Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([CH:14]=[O:15])=[CH:3][CH:2]=1.[BH4-].[Na+].O>C(O)C>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([CH2:14][OH:15])=[CH:3][CH:2]=1
Reactant: O=Cc1cccc2c1oc1ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCc1cccc2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
1 g (5.1 mmol) of Dibenzofuran-4-carboxaldehyde is dissolved in 5 ml of ethanol. 0.24 g of NaBH4 is then added portionwise to the stirred solution during a period 20 minutes. The solution is maintained under stirring at room temperature for 2 hours, following which the solvent is evaporated. The residue obtained is treated with water, and aqueous layer is then extracted with ether. Evaporation of the organic phase yielded 0.90 g of Dibenzofuran-4-ylmethanol.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]2[C@@H:17]3[C@@H:12]([C:13]4[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:14]=4[CH2:15][CH2:16]3)[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:30][N:31]=[C:32]=[O:33].C(=O)([O-])O.[Na+].[ClH:39]>C(#N)C.C(O)C>[ClH:39].[CH3:30][NH:31][C:32](=[O:33])[O:22][C:18]1[C:14]2[CH2:15][CH2:16][C@H:17]3[C@H:12]([CH2:11][CH2:10][N:9]3[CH2:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:13]=2[CH:21]=[CH:20][CH:19]=1
Reactant: CN=C=O
Reactant: Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCC1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNC(=O)Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCC1CCCCC1
Yield: 60 %

Procedure:
A suspension of 2.00 g (0.0067 mol) of (+)-cis-3-(2-cyclohexylethyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-ol in 100 ml of acetonitrile was treated with 1.9 ml (0.013 mol) of triethylamine and 1.6 ml (0.027 mol) of methyl isocyanate. The mixture was boiled under reflux for 5 hours and the poured into aqueous sodium hydrogen carbonate solution, whereupon the mixture was extracted with methylene chloride. After drying the organic phase with sodium sulphate and distillation of the solvent the residue was chromatographed over silica gel with methylene chloride/methanol 20:1. The oil obtained was dissolved in ethanol and treated with an equimolar amount of ethanolic HCl. After concentration the residue was dissolved in methylene chloride, treated with active charcoal and sodium sulphate, filtered and the solvent was distilled off. The residue was suspended in ethyl acetate, filtered off and dried in a vacuum. There were obtained 1.58 g (60%) of (+)-cis-3-(2-cyclohexylethyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-yl methylcarbamate hydrochloride with m.p. 209°-212°.
Reaction SMILES: [N:1]([CH:4]1[CH2:19][CH2:18][C:7]2=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:9][C:10]([S:11][CH3:12])=[C:6]2[C:5]1=[O:20])=[N+]=[N-].[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(O)(=O)C>[C:21]([NH:1][CH:4]1[CH2:19][CH2:18][C:7]2=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:9][C:10]([S:11][CH3:12])=[C:6]2[C:5]1=[O:20])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1sc(SC)c2c1CCC(N=[N+]=[N-])C2=O
Solvent: CC(=O)O
Product: CCOC(=O)c1sc(SC)c2c1CCC(NC(C)=O)C2=O
Yield: 73.8 %

Procedure:
A mixture of ethyl 5-azido-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]thiophene-1-carboxylate (3.62 g), palludium-carbon (5%, 50% wet, 4.0 g), acetic acid (70 ml) and acetic anhydride (35 ml) was subjected to a catalytic reduction reaction at room temperature under 1 atm. The insoluble substances were filtered off; the filtrate was concentrated under reduced pressure; the residue was dissolved in ethyl acetate-tetrahydrofuran (3;1, v/v). This solution was washed with water, a saturated aqueous solution of sodium hydrogen carbonate and water in that order, and dried (MgSO4), after which the solvent was distilled off to yield ethyl 5-acetylamino-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]thiophene-1-carboxylate (2.81 g, 73.8%), which was then recrystallized from chloroform-ethanol. Colorless needles. Melting point 215-216° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.C1(C)C=CC=CC=1.[N+:26]([C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Br)([O-:28])=[O:27]>O1CCCC1>[CH3:1][O:2][C:3](=[O:18])[CH:4]([CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:9][CH2:10]1)[CH2:31][C:30]1[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=1[N+:26]([O-:28])=[O:27]
Reactant: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=[N+]([O-])c1ccccc1CBr
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccccc1[N+](=O)[O-])C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 41 %

Procedure:
tert-Butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (240 mg, 0.93 mmol) was dissolved in tetrahydrofuran (7 mL). Mixture was cooled to −78° C. A 0.5 M solution of potassium bistrimethylsilyl)amide in toluene (2.2 mL, 1.1 mmol) was added to the mixture drop-wise. Reaction stirred at −78° C. for 20 minutes. A solution of 2-nitrobenzylbromide (240 mg, 1.1 mmol) in tetrahydrofuran (2 mL) was added to the reaction mixture drop-wise. Reaction stirred at −78° C. for 40 minutes. Dry ice bath was removed and the reaction mixture was allowed to warm to room temperature over 30 minutes. Reaction was quenched with aqueous ammonium chloride. Mixture was extracted with ethyl acetate (2×20 mL). Combined extracts were dried (magnesium sulfate), filtered and concentrated in vacuo. Silica gel chromatography afforded the title compound as yellow oil in 41% yield. MS m/e (M−C4H8+H)+=337.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@@H:4]1[CH2:8][CH2:7][C:6](=[O:9])[NH:5]1.[H-].[Na+].[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)#[N:14]>C1COCC1>[CH3:1][O:2][C:3](=[O:10])[C@@H:4]1[CH2:8][CH2:7][C:6](=[O:9])[N:5]1[CH2:19][C:18]1[CH:21]=[CH:22][C:15]([C:13]#[N:14])=[CH:16][CH:17]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCC(=O)N1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
L-Pyroglutamic acid methyl ester (1.36 g, 0.0095 mol) was dissolved in dry THF (20 mL) under Ar, treated with NaH (60% oil dispersion) (0.58 g, 0.0145 mol) with stirring for 5 min, then the mixture was cooled to 0° C. p-Cyanobenzylbromide (1.78 g, 0.0091 mol) was added, and the mixture left to slowly warm to ambient temperature. After 48 h the reaction mixture was partitioned between EtOAc and satd NaHCO3 solution, the aqueous layer separated and washed with CH2Cl2, the organics combined, washed with brine and dried (MgSO4). Filtration and concentration to dryness followed by trituration with ether gave the white solid product. 1H NMR(CDCl3, 400 MHz) δ 7.62(2H, d, J=8 Hz), 7.33(2H, d, J=8 Hz), 4.98(1H, d, J=15.4 Hz), 4.13(1H, d, J=15.4 Hz), 3.99(1H, dd, J=3, 9 Hz) and 2.5-2.6 (1H, m), 2.4-2.5 (1H, m), 2.2-2.45 (1H, m), 2.1-2.2 (1H, m) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:33])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25]C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.O1CCOCC1>O1CCCC1>[NH2:1][C:2]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:33])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)NCCCCCCC(=O)N1CCC(c2nc(N)nc3ccccc23)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NCCCCCCC(=O)N1CCC(c2nc(N)nc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.9 %

Procedure:
To a solution of 2-amino-4-[1-(7-t-butoxycarbonylaminoheptanoyl)-4-piperidinyl]quinazoline (160 mg) obtained in Example 27 in tetrahydrofuran (1 ml) was added 4N hydrogen chloride-dioxane solution (1 ml). The reaction mixture was stirred for about 1 hour at room temperature and was evaporated. The residue was triturated with diethyl ether to give the title compound (131 mg) as hydrochloride.
Reaction SMILES: C([O:5][C:6](=[O:24])[CH:7]([C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([Br:23])[CH:16]=1)C(OC(C)(C)C)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Br:23][C:17]1[CH:16]=[C:15]([CH2:7][C:6]([OH:24])=[O:5])[CH:20]=[CH:19][C:18]=1[C:21]#[N:22]
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(C#N)c(Br)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(CC(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.1 %

Procedure:
To the di-tert-butyl(3-bromo-4-cyanophenyl)malonate (2.2 g, 5.4 mmol) in dichloromethane (30 mL) was added triflouroacetic acid (10 mL) and the reaction mixture stirred for 12 h at room temperature. The solution was concentrated under reduced pressure and chased with toluene (2×) to give the crude product as a yellowish oil (1 g, 77%, and 85% purity as indicated by NMR). The residue was used in the next step without further purification. 1H NMR (500 MHz, DMSO-d6) δ 12.80 (br s, 1H), 7.87 (d, J=8 Hz, 1H), 7.80 (s, 1H), 7.48 (d, J=8 Hz, 1H), 3.73 (s, 2H). LC-MS (IE, m/z): 240 [M+1]+.
Reaction SMILES: [NH2:1][CH:2]([CH:6]=[CH:7][CH2:8][P:9]([OH:12])([OH:11])=[O:10])[C:3]([OH:5])=[O:4].Cl>C(O)CCCC>[CH2:3]([O:4][C:3](=[O:5])[CH:2]([NH2:1])/[CH:6]=[CH:7]/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[CH2:2][CH2:6][CH2:7][CH3:8]
Reactant: NC(C=CCP(=O)(O)O)C(=O)O
Agent: Cl
Solvent: CCCCCO
Product: CCCCCOC(=O)C(N)/C=C/CP(=O)(O)O

Procedure:
1.5 g of 2-amino-5-phosphono-3-pentenoic acid are suspended in 30 ml of n-pentanol and the suspension is saturated with hydrogen chloride gas for 3 hours at 50°. After concentration, the residue is dissolved in 15ml of n-pentanol, 15 ml of propylene oxide are added and the precipitate isfiltered off. Recrystallisation from water/acetone 1:1 yields E-2-amino-5-phosphono-3-pentenoic acid pentyl ester, m.p. 160°-161°.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C[O:16][C:17](=[O:29])[CH2:18][C@H:19]1[C:23]2[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=2[O:21][CH2:20]1>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:28][C:26]3[CH:25]=[CH:24][C:23]4[C@H:19]([CH2:18][C:17]([OH:29])=[O:16])[CH2:20][O:21][C:22]=4[CH:27]=3)=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: ClCc1cccnc1SC1CCCC1
Product: O=C(O)C[C@@H]1COc2cc(OCc3cccnc3SC3CCCC3)ccc21
Yield: 67.4 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (11 mg, 0.05 mmol) obtained in Step C of Preparation Example 8 and ((S)-6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (10 mg, 0.05 mmol) obtained in Preparation Example 56 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (13 mg, 70%).
Reaction SMILES: [OH-].[Na+].[CH3:3][Si:4]([CH2:8][O:9][C:10]1[CH:30]=[CH:29][C:13]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][Si:24]([CH3:28])([CH3:27])[O:25]C)=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1)([CH3:7])[O:5]C.P([O-])(O)(O)=O.[K+]>O.C(O)C.CO>[CH3:28][Si:24]([CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]([C:13]2[CH:29]=[CH:30][C:10]([O:9][CH2:8][Si:4]([CH3:7])([CH3:3])[OH:5])=[CH:11][CH:12]=2)=[O:15])=[CH:17][CH:18]=1)([CH3:27])[OH:25]
Reactant: CO[Si](C)(C)COc1ccc(C(=O)c2ccc(OC[Si](C)(C)OC)cc2)cc1
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: O
Product: C[Si](C)(O)COc1ccc(C(=O)c2ccc(OC[Si](C)(C)O)cc2)cc1
Temperature: 0 °C
Yield: 61.4 %

Procedure:
A reaction procedure similar to step (2) of Example 1 was followed using 18.8 grams of sodium hydroxide, 13 grams of water, 86 ml of methanol, 50 grams (0.12 mol) of 4,4'-bis[(dimethylmethoxysilyl)methoxy]benzophenone resulting from step (1), 120 ml of ethanol, 18.8 grams of sodium hydroxide, 86 ml of water, 137 grams of potassium dihydrogen phosphate, and 2,200 grams of ice water. Recrystallization from toluene gave 28.8 grams (yield 61%) of pale yellow crystals.
Reaction SMILES: [CH2:1]([C:6]1[CH2:11][CH2:10][CH:9]([C:12]([O:14]CC)=[O:13])[CH2:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[K+].Cl>O>[CH2:1]([C:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=[O:13])[CH2:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1=CCC(C(=O)OCC)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCC1=CCC(C(=O)O)CC1
Temperature: 0 °C

Procedure:
Ethyl 4-pentyl-3-cyclohexen-l-carboxylate (3.0 g) is added to a solution of water (27 ml) and potassium hydroxide (2.6 g). The mixture is stirred under reflux for 16 hours. The reaction mixture is then neutralized with a mixture of concentrated HCl (40 ml), water (40 ml), and ice (ca. 40 g), and the mixture extracted with dichloromethane (100 ml). The combined organic extracts are dried with sodium sulfate, and the solution concentrated in vacuo. The solid is recrystallized from a mixture of methanol (70 ml) and water (25 ml), resulting in the product, 4-pentyl-3-cyclohexen-1-carboxylic acid.
Reaction SMILES: [C:1]([O:20][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].CS(O)(=O)=O>CO.[Pd].C(P(CC1C=CC=CC=1CP(C(C)(C)C)C(C)(C)C)C(C)(C)C)(C)(C)C>[CH3:21][O:20][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:3][CH2:2][C:1]([O:20][CH3:21])=[O:19])=[O:19]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Agent: [Pd]
Agent: CC(C)(C)P(Cc1ccccc1CP(C(C)(C)C)C(C)(C)C)C(C)(C)C
Agent: CS(=O)(=O)O
Solvent: CO
Product: COC(=O)CCCCCCCCCCCCCCCCCCCC(=O)OC
Yield: 76 %

Procedure:
210 ml of crude methyl oleate are reacted with 2.4 mol % of catalyst, in this example Pd/bis(di-tert-butylphosphinomethyl)benzene, in 770 ml of methanol and in the presence of 45 mol % of methanesulfonic acid at a temperature of 80° C. and a CO partial pressure of 30 000 hPa in a reaction time of 22 hours with constant stirring to give the alpha,omega-dicarboxylic diester, here 1,19-nonadecanedicarboxylic dimethyl ester. The catalyst was preformed in the same way as under example 1. The crude diester is purified as described under example 1. The yield is 76%, based on methyl oleate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@H:4]([CH2:13][CH2:14][S:15][CH3:16])[NH:5][C:6]([O:8]C(C)(C)C)=[O:7].N1C(C)=CC=CC=1C.[Si:26](OS(C(F)(F)F)(=O)=O)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].[Cl-].[NH4+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C@H:4]([CH2:13][CH2:14][S:15][CH3:16])[NH:5][C:6]([O:8][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[O:7]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COC(=O)[C@H](CCSC)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)[C@H](CCSC)NC(=O)O[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h

Procedure:
To a methylene chloride solution (1.0 ml) of N-t-butoxycarbonyl-L-methionine methyl ester (131.5 mg, 0.5 mmol) and 2,6-lutidine (0.116 ml, 1.0 mmol), t-butyldimethylsilyltrifluoromethane sulfonate (TBDMSOTf) (0.172 ml, 0.75 mmol) was added dropwise at room temperature in a nitrogen atmosphere. After the mixture was stirred for 15 minutes, a saturated aqueous solution of ammonium chloride (2 ml) was added to quench the reaction and extraction with ether was conducted. The organic layer was dried over anhydrous magnesium sulfate and filtered. By distilling off the solvent under vacuum, the titled compound was obtained in an amount of 146 mg.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[N:14]([C:15](=[O:36])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])=[O:25])=[C:19]([O:34][CH3:35])[CH:18]=2)[C@H:13]([CH2:37][O:38][C:39]2[CH:40]=[C:41]([CH:46]=[CH:47][CH:48]=2)[C:42]([O:44]C)=[O:43])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.C1COCC1>[CH2:1]([O:8][CH2:9][C@@H:10]1[N:14]([C:15](=[O:36])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])=[O:25])=[C:19]([O:34][CH3:35])[CH:18]=2)[C@H:13]([CH2:37][O:38][C:39]2[CH:40]=[C:41]([CH:46]=[CH:47][CH:48]=2)[C:42]([OH:44])=[O:43])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(OC[C@@H]2CC[C@H](COCc3ccccc3)N2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(CC(=O)N2[C@@H](COCc3ccccc3)CC[C@H]2COc2cccc(C(=O)O)c2)ccc1NC(=O)Nc1ccccc1C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 3-[5-(R)-benzyloxymethyl-1-[4-[N′-(2-methylphenyl) ureido]-3-methoxyphenylacetyl]-2-(S)-pyrrolidinylmethoxy]benzoate (185 mg, 0.28 mmol) in MeOH-THF (2:5, 7 ml) was added 1.0 M-NaOH (860 ml, 0.86 mmol) at rt, and the resulting mixture was heated at 60° C. with stirring for 1 h. The reaction mixture was poured into 1N-HCl, then extracted with CHCl3. The organic layer was washed with brine, drying over anhydrous Na2SO4, then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl3-MeOH (5:1) as eluent to give129 (171 mg, 94%) as a colorless amorphous solid. MW 637.72 1H-NMR (CD3OD), mixture of rotamars δ 1.89–2.37 (series of m, 4 H), 2,29 (s, 3 H), 3.52–4.53 (series of m, 8 H), 3.66 and 3.74 (s, total 3 H), 4.85 (s, 2 H), 6.66–7.98 (series of m, 16 H); MS (ESI) m/z, 638 (M++H), 660 (M++Na+); Anal. Calcd for C37H39N3O7.H2O: C, 67.77; H, 6.30; N, 6.41. Found: C, 67.40; H, 5.95: N, 6.14.
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[CH3:9][C:10]([C:12]1[O:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH2:22][C@@H:23]([OH:41])[CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([C:31]4[CH:40]=[CH:39][C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH:32]=4)[CH2:27][CH2:26]3)[C:14]=2[CH:13]=1)=[O:11].[BH4-].[Na+].[Cl-].[NH4+]>CO>[OH:41][CH:23]([CH2:24][N:25]1[CH2:26][CH2:27][CH:28]([C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=2)[CH2:29][CH2:30]1)[CH2:22][O:21][C:20]1[C:14]2[CH:13]=[C:12]([CH:10]([OH:11])[CH3:9])[O:16][C:15]=2[CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)c1cc2c(OC[C@@H](O)CN3CCC(c4ccc5ccccc5c4)CC3)cccc2o1
Agent: O=C(O)/C=C\C(=O)O
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Product: CC(O)c1cc2c(OCC(O)CN3CCC(c4ccc5ccccc5c4)CC3)cccc2o1
Reaction time: 0.33 h
Yield: 100.5 %

Procedure:
(S)-4-(2-Hydroxy-3-(4-(naphthalen-2-yl)piperidino)-propyloxy)benzo(b)furan-2-yl methyl ketone (0.30 g) obtained in Example 56 was dissolved in methanol and sodium borohydride (30 mg) was added at room temperature. The mixture was stirred for 20 min. To the reaction mixture was added saturated aqueous ammonium chloride solution and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethyl acetate, and the mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.24 g) as brown crystals, melting point 143-144° C.
Reaction SMILES: [CH2:1]([SH:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[H-].[Na+].Cl[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[N:11]=1>O1CCCC1>[C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([S:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])[N:11]=1)#[N:17]
Reactant: CC(C)CCS
Reactant: N#Cc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)CCSc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
Isopentyl mercaptan (0.83 g, 7.9 mmol) was dissolved in tetrahydrofuran (100 ml) and added dropwise to sodium hydride (60% oil, 0.35 g, 8.7 mmol). The reaction mixture was stirred at room temperature for 1 hr. A solution of 2-chloro-6-cyanopyridine (1.00 g, 7.2 mmol) in tetrahydrofuran (10 ml) was added to the mixture, and the mixture was stirred at room temperature for 18 hrs. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure to give the titled compound (1.48 g, ca. 100%) as an oil.
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[OH:12][C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.N>CN1C(=O)CCC1.CO.C(Cl)Cl>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:15]3[CH2:16][CH2:17][C@H:13]([OH:12])[CH2:14]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: Fc1ccc2nnc(Cl)n2c1
Reactant: O[C@H]1CCNC1
Agent: N
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CO
Product: O[C@H]1CCN(c2nnc3ccc(F)cn23)C1
Temperature: 160 °C
Yield: 38.8 %

Procedure:
A mixture of Intermediate 24b (300 mg, 1.74 mmol) and (S)-3-hydroxypyrrolidine (600 mg, 9.96 mmol) in NMP (6 mL) was heated in the microwave at 160° C. for 2 h. The reaction mixture was applied to an SCX-2 cartridge (70 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-8% [2M NH3 in MeOH] in DCM, gave the title compound (150 mg, 38%). LCMS (Method 1): Rt 1.45 min, m/z 223 [MH+].
Reaction SMILES: CN(C=O)C.[C:6]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([O:32][CH3:33])=[N:15][N:16]2[C:20]([C:21]3[C:26]([O:27][CH3:28])=[CH:25][C:24]([OH:29])=[CH:23][C:22]=3[O:30][CH3:31])=[CH:19][S:18][C:17]=12)([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].I[CH2:42][CH2:43][F:44]>O>[C:6]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([O:32][CH3:33])=[N:15][N:16]2[C:20]([C:21]3[C:22]([O:30][CH3:31])=[CH:23][C:24]([O:29][CH2:42][CH2:43][F:44])=[CH:25][C:26]=3[O:27][CH3:28])=[CH:19][S:18][C:17]=12)([CH3:9])([CH3:8])[CH3:7]
Reactant: FCCI
Reactant: COc1cc(O)cc(OC)c1-c1csc2c(NC(=O)OC(C)(C)C)c(OC)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OCCF)cc(OC)c1-c1csc2c(NC(=O)OC(C)(C)C)c(OC)nn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a DMF (2.28 ml) solution of tert-butyl[3-(4-hydroxy-2,6-dimethoxyphenyl)-6-methoxypyrazolo[5,1-b][1,3]thiazol-7-yl]carbamate (115 mg, 0.273 mmol) were added potassium carbonate (49.0 mg, 0.355 mmol) and 1-iodo-2-fluoroethane (61.7 mg, 0.355 mmol), and the mixture was stirred at room temperature for 20 hours and 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product of the title compound (128 mg, 0.273 mmol)
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[C:6]=2[N:5]=[C:4]([C:25]([OH:27])=[O:26])[CH:3]=1.[NH2:28][CH2:29][CH2:30][OH:31]>CCN(C(C)C)C(C)C.O>[OH:31][CH2:30][CH2:29][NH:28][C:2]1[C:7]2[N:8]=[C:9]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[C:6]=2[N:5]=[C:4]([C:25]([OH:27])=[O:26])[CH:3]=1
Reactant: O=C(O)c1cc(Cl)c2nc(N3CCOCC3)nc(-c3cccc(O)c3)c2n1
Reactant: NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(O)c1cc(NCCO)c2nc(N3CCOCC3)nc(-c3cccc(O)c3)c2n1

Procedure:
A mixture of Example 9 (0.1 g, 0.25 mmol) and 2-amino ethanol (24 mg, 0.38 mmol) in DIEA (1 mL) and water (0.5 mL) was stirred at 170° C. for 2 hours. The two phases were separated and the aqueous layer concentrated in vacuo. Purification by column chromatography (increasing amount of MeOH in DCM) followed by washing with Et2O afforded the title compound as a yellow solid.