Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:15][C:9]2=[N:10][C:11]([Cl:14])=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2].CC(C)([O-])C.[K+].[C:22]([O:26][C:27]([N:29]1[CH2:33][C@H:32]([CH3:34])OS1(=O)=O)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:15]([C@H:32]([CH3:34])[CH2:33][NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[C:9]2=[N:10][C:11]([Cl:14])=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2ccc(Cl)nc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(Cl)nc2n1[C@H](C)CNC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A solution of 3.0 g (13.3 mmol) 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester in 70 ml N,N-dimethylformamide was cooled to 0 deg C. and 1.58 g (14.0 mmol) potassium tert-butoxide was added. After 30 min, 3.49 g (14.7 mmol) (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester was added in one portion. The cooling bath was removed and after 1.5 h the reaction mixture was poured into 100 ml 10% aqueous citric acid. The layers were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed four times with water, once with brine and then were dried over magnesium sulfate. After filtration the solvent was removed on a rotary evaporator and the residue was purified by flash-chromatography over silica gel (0.032–0.063 mm) with n-hexane:ethyl acetate (9:1, then 5:1) as eluant to afford the product as a yellow oil (98.0%).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[CH3:9][S-:10].[Na+].C(OCC)(=O)C>CN(C)C=O>[CH3:9][S:10][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8]
Reactant: C[S-]
Reactant: O=Cc1sccc1Br
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ccsc1C=O
Reaction time: 3 h
Yield: 91.4 %

Procedure:
4.44 g of 3-bromo-2-thiophenecarboxaldehyde and 1.63 g of sodium thiomethoxide were dissolved in 20 ml of N,N-dimethylformamide, and the mixture was stirred for 3 hours under ice-cooling. Ethyl acetate was added to the reaction solution. The mixture was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:9), to give 3.36 g of the title compound as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([CH:19]=O)[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[BH4-].[Na+].Cl>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][NH:21][CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1cc(C=O)cc(-c2cccc(C#N)c2)c1
Reactant: NCC1CCNCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(CNCC2CCNCC2)cc(-c2cccc(C#N)c2)c1
Reaction time: 1 h
Yield: 70.6 %

Procedure:
In 30 ml of toluene, were dissolved 3.00 g of the compound obtained in Example 11 and 1.50 g of 4-aminomethylpiperidine. The resulting solution was refluxed for 3 hours to remove the produced water. The solvent was evaporated from the reaction solution under reduced pressure, and 10 ml of tetrahydrofuran and 20 ml of methanol were added to the residue to provide a solution. To the resulting solution, was added 0.500 g of sodium borohydride under cooling with ice. The mixture was stirred at this temperature for 1 hour, then returned to room temperature and stirred for another hour. To the resulting solution was added a 1 M hydrochloric acid to quench the reaction. The resulting solution was washed with ethyl acetate. A 1 M aqueous solution of sodium hydroxide was added to the obtained aqueous layer until the pH attained 10. The resulting solution was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine and subsequently dried over sodium sulfate, and the solvent was removed under reduced pressure to provide 2.9 g (71%) of the title compound as an oil.
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=3)[CH:14]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].CCO>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([O:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=3)=[CH:12][CH:11]=2)[CH2:16][NH:8]1
Reactant: [H][H]
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CN(Cc2ccccc2)C3)nc1
Agent: [Pd]
Solvent: CCO
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CNC3)nc1
Yield: 11.9 %

Procedure:
Combine 6-(2-Benzyl-2,3-dihydro-1H-isoindol-5-yloxy)-nicotinamide (230.0 mg, 0.67 mmol), EtOH (5 mL), 10% Pd—C (45.0 mg), and a Hydrogen balloon. Stir the reaction at room temperature for 168 hours at atmospheric pressure. Filter the reaction mixture through a pad of Celite using MeOH eluent and then concentrate the filtrate under reduced pressure. Add the mixture to a 2 g SCX column, wash with MeOH, and elute using 1N NH3-MeOH. After concentrating under reduced pressure, purify the mixture by flash chromatography using 10% 1N NH3-MeOH/DCM eluent to afford 19.2 mg, 0.08 mmol (11% yield) of the title compound as a white solid: 1H NMR (500 MHz, d-Methanol); 4.1-4.3 (4H, br m), 6.9-7.1 (3H, m), 7.3-7.4 (1H, m), 8.2-8.3 (1H, m), 8.6 (1H, s); MS m/z 254 (M).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:23][CH:22]4[NH2:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.CCN(CC)CC.[C:34]1([N:40]=[C:41]=[S:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[C:34]1([NH:40][C:41]([NH:24][CH:22]2[CH2:23][CH:21]2[C:18]2[CH:19]=[CH:20][C:15]([C:12]3[N:13]=[CH:14][N:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=4)[N:11]=3)=[CH:16][CH:17]=2)=[S:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NC1CC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: S=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(C4CC4NC(=S)Nc4ccccc4)cc3)n2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 33.2 %

Procedure:
The amine trifluoroacetate salt from Example 5 (0.064 g, 0.135 mmol) was dissolved in THF (0.5 mL). Et3N (0.037 mL, 0.27 mmol) was added, followed by phenyl isothiocyanate (0.020 mL, 0.15 mmol). The resulting dark yellow solution was heated to 80° C. and stirred for 4 h. The solution was cooled to 25° C., loaded directly onto a silica gel column and purified (gradient elution with 15% to 40% to 80% EtOAc in hexanes) to afford the product (0.0222 g, 33%) as a yellow oil: IR νmax 3380, 3218 (br), 1617, 1598, 1518, 1497, 1448, 1356, 1326, 1264, 1221, 1168, 1111, 1065, 986, 910, 851, 756, 732, 694 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 8.11 (d, J=8.3 Hz, 2H), 7.90 (br s, 1H), 7.78 (d, J=9.0 Hz, 2H), 7.46-7.32 (m, 5H), 7.31-7.21 (m, 5H), 3.10 (br s, 1H), 2.25 (br s, 1H), 1.51-1.30 (m, 2H); HRMS-ESI (m/z) [M]+ calcd for C25H20F3N5OS, 495.134. found, 495.1341.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.CS([C:13]1[N:18]=[C:17]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([O:28][CH3:29])=[N:20]2)[CH:16]=[CH:15][N:14]=1)(=O)=O>CN1C(=O)CCC1>[CH3:29][O:28][C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:1][C@H:2]3[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]3)[N:18]=2)[N:20]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: COc1nn(-c2ccnc(S(C)(=O)=O)n2)c2ccccc12
Solvent: CN1CCCC1=O
Product: COc1nn(-c2ccnc(N[C@H]3CC[C@H](O)CC3)n2)c2ccccc12
Temperature: 120 °C

Procedure:
trans-4-Aminocyclohexanol (870 mg, 8 mmol) was added to 1-(2-methanesulfonyl-pyrimidin-4-yl)-3-methoxy-1H-indazole (440 mg, 1 mmol) in NMP (15 mL), and the resulting mixture heated to 120° C. for 3 h. The reaction mixture was cooled and partitioned between EtOAc and water. The organic layer was separated, washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude yellow solid. This crude material was purified by flash chromatography (MeOH/DCM, 5:95) and recrystallized from DCM/hexanes to give trans-4-[4-(3-methoxy-indazol-1-yl)-pyrimidin-2-ylamino]-cyclohexanol (181 mg (37% yield) as a white solid. MS=340 [M+H]+; MP=202.3-205.1° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].Br[CH2:25][C:26]#[N:27]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:25][C:26]#[N:27])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12]
Reactant: N#CCBr
Reactant: CC(c1ccc(Cl)cc1Cl)C(O)(c1cc[nH]c(=O)c1)C(F)(F)F
Product: CC(c1ccc(Cl)cc1Cl)C(O)(c1ccnc(OCC#N)c1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to Example 120 from 4-[2-(2,4-Dichloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1H-pyridin-2-one (Example 119, 100 mg) and bromo-acetonitrile (0.022 mL). MS (m/e)=405.2 (MH+).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([N+:22]([O-])=O)=[C:7]([O:20][CH3:21])[C:8]([C:16](=[O:19])[NH:17][CH3:18])=[C:9]([N+:13]([O-])=O)[C:10]=1[O:11][CH3:12])=[O:4].CO.Cl>[Pd].C(O)CCC.C(O)(=O)C.O>[CH3:18][NH:17][C:16]([C:8]1[C:9]([NH2:13])=[C:10]([O:11][CH3:12])[C:5]([C:3](=[O:4])[NH:2][CH3:1])=[C:6]([NH2:22])[C:7]=1[O:20][CH3:21])=[O:19]
Reactant: CNC(=O)c1c(OC)c([N+](=O)[O-])c(C(=O)NC)c(OC)c1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCCCO
Product: CNC(=O)c1c(N)c(OC)c(C(=O)NC)c(N)c1OC
Reaction time: 4 h

Procedure:
A mixture consisting of 978 mg (2.84 mmol) of 7, 100 mg 5% Pd/C, and 100 mL of methanol was shaken under 50 psi of H2 for 4 hours. Upon completing the reduction, 10 mL of concentrated hydrochloric acid was added to the reaction mixture with stirring. After filtering the solution through CELITE and washing the filtrate with methanol, the solvent was removed in vacuo and the residue dried for several hours. The dihydrochloride salt of 9 was recrystallized by dissolution in a minimum amount of hot methanol followed by cooling and then addition of ethyl acetate: 893 mg (88%) yield; TLC (n-butanol/acetic acid/water [5:2:3]), Rf =0.44; 1H NMR (dimethyl-d6 sulfoxide) δ8.40 (2H, brs, 3- and 6-carbamyl proton), 3.64 (6H, s, methoxys), 2.81 (6H, d, J=4.0 Hz, 3- and 6-carbamyl methyls); mass spectrum (EI mode), m/z 282 (P+).
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]([CH3:28])([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[N:11]1[CH2:16][CH2:15][C:14]2[S:17][CH:18]=[CH:19][C:13]=2[CH2:12]1)C.O.[OH-].[K+]>C(O)C>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:10]([N:11]1[CH2:16][CH2:15][C:14]2[S:17][CH:18]=[CH:19][C:13]=2[CH2:12]1)[CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:28])([CH3:27])[C:4]([OH:29])=[O:3]
Reactant: CCOC(=O)C(C)(C)CCCCC(c1ccccc1Cl)N1CCc2sccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(CCCCC(c1ccccc1Cl)N1CCc2sccc2C1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.5 %

Procedure:
7-(2-Chlorophenyl)-7-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2-dimethylheptanoic acid ethyl ester (2.80 g, 7.23 mmol) was dissolved in ethanol (40 mL) and water (25 mL) containing potassium hydroxide (10 g, 250 mmol). The mixture was heated to reflux for 24 hours. After 24 hours, the flask was cooled to room temperature and concentrated. Water (50 mL) was added and extracted with 10% ethyl acetate in heptane. The aqueous fraction was acidified (to pH=6) with concentrated hydrochloric acid and the product was extracted with dichloromethane (2×100 mL). The dichloromethane extracts were combined, dried over sodium sulfate, filtered and concentrated. The remaining tan oil (3.0 g) was purified by flash column chromatography on silica gel (100 g), eluting with heptane-ethyl acetate (2:1) to provide 7-(2-chlorophenyl)-7-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2-dimethylheptanoic acid as a white solid (2.1 g, 71.6% yield). The product was dissolved in water (ASTM 1, 200 mL) containing hydrochloric acid (1%) and acetone (25 mL). Most of the acetone and excess hydrochloric acid was removed under reduced pressure. The remaining water (200 mL) was freeze-dried to provide 7-(2-chlorophenyl)-7-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2-dimethylheptanoic acid, hydrochloride salt (Compound Ig hydrochloride, 2.2 g, mp 97-100° C., 99.47% purity by HPLC) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ=12.25 (br s, 0.5H), 12.12 (br s, 0.5H), 8.24 (br s, 1H), 7.60-7.38 (m, 4H), 6.94 (d, 1H, J=4.5 Hz), 6.77 (d, 1H, J=4.5 Hz), 4.90-4.68 (m, 1.5H), 4.38 (dd, 0.5H, J=14.4, 5.4 Hz), 4.01 (m, 1H), 3.80 (dd, 0.5H, J=14.4, 5.1 Hz), 3.60-3.30 (m, 1.5H), 3.20-2.85 (m, 2H), 2.42 (m, 1H), 2.23 (m, 1H), 1.40-1.0 (m, 5H), 1.01 (s, 6H), 0.79 (m, 1H). (mixture of rotational isomers). 13C NMR (75 MHz, DMSO-d6): δ=178.41, 134.70, 134.60, 131.83, 131.49, 131.23, 131.05, 129.93, 129.75, 128.38, 128.35, 128.10, 125.43, 125.26, 124.87, 124.86, 64.35, 63.17, 49.87, 48.70, 48.00, 47.13, 41.16, 30.78, 30.30, 30.12, 25.77, 25.02, 24.14, 21.78, 21.37. (mixture of rotational isomers). HRMS (MMI-TOF): Calculated for C22H29Cl2NO2S (MH+): 406.1202. found 406.1594.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:14])=[C:8]([CH2:12][CH3:13])[C:9]=2[CH3:11])[S:4][C:3]=1[C:15]([OH:17])=O.N=C=N.[C:21]1([C:27]2NN=[N:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClC(Cl)C.CN(C=O)C>[CH2:12]([C:8]1[C:9]([CH3:11])=[C:10]2[C:2]([NH2:1])=[C:3]([C:15]3[O:17][C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:28][N:29]=3)[S:4][C:5]2=[N:6][C:7]=1[CH3:14])[CH3:13]
Reactant: CCc1c(C)nc2sc(C(=O)O)c(N)c2c1C
Reactant: c1ccc(-c2nnn[nH]2)cc1
Agent: N=C=N
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: CCc1c(C)nc2sc(-c3nnc(-c4ccccc4)o3)c(N)c2c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.2 %

Procedure:
To a solution of 3-amino-5-ethyl-4,6-dimethyl-thieno[2,3-b]pyridine-2-carboxylic acid (0.16 g, 0.63 mmol) in a mixture of dichloroethane (8 mL) and DMF (2 mL) was added PS-carbodiimide (1.0 g, 1.26 mmol). The mixture was shaken for 15 min at room temperature, followed by the addition of 5-phenyltetrazole (0.042 g, 0.32 mmol). Then, the mixture was shaken at 80° C. overnight. The resin was then removed by filtration and washed with hot chloroform (2×5 mL). The filtrate was evaporated in vacuum to dryness and purified by chromatography (silica gel, dichloromethane/ethyl acetate, 9/1) to furnish the product 5-ethyl-4,6-dimethyl-2-(5-phenyl-[1,3,4]oxadiazol-2-yl)-thieno[2,3-b]pyridin-3-yl amine (0.063 g, 56%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=CC=CC=2CN)[C:3]=1[S:14]([OH:17])(=[O:16])=[O:15].OC1C2C(=CC(S(O)(=O)=O)=CC=2N)C=C(S(O)(=O)=O)C=1.C([O-])(=O)C.[Na+].[OH-].[Na+].C(=O)(O)[O-].[Na+]>>[S:14]([OH:17])(=[O:16])([C:3]1[C:2]([NH2:1])=[CH:11][CH:10]=[CH:9][CH:4]=1)=[O:15]
Reactant: NCc1cccc2c(S(=O)(=O)O)c(N)ccc12
Agent: CC(=O)[O-]
Agent: Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(O)c12
Agent: O=C([O-])O
Product: Nc1ccccc1S(=O)(=O)O

Procedure:
The diazotisation product prepared according to the instructions of Example 3 from 36.5 parts of 2-amino-1-sulpho-5-aminomethyl-naphthalene is mixed with a neutral solution of 46 parts of 1-hydroxy-8-amino-3,6-disulphonaphthalene. To accelerate the coupling, the mixture is buffered to pH 2 by adding sodium acetate solution. The acid coupling is complete after stirring for several hours. The dyestuff solution is neutralised with sodium hydroxide solution. 40 Parts of sodium bicarbonate and a little CaO are added and the diazotisation product obtained from 25 parts of o-sulphanilic acid is then added. The diazo dyestuff is separated out by adding salt. The paste is stirred into 1,000 parts by volume of water. 16 Parts by volume of 2,4,6-trifluoro-5-chloro-pyrimidine are added dropwise at 15° and pH 8.5. The pH is kept at 8.5 by simultaneous addition of 2 N sodium hydroxide solution. After completion of the acylation, the dyestuff is salted out, dried and ground. An easily water-soluble black dyestuff powder is obtained. In the form of the free acid, the dyestuff corresponds to the structure: ##STR22##
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7](C(OC(C)(C)C)=O)[CH2:8][C@@H:9]([O:10][S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C@H:5]2[O:4][CH2:3]1.O1CCOCC1.[ClH:34]>>[ClH:34].[CH3:18][C:17]1[CH:19]=[CH:20][C:14]([S:11]([O:10][C@@H:9]2[CH2:8][NH:7][C@@H:6]3[C@@H:2]([OH:1])[CH2:3][O:4][C@H:5]23)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OC(C)(C)C)[C@H]3[C@@H]2OC[C@@H]3O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CN[C@H]3[C@@H]2OC[C@@H]3O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Boc alcohol (35b) (11.0 g, 27.6 mmol) was dissolved in 4N HCl in dioxan (100 mL, 400 mmol) and the mixture stirred at ambient temperature for 1 hour. The mixture was then concentrated in vacuo and azeotroped three times from toluene to give a pale brown solid (Yield 9.25 g). HPLC-MS 3001 [M+H]+; δH (500 MHz, d6-DMSO) 2.44 (3H, s, CH3-aryl), 3.13 (1H, dd, J=7.8 Hz, NHCH2), 3.38 (1H, dd, J=6.7 Hz, NHCH2), 3.68 (1H, dd, J=2.0, 9.9 Hz, CHOCH2), 3.93 (1H, d, J=5.3 Hz, NHCHCH), 3.98 (1H, dd, 4.3, 9.9 Hz, CHOCH2), 4.50 (1H, m, NHCHCH), 4.57 (1H, t, J=4.9 Hz, TsOCHCH), 5.03 (1H, m, TsOCHCH), 5.71 (1H, b, NH), 7.52 (2H, d, J=8.0 Hz, aryl), 7.84 (2H, d, J=8.0 Hz, aryl), 9.92 (2H, b, OH+HCl); δC (125 MHz, d6-DMSO) 21.25 (aryl-CH3), 45.99 (NHCH2), 67.60 (NHCH), 72.63 (OCH2CHOH), 75.94 (OCH2CHOH), 77.18 (TsOCHCH), 79.15 (TsOCHCH), 127.84 and 130.40 (aromatic CH), 132.28 (CHOSO2C quaternary), 145.65 (CH3C quaternary).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32]>>[OH:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1
Reactant: NCCCCCCO
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCCCCCCO)cn1
Yield: 20 %

Procedure:
As described for example 220, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (180 mg, 0.55 mmol) was converted, using 6-amino-1-hexanol instead of 3-amino-1-propanol, to the title compound (45 mg, 20%) which was obtained as a white solid. MS: m/e=410.3 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH:12]=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10].C(O)(=O)C.O>CC(O)C.ClCCl>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH2:12][OH:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: O=CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: OCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
Sodium borohydride (2.03 g) was added portionwise to a solution of 2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butan-1-al (17.02 g) (see Preparation 27) in 2-propanol (250 ml). The mixture was stirred at room temperature overnight and glacial acetic acid (4 ml) carefully added, followed by addition of water (2 ml). The solvent was removed under reduced pressure to give a residue which was dissolved in dichloromethane and washed sequentially with water, dilute aqueous sodium hydrogen carbonate solution and brine. The solution was dried over anhydrous sodium sulphate and the solvent removed under reduced pressure. The crude product was chromatographed on silica gel eluting with 1:1, by volume, ethyl acetate:hexane to give 2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butan-1-ol (14.7 g) as a colourless oil and as a mixture of diastereomers.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH3:19])[C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C.O>[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH:19]=[CH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1
Reactant: C#CCOc1ccc2c(C)cc(=O)oc2c1C(C)=O
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C#CCOc1ccc2c(C)cc(=O)oc2c1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Yield: 31 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 4-methyl-7-prop-2-ynyloxy-8-acetylcoumarin (1.92 g, 0.0075 mol) and benzaldehyde (0.8 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified. The precipitate is separated by filtration and dried under vacuum. The compound is crystallized by ethanol to give 0.8 g of product m.p. 140-42° C., 1H-NMR (CDCl3) δ: 2.45 (s, 3H); 2.53-2.56 (m, 1H); 4.82 (d, 2H, J=2.2 Hz); 6.20 (s, 1H); 7.02 (d, 1H, J=16 Hz); 7;13 (d, 1H, J−=8.9 Hz); 7.32 (d, 1H, J=16 Hz); 7.35-7.45 (m, 3H); 7.48-7.52 (m, 2H); 7.67 (d, 1H, J=8.9 Hz).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].C(N(CC)CC)C.[C:15](Cl)(=[O:19])[C:16]([CH3:18])=[CH2:17].O>C(Cl)Cl>[C:15]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6])(=[O:19])[C:16]([CH3:18])=[CH2:17]
Reactant: C=CCCCCO
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C=CCCCCOC(=O)C(=C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Hexen-1-ol (5.0 g; 50.0 mmol) and triethylamine (15.0 g, 150 mmol) were combined in a round-bottom flask and dissolved in methylene chloride (50 mL). After cooling in an ice bath, methacryloyl chloride (5.2 g, 50.0 mmol) was slowly added to the solution by syringe. The solution was warmed to room temperature and allowed to stir overnight. Water was added, and the organic phase was washed with sodium bicarbonate solution followed by brine solution. The organic layer was dried over magnesium sulfate and filtered to give a clear solution. After solvent removal, the crude product was purified by passing it through a silica column (1:40 ethyl acetate:hexanes). The product was obtained as a clear liquid, which was stored at 0° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].[CH2:24]([SH:26])[CH3:25]>O1CCOCC1.C(OCC)(=O)C.O1CCCC1.C(P(C(C)C)[C-]1C=CC=C1)(C)C.[C-]1(P(C(C)C)C(C)C)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([S:26][CH2:24][CH3:25])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(Br)cc2C1
Reactant: CCS
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCSc1ccc2c(c1)CN(C(=O)OC(C)(C)C)C2
Temperature: 100 °C
Reaction time: 16 h

Procedure:
Lit. Tetrahedron 2004, 60, 7397-7403. To a stirred suspension of 1.34 mmol 5-bromo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (CAS: 201940-08-1) in 2 ml dioxane were added 0.03 mmol 1,1′-bis(diisopropylphosphino)ferrocene, 0.03 mmol palladium acetate, 1.61 mmol sodium tert-butoxide and 2.68 mmol ethanethiol and the mixture was stirred at 100° C. for 16 h. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate/tetrahydrofuran and washed with brine. The organic phase was dried over sodium sulfate and concentrated in vacuo to yield the title compound as a brown oil which was used in the next step without further purification.