solvent, basic extraction (0.1 M NaOH), alumina chromatography, and washing with 1 M NaBr afforded the pure product.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH:5]([O:15][CH3:16])[CH2:6][NH:7][S:8]([CH2:11][CH2:12][CH2:13]Cl)(=[O:10])=[O:9]>CN(C)C=O>[CH3:3][O:4][CH:5]([O:15][CH3:16])[CH2:6][N:7]1[CH2:13][CH2:12][CH2:11][S:8]1(=[O:10])=[O:9]
Reactant: COC(CNS(=O)(=O)CCCCl)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(CN1CCCS1(=O)=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) suspension of sodium hydride (267 mg, 60% in oil, 6.67 mmol) in N,N-dimethylformamide (30 mL) was added N-[2,2-bis(methyloxy)ethyl]-3-chloro-1-propanesulfonamide (1.49 g, 6.06 mmol) in N,N-dimethylformamide (10 mL) dropwise. The reaction mixture was warmed to room temperature and stirred one hour. The reaction mixture was poured onto ice and extracted with toluene. The organic layer was washed with water and brine, then dried over sodium sulfate. Filtration and concentration provided 2-[2,2-bis(methyloxy)ethyl]isothiazolidine 1,1-dioxide as a clear oil. 1H NMR (400 MHz, CDCl3) δ 4.51 (t, J=5.3 Hz, 1 H), 3.41-3.37 (m, 8 H), 3.17-3.11 (m, 4 H), 2.35 (m, 2 H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[C:5]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=1>CO.[Pd]>[NH2:9][C:8]1[C:3]([NH:2][CH3:1])=[N:4][C:5]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CNc1nc(Sc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNc1nc(Sc2ccccc2)ccc1N
Yield: 83.7 %

Procedure:
A procedure similar to that described in Example 6, was repeated, except that 5.40 g of 2-methylamino-3-nitro-6-phenylthiopyridine (prepared as described in Preparation 88) were hydrogenated in 80 ml of methanol in the presence of 1.10 g of 10% w/w palladium-on-charcoal. After working up the product as described in Example 6, 4.00 g of the title compound having Rf=0.69 (on silica gel thin layer chromatography using ethyl acetate as the developing solvent) were obtained.
Reaction SMILES: Cl.[F:2][C:3]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4]1.CCN(C(C)C)C(C)C.Cl[C:19]1[C:38]([C:39]2[NH:43][N:42]=[CH:41][CH:40]=2)=[CH:37][C:22]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([Cl:36])([F:35])[F:34])=[CH:28][CH:27]=2)=[O:24])=[CH:21][N:20]=1.O>CC(O)C>[Cl:36][C:33]([F:34])([F:35])[O:32][C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:23](=[O:24])[C:22]2[CH:37]=[C:38]([C:39]3[NH:43][N:42]=[CH:41][CH:40]=3)[C:19]([N:5]3[CH2:6][CH2:7][C:3]([F:8])([F:2])[CH2:4]3)=[N:20][CH:21]=2)=[CH:31][CH:30]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Reactant: FC1(F)CCNC1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CCC(F)(F)C2)c(-c2ccn[nH]2)c1
Temperature: 140 °C
Reaction time: 3 h

Procedure:
3,3-Difluoropyrrolidine hydrochloride (69.8 mg, 0.486 mmol) and DIPEA (0.170 mL, 0.972 mmol) were added to 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide (Stage 48.1, 100 mg, 0.243 mmol) in iPrOH (0.5 mL) and stirred at 140° C. for 3 h. The RM was treated with water, and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude material which was purified by crystallization from DCM/EtOAc to give the title product as a white solid. HPLC (Condition 7) tR=6.746 min, UPLC-MS (Condition 3) tR=1.11 min, m/z=470.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.32-2.45 (m, 2H) 3.42-3.51 (m, 2H) 3.56 (t, J=13.29 Hz, 2H) 6.48 (s, 1H) 7.34 (d, J=8.60 Hz, 2H) 7.73-7.88 (m, 3H) 8.13 (d, J=2.35 Hz, 1H) 8.79 (s, 1H) 10.30 (s, 1H) 13.01 (br.s, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH3:4].Cl[CH2:18][C:19]([CH:21]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20]>CN(C)C=O>[CH2:3]([O:5][C:6](=[O:16])[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:18][C:19]([CH:21]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[CH:10][CH:9]=1)[CH3:4]
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Reactant: O=C(CCl)C1CCCCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1ccc(OCC(=O)C2CCCCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
55% Sodium hydride (0.14 g) was stirred with 4-hydroxy-alpha-oxobenzeneacetic acid ethyl ester (0.622 g) in dimethylformamide (8 mL) under argon for 30 minutes and then the solution was treated with 2-chloro-1-cyclooctylethanone (0.53 g) in dimethylformamide (3 mL). The mixture, stirred at room temperature overnight and the at 60° C. for 1 hour, was worked up as in Example 20. The residual oil was purified by flash chromatography over silica gel (3% ethyl acetate in dichloromethane-hexane 1:1 ) to provide of 0.399 g of 4-(2-cyclooctyl-2-oxoethoxy)-alpha-oxobenzeneacetic acid ethyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[NH2:11][NH2:12].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[N:5]=[C:6]([NH:11][NH2:12])[CH:7]=1
Reactant: NN
Reactant: COc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1nc(Cl)cc(NN)n1
Reaction time: 72 h
Yield: 38.2 %

Procedure:
4,6-dichloro-2-methoxy-pyrimidine (1.1 g, 6.2 mmol) was dissolved in 100 mL of anhydrous tetrahydrofuran. To the resultant reaction solution hydrazine (0.19 mL, 6.2 mmol) and potassium carbonate (2.6 g, 18 mmol) were added and the reaction mixture was stirred for 3 days. The potassium carbonate was removed by filtration and the filtrate was concentrated in vacuo. Crystallization of the residue from ethyl acetate:hexanes yielded 414 mg (39%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([OH:13])=O)=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C(Cl)Cl.CCN=C=NCCCN(C)C.Cl>>[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][N:23]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:11]([C:10]2[C:2]([F:1])=[CH:3][CH:4]=[C:5]3[C:9]=2[NH:8][CH:7]=[CH:6]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)cc2)cc1
Reactant: O=C(O)c1c(F)ccc2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)cc2)C(=O)c2c(F)ccc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 38.1 %

Procedure:
To a solution of 59 mg (0.33 mmol) of 6-fluoro-1H-indole-7-carboxylic acid and 86 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(4-fluoro-phenyl)-ethyl]-amine in 3 ml DCM 63 mg (0.33 mmol) of EDC.HCl were added and the reaction mixture was stirred over night at rt. The product was purified by column chromatography (20 g silica gel; heptane/EtOAc 4:1) to yield 51 mg (38%) product as a colorless viscous oil. MS (ISP) 447.4 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=[O:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17](O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:17]([O:13][C:12](=[O:14])[CH:11]1[CH2:15][CH2:16][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)OCc2ccccc2)CC1
Reaction time: 6 h

Procedure:
To a solution of N-t-butoxycarbonyl isonipecotic acid (12.0 g, 52.3 mmol) from example 3 step A, in anhydrous CH2Cl2 (100 ml), was added benzyl alcohol (6.0 ml, 58 mmol), followed by EDC (11.04 g, 57.6 mmol), and DMAP (642 mg, 5.25 mmol). The resulting mixture was stirred for 6 hrs, then diluted with CH2Cl2 (150 ml) and washed successively with water, 10% aqueous citric acid, saturated NaHCO3, and brine and dried (MgSO4). Concentration in vacuo afforded a colorless oil which was chromatographed (SiO2, 20% EtOAc in hexanes) to afford the product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:24]=2[Cl:31])=[O:22])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[OH:37][C:35]([C:34]([F:39])([F:38])[F:33])=[O:36].[CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]2[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:24]=2[Cl:31])=[O:22])=[CH:18][CH:19]=1)[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2cc(C#N)ccc2Cl)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2cc(C#N)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
To a solution of 4-[(2-chloro-5-cyanophenylcarbonyl)amino]-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (1.2 mmol, 0.55 g) in dichloromethane (12 mL) was added trifluoroacetic acid (3 mL) at room temperature. The reaction mixture was stirred for 15 h at room temperature at which time TLC analysis of the mixture indicated the absence of starting material. Then, the solvent was removed under vacuum and the residue was azeotroped with toluene (2×10 mL) and dried under high vacuum to afford 0.43 g (100%) of a yellow solid. HR MS (C18H16ClN3O3): Obs mass, 358.0963. Calcd mass, 358.0959 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[CH2:16]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: COC(=O)c1ccc2cc(OCc3ccccc3)ccc2c1
Reaction time: 3 h

Procedure:
Methyl 6-hydroxy-2-naphthoate (50 g), benzyl chloride (31.3 g), anhydrous potassium carbonate (100 g) and 2-butanone (350 ml) were stirred and refluxed together for 17 hours. Tlc showed the presence of some unreacted starting material and so a further 5 g benzyl chloride was added and refluxing continued for 3 hours. The product was isolated by pouring into water (1 liter), extracting the aqueous layer with 3×600 ml and 2×350 ml 2-butanone, followed by evaporation to dryness. The residue (65.7 g brown solid) was chromatographed over alumina (330 g) and silica gel (130 g) in dichloromethane, and the product was recrystallised from ethyl acetate (350 ml). Yield 37.3 g (51.6% theory) mpt 148.4°-149.3° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]([CH3:25])([CH3:24])[CH2:12][C@H:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O.C(NC(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CC(N1C2C(=CC=CC=2)CC(C(OCC)=O)C1)=O)CCC>C(N(CC)CC)C>[CH2:1]([O:8][CH2:9][CH2:10][C:11]([CH3:25])([CH3:24])[CH2:12][C@H:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CCOCc1ccccc1)C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(C(=O)OCC)Cc2ccccc21)NC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(CCOCc1ccccc1)C[C@@H](C=O)NC(=O)OC(C)(C)C

Procedure:
The title compound is prepared starting from 28.1 g of 6-benzyloxy-2(S)-tert-butoxycarbonylamino-4,4-dimethyl-hexan-1-ol, 10.5 ml of oxalyl chloride, 11.4 ml of dimethyl sulfoxide and 45 ml of triethylamine analogously to Example 1g): Rf (A)=0.62; Rt (I)=28.1 min; FAB-MS: (M+H)+ =350.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[Br:8].C(N(CC)CC)C.[OH-].[Na+].C(OC)(C)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C@@H:10]([OH:14])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[Br:8]
Reactant: O=C(O)C(=O)Cc1ccc(Br)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: O=C(O)[C@H](O)Cc1ccc(Br)c(Br)c1
Temperature: -35 °C
Reaction time: 1 h

Procedure:
A solution of 6.1 g (19.0 mmol) (1R)-B-chlorodiisopinocampheylborane in 40 mL THF was added dropwise within 30 min to a solution of 5.1 g (15.8 mmol) 3-(3,4-dibromo-phenyl)-2-oxo-propionic acid and 2.2 mL (15.8 mmol) triethylamine in 20 mL THF which had been cooled to −35° C. and the reaction mixture was kept at this temperature for 1 h. The reaction solution was carefully combined with 30 mL 1 M NaOH (exothermic) and 30 mL tert-butylmethylether, stirred for 15 min, the organic phase was separated off, then extracted with 25 mL water and 15 mL 1 M NaOH. The combined aqueous phases were acidified with 2 M HCl, extracted three times with in each case 40 mL tert-butylmethylether and the combined organic phases were dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was purified by chromatography (silica gel, EtOAc/MeOH/NH3 70:30:3).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:17])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([O:15]C)([CH3:14])[CH2:6][CH2:5]2.CC1C(O)=C(C)C(C)=C(C=1)O.CC(C)=O.Cl>O>[OH:15][C:7]1([CH3:14])[CH2:6][CH2:5][C:4]2[C:9](=[C:10]([CH3:13])[C:11]([CH3:12])=[C:2]([OH:1])[C:3]=2[CH3:17])[O:8]1
Reactant: COC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Agent: Cc1cc(O)c(C)c(C)c1O
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(O)O2

Procedure:
A solution of (±)-6-hydroxy-2-methoxy-2,5,7,8-tetramethylchroman, prepared as described in Example 1 from 1.0 mole of trimethylhydroquinone, in 1250 ml. of acetone, 1000 ml. of H2O and 8.30 ml. of conc. HCl was heated at reflux under N2. The solvent was removed by distillation until the distilling head temperature reached 95°. The suspension was cooled to 70°, diluted with 800 ml. of acetone, cooled to ca. 15° and stripped of solvent at reduced pressure and 30° to ca. 1000 ml. The resulting suspension was cooled, filtered and dried to give (±)-2,6-dihydroxy-2,5,7,8-tetramethylchroman as a grey-tan powder, m.p. 105°-107°.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10](O)[C:9]2[C:4](=[C:5]([O:14][CH3:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:17]>P(Cl)(Cl)(Cl)=O>[CH3:1][C:2]1[C:11]([CH3:12])=[C:10]([Cl:17])[C:9]2[C:4](=[C:5]([O:14][CH3:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1cccc2c(O)c(C)c(C)nc12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc2c(Cl)c(C)c(C)nc12
Temperature: 25 °C
Yield: 185.7 %

Procedure:
2.09 g of 2,3-dimethyl-4-hydroxy-8-methoxy-quinoline, 10 ml of phosphorus oxychloride and 0.43 g of phosphorus pentachloride are introduced into a 25 ml two-necked flask fitted with a condenser. The mixture is refluxed for 1 h. The reaction medium, cooled to room temperature, is poured onto 100 g of ice and extracted with ethyl acetate (2×100 ml). The organic phases are combined, washed with saturated sodium bicarbonate solution (200 ml), dried over magnesium sulphate and concentrated. The residue is purified by column chromatography on silica (elution solvent: dichloromethane). 0.85 g (yield: 37%) of 2,3-dimethyl-4-chloro-8-methoxyquinoline is obtained—m.p.: 130° C.
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([O:35][CH3:36])=[C:14]([O:19][C@H:20]3[CH2:25][CH2:24][C@@H:23]([N:26](C(OC(C)(C)C)=O)[CH3:27])[CH2:22][CH2:21]3)[CH:15]=2)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:37]>C(O)C>[ClH:37].[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([O:35][CH3:36])=[C:14]([O:19][C@H:20]3[CH2:21][CH2:22][C@@H:23]([NH:26][CH3:27])[CH2:24][CH2:25]3)[CH:15]=2)[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncn(Cc3ccccc3)c(=O)c2cc1O[C@H]1CC[C@@H](N(C)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCO
Product: CN[C@H]1CC[C@@H](Oc2cc3c(=O)n(Cc4ccccc4)cnc3cc2OC)CC1

Procedure:
Prepared by treating 3-benzyl-3,4-dihydro-4-oxo-6-{cis-4-[N-(tert-butyloxycarbonyl)-N-methyl-amino]-cyclohexyl-oxy}-7-methoxy-quinazoline with isopropanolic hydrochloric acid in ethanol at 40° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:32])[CH:20]=[CH:21][C:22]3[CH:31]=[N:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([OH:32])[CH:20]=[CH:21][C:22]3[CH:31]=[N:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH:12]=[CH:11][CH:10]=2)=[CH:33][CH:34]=1
Reactant: COc1ccc(CNc2cccc(CCCCC(=O)C=Cc3cnc4ccccc4n3)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNc2cccc(CCCCC(O)C=Cc3cnc4ccccc4n3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
A solution of the enone 22-2 (1.0 g, 2.2 mmol) in MeOH (50 mL) at 0° C. was treated with NaBH4 (0.092 g, 2.4 mmol). The ice bath was removed and the solution was stirred at room temperature for 1 hr. The reaction was quenched with water (25 mL) and extracted with EtOAc (3×125 mL). The organics were combined, dried (Na2SO4), concentrated in vacuo, and purified on silica gel (90:5:5 CHCl3:EtOAc:MeOH) to afford 0.26 g of 22-3.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6]C=1.[Cl-].[NH4+].CO.C1C[O:22][CH2:21]C1>>[S:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:3]1([CH:4]=[CH:9][CH:8]=[CH:7][CH2:6]1)[CH2:21][OH:22]
Reactant: C1CCOC1
Reactant: c1ccc(Cc2cccs2)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: OCC1(c2cccs2)C=CC=CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 92 %

Procedure:
Sodium borohydride (0.37 g, 10 mmol) was added to 2-benzylthiophene (1.88 g, 10 mmol) dissolved in methanol/THF mixture (1:10 ratio, 11 ml). This was stirred at room temperature for 10 h. The reaction mixture was decomposed by addition of saturated ammonium chloride solution (50 ml) and was extracted with ethyl acetate (2×50 ml). The combined organic layer was dried over anhydrous MgSO4. Removal of the solvent gave 1-(2-thienyl)benzyl alcohol as a solid (1.75 g, 92% yield).