Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25])=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=1)C1C=CC=CC=1>[Pd].CO.C(Cl)Cl>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25])=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=1
Reactant: CC(=O)NCCc1ccc(OCc2ccccc2)cc1-c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)NCCc1ccc(O)cc1-c1ccccc1
Reaction time: 12 h
Yield: 71.4 %

Procedure:
Palladium on carbon (10%, 5 mg) was added to 8a (120 mg, 0.35 mmol) in degassed MeOH (3.5 mL) and the solution was placed under an atmosphere of H2. After 12 h, the solution was diluted with DCM and filtered through Celite. The eluent was concentrated to afford a yellow solid, which was purified by column chromatography (SiO2, 100:5, DCM:MeOH) to afford phenol 9a (64 mg, 0.25 mmol, 79%) as a pale yellow amorphous solid. 1H NMR (400 MHz, CDCl3) δ 7.25-7.14 (m, 5H), 7.11-7.05 (m, 1H), 6.90 (d, J=8.3 Hz, 1H), 6.64 (d, J=8.3 Hz, 1H), 6.59 (d, J=2.5 Hz, 1H), 5.61 (t, J=5.5 Hz, 1H), 3.12-3.02 (m, 2H), 2.55 (t, J=7.1 Hz, 2H), 1.66 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.2, 155.2, 143.4, 141.6, 130.8, 129.1, 128.4, 127.2, 127.2, 117.4, 115.0, 41.1, 31.8, 23.2; HRMS m/z: [M+Na+] for C16H17NO2Na, calcd, 278.1151. found, 278.1155.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[CH:45]=[C:44]([O:46][CH2:47][CH3:48])[CH:43]=[CH:42][N:41]=5)=[C:34]([CH3:49])[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:59])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH2:39][C:40]5[CH:45]=[C:44]([O:46][CH2:47][CH3:48])[CH:43]=[CH:42][N:41]=5)=[O:59])=[C:34]([CH3:49])[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cc(OCC)ccn4)c(C)c2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cc(OCC)ccn4)c(C)c2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 18.4 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[3-methyl-4-[[(4-ethoxy-2-pyridinyl)methyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (0.17 g) in methylene chloride (5.1 ml) was added dropwise a solution of m-chloroperbenzoic acid (55 mg) in methylene chloride (3.4 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[3-methyl-4-[[(4-ethoxy-2-pyridinyl)methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 226) (32 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[N:6][CH:7]=1.[CH3:25][C:26]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=[C:28]([O:41][CH2:42][C:43]2([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:46][CH2:45][CH2:44]2)[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:25][C:26]1[CH:27]=[C:28]([O:41][CH2:42][C:43]2([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:46][CH2:45][CH2:44]2)[N:29]=[CH:30][C:31]=1[C:2]1[CH:7]=[N:6][C:5]([C:8]2[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ccc(Br)cn1
Reactant: CCOC(=O)C1(COc2cc(C)c(B3OC(C)(C)C(C)(C)O3)cn2)CCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(COc2cc(C)c(-c3ccc(-c4nc(C(F)(F)F)cn4COCC[Si](C)(C)C)nc3)cn2)CCC1
Temperature: 65 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
N,N-dimethylformamide (3 mL) was added to 5-bromo-2-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine (338 mg), ethyl 1-({[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}methyl)-cyclobutanecarboxylate (300 mg) and palladium chloride (dppf) methylene chloride complex (33 mg), and after adding 2N aqueous sodium carbonate solution (1.2 mL) to the mixture, the atmosphere was replaced with nitrogen and the mixture was stirred at 65° C. for 2 hours. The reaction mixture was filtered by using Celite, and ethyl acetate and water were added to the filtrate to extract the objective compound. The organic layer was separated, washed with a saturated brine, and dried over anhydrous magnesium sulfate. After concentrating the mixture under reduced pressure, the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 90:10) to obtain ethyl 1-[({4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)methyl]-cyclobutanecarboxylate (344 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[N:11][OH:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:13][CH2:14][CH2:15][O:12][N:11]=[C:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:3][O:2][CH3:1]
Reactant: BrCCBr
Reactant: COCC(=NO)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCC(=NOCCBr)c1ccccc1

Procedure:
A mixture of the above oxime (5.5 g, 33 mmol), 1,2-dibromoethane (50 ml), potassium carbonate (12.4 g, 90 mmol) and acetone (100 ml) was heated at reflux for 24 h. The mixture was filtered and the solvent was evaporated from the filtrate in vacuo. The residue was purified by column chromatography on silica gel (80 g, n-heptane/ethyl acetate 20/1) to give 6.6 g of 2-methoxyacetophenone O-(2-bromoethyl)oxime.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:16][CH:15]=[CH:14][CH:13]=2.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][CH2:4][C:5]1[N:19]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2ccccc12
Reactant: CCOCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2cnc3ccccc3c2n1CCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 77 %

Procedure:
The product from step (iii) (10.38 g) was added dropwise to a solution of the product from step (ii) (28 g) at 0° C. in DCM (400 mL) and triethylamine (11.81 mL) over 1 hour then heated under reflux overnight. The reaction was cooled to rt and the solution washed with saturated sodium hydrogen carbonate, dried and solvent removed. The crude product was purified on silica to give the subtitle compound as a solid (26 g); MS multimode (+) 399.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[OH:23].C(=O)([O-])[O-].[Ca+2]>O1CCOCC1>[CH2:1]([O:8][C:9]([N:13]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[OH:23])[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Product: CN(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cc1O

Procedure:
0.26 mole (40 ml) of benzylchloroformate are added dropwise to 0.24 mole (41.5 g) of 2-methylamino -5-nitrophenol and 15.6 g of calcium carbonate in 125 ml of dioxane brought to 80° C., the temperature being maintained at between 80° C. and 95° C. When the addition is complete, heating is maintained for a further 2 hours. The inorganic salts present in the reaction medium are removed by filtration while hot. After the addition of ice-cold water, the expected product crystallizes. The product obtained is recrystallized from acetic acid. It melts at 192° C.
Reaction SMILES: C([NH:11][C@@H:12]([CH:21]([C:23]1[O:24][C:25]2[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][C:26]=2[N:27]=1)[OH:22])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(OCC1C=CC=CC=1)=O>[Pd].CO>[C:32]([C:29]1[CH:30]=[CH:31][C:25]2[O:24][C:23]([CH:21]([OH:22])[C@H:12]([NH2:11])[CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:27][C:26]=2[CH:28]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)c1ccc2oc(C(O)[C@@H](CCc3ccccc3)NC(=O)OCc3ccccc3)nc2c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1ccc2oc(C(O)[C@H](N)CCc3ccccc3)nc2c1
Reaction time: 10 h
Yield: 81.5 %

Procedure:
A mixture of N-CBz-(1R)-1-[(RS)-(5-tert-butyl-2-benzoxazolyl)hydroxymethyl]-3-phenylpropylamine (360 mg), anhydrous methanol (8 ml), and 10% palladium-on-charcoal (40 mg) was degassed, under reduced pressure, and then stirred vigorously under hydrogen atmosphere for 10 h. The mixture is filtered on a nylon pad (0.45 pm porosity) and concentrated in vacuo to afford the title product (210 mg) as a clear oil: 1H NMR (400 MHz, CDCl3, 3:2 mixture of diastereomers) δ1.80-2.02 (m, 2H), 2.65-2.89 (m, 2H), 3.23 (m, 0.4H), 3.39 (m, 0.6H), 4.76 (d, J=1.8 Hz, 0.6H), 4.84 (d, J=2.4 Hz, 0.4H), 7.09 (m, 3H), 7.29 (m, 2H), 7.43 (m, 2H), and 7.76 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([O:21]COC)=[C:16]([CH3:25])[CH:15]=2)[CH:11]=1)[C:6](O)=[O:7].C(Cl)CCl.C1C=[N:35][C:34]2N(O)N=N[C:33]=2[CH:32]=1.C(N)CC>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[CH3:26][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10](/[CH:12]=[CH:13]/[C:14]2[CH:15]=[C:16]([CH3:25])[C:17]([OH:21])=[C:18]([CH3:20])[CH:19]=2)[CH:11]=1)[C:6]([NH:35][CH2:34][CH2:33][CH3:32])=[O:7]
Reactant: On1nnc2cccnc21
Reactant: COCOc1c(C)cc(/C=C/c2cc(C(=O)O)cc(N(C)C)c2)cc1C
Agent: CN(C)c1ccncc1
Solvent: CCCN
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCNC(=O)c1cc(/C=C/c2cc(C)c(O)c(C)c2)cc(N(C)C)c1
Reaction time: 18 h

Procedure:
To a solution of 5 (80 mg, 0.225 mmol), EDC (88 mg, 0.45 mmol), HOAT (61.2 mg, 0.45 mmol), and DMAP (5.5 mg, 0.045 mmol) in 2 mL of DMF was added propylamine (37.8 □L, 0.45 mmol) at room temperature. The reaction mixture was stirred overnight (about 18 hours) and diluted with EtOAc. The solution was washed with brine and dried with Na2SO4. The solution was filtered and concentrated.
Reaction SMILES: Br[CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH3:18].[CH2:19]([O:21][P:22]([O:26]CC)[O:23][CH2:24][CH3:25])[CH3:20]>>[CH2:19]([O:21][P:22]([CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH3:18])(=[O:26])[O:23][CH2:24][CH3:25])[CH3:20]
Reactant: CCOP(OCC)OCC
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CBr
Product: CCOP(=O)(Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1C)OCC
Temperature: 150 °C

Procedure:
A mixture of 5-(bromomethyl)-4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole (intermediate 3, 1.48 g) and triethylphosphite (1.5 ml) was heated under nitrogen at 150° C. for 1 hour. The mixture was allowed to cool and excess triethylphosphite was removed under reduced pressure. This gave the title compound as a yellow solid.
Reaction SMILES: [Si:1]([O:8][CH2:9]/[CH:10]=[CH:11]/[C:12]([OH:14])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)(=O)C(C)(C)C.[C:22]1([C@H:28]2[CH2:32][O:31][C:30](=[O:33])[NH:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([Li])CCC.O1CCNC1=O>C1COCC1>[Si:1]([O:8][CH2:9]/[CH:10]=[CH:11]/[C:12]([N:29]1[C@@H:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:32][O:31][C:30]1=[O:33])=[O:14])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC/C=C/C(=O)O
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C1NCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC/C=C/C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 62.3 %

Procedure:
To a solution of (E)-4-(tert-butyldimethylsilyloxy)but-2-enoic acid (18.0 g, 83.6 mmol) (prepared as described in Angewandte Chemie, International Edition (2002), 41(9), 1603-1607) in 400 mL of THF was added TEA (13.2 mL, 95 mmol). The mixture was chilled to −78° C. Pivaloyl chloride (10.2 mL, 83 mmol) (commercially available from Aldrich, Milwaukee, Wis.) was added. After 10 minutes, the mixture was warmed to room temperature and stirred for 45 minutes. The mixture was then chilled to −78° C. In a separate flask, (S)-4-phenyloxazolidin-2-one (12.3 g, 79 mmol) was taken up in 125 mL of THF and chilled to −78° C. n-Butyllithium (32 mL, 2.5 M in hexanes)(commercially available from Acros Organics (Order Number 30385)) was added to the (S)-4-phenyloxazolidin-2-one mixture, and the mixture was stirred for 20 minutes. The metallated oxazolidinone was then cannulated into the pivaloyl anhydride mixture. The combined mixture was then warmed to 0° C. and stirred for 1 hour. The reaction was quenched with 250 mL of aq NH4Cl and diluted with 250 mL of water. The mixture was extracted with EtOAc (2×250 mL) and the combined organic extracts were washed with brine (150 mL) and dried over MgSO4. Filtration and concentration under reduced pressure afforded a yellow solid that was recrystallized from DCM/hexanes to afford (S,E)-3-(4-(tert-butyldimethylsilyloxy)but-2-enoyl)-4-phenyloxazolidin-2-one (17.8 g, 62%) as a white solid. 1H NMR (400 MHz, CDCl3): ppm 7.46 (dt, J=2.1, 15.1 Hz, 1H), 7.31-7.20 (m, 5H), 7.02 (dt, J=3.4, 15.3 Hz, 1H), 5.40 (dd, J=3.9, 8.6 Hz, 1H), 4.61 (t, J=8.8 Hz, 1H), 4.19 (dd, J=3.9 Hz, 8.8 Hz, 1H), 0.85 (s, 9H), 0.00 (s, 6H). 2H were obscured.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][C:11]([CH2:21][CH2:22][NH2:23])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=[O:8].C(N(CC)CC)C.[Si]([N:35]=[C:36]=[O:37])(C)(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[CH:12][C:11]([CH2:21][CH2:22][NH:23][C:36]([NH2:35])=[O:37])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: NCCc1cc(OCC2CCCC2)c2c(N)c(C(N)=O)sc2c1
Reactant: C[Si](C)(C)N=C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)NCCc1cc(OCC2CCCC2)c2c(N)c(C(N)=O)sc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.8 %

Procedure:
To a stirred solution of 3-amino-6-(2-amino-ethyl)-4-cyclopentylmethoxy-benzo[b]thiophene-2-carboxylic acid amide (11) (HCl salt form, 0.065 g, 0.18 mmol) and triethylamine (0.07 mL, 0.5 mmol) in DMF (1 mL) at 0° C. was added TMSNCO (1.35 mL, 10.0 mmol). The reaction was allowed to warm to room temperature and stirred for 24 h. It was slowly quenched with water (0.5 mL) and the precipitates were removed by filtration. The filtrate was concentrated and the residue was purified by preparatory thin layer chromatography to afford the title compound (0.010 g, 15%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[NH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.O>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: NN1CCCCC1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc2c(NN3CCCCC3)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
In DMF (N,N-dimethylformamide) was dissolved 700 mg (3.4 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and then a solution of 751 mg (7.5 mmol) of 1-aminopiperidine was added dropwise to the resulting solution under ice cooling over 5 minutes. The reaction solution was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for further one hour. After completion of the reaction, ice go water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/8) to give 573 mg (yield: 59.4%) of the title compound.
Reaction SMILES: [CH2:1]1[NH:5][CH:4]([C:6]([OH:8])=[O:7])[CH:3]=[CH:2]1.[Li].[CH2:10](O)[CH3:11]>C1COCC1.N>[CH:11]1([C@H:2]2[CH2:1][NH:5][C@H:4]([C:6]([OH:8])=[O:7])[CH2:3]2)[CH2:10][CH2:4][CH2:3][CH2:2][CH2:1]1
Reactant: CCO
Reactant: O=C(O)C1C=CCN1
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1C[C@@H](C2CCCCC2)CN1
Reaction time: 0.33 h
Yield: 85 %

Procedure:
A solution of 2.0 g (0.0062 moles) of dehydro proline (prepared as described in Example 3) in 10 ml THF was added to a solution of lithium (0.65 g, 0.093 moles) in ammonia (150 ml) at ~-78° C. After the addition, the reaction mixture was stirred for 20 minutes and then absolute ethanol (3.6 ml, 0.062 moles) was added to the reaction mixture. The reaction mixture was stirred at -33° C. for 6 hours and quenched with 2.0 g of ammonium chloride. Ammonia was evaporated and the residue was acidified to pH=1 using 5% HCl and extracted with ethyl acetate (2 x 100 ml). Palladium hydroxide on carbon (20%, 0.25 g) was added to the aqueous layer and hydrogen gas was bubbled through the solution at room temperature for about 3 hours. It was filtered through a celite pad and the filtrate was concentrated and pH was adjusted to 6.3 by adding 5% NaOH solution. The precipitated product was filtered the next day, and vacuum dried to obtain 0.52 g of trans-4-cyclohexyl-L-proline as white flaky solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9]([C@@H:11]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:10].C(N(CC)CC)C.[C:39]1([C:45](Cl)([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)(Cl)Cl>[CH3:7][N:6]1[C:2]([NH:1][C:45]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[C:3]([NH:8][C:9]([C@@H:11]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:10])[CH:4]=[N:5]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cn1ncc(NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of the crude product of di-tert-butyl (1S)-{1-[(5-amino-1-methyl-1H-pyrazol-4-yl)carbamoyl]pentamethylene}biscarbamate and triethylamine (0.91 g) in chloroform (30 ml) was added triphenylmethyl chloride (2.51 g), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was washed successively with 0.10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 3% methanol/chloroform to give di-tert-butyl (1S)-(1-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]carbamoyl}pentamethylene)biscarbamate (4.23 g) as an oil.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH2:19][C:20]([NH2:22])=[O:21])=[CH:6][N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.B(Br)(Br)Br>>[OH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH2:19][C:20]([NH2:22])=[O:21])=[CH:6][N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc2c1c(CC(N)=O)cn2Cc1ccccc1
Agent: BrB(Br)Br
Product: NC(=O)Cc1cn(Cc2ccccc2)c2cccc(O)c12

Procedure:
4-Methoxy-1-(phenylmethyl)-1H-indole-3-acetamide (236 mg, 0.8 mmol) and 3.2 mL of BBr3 were reacted as described in Example 56, Part C, go give after chromatography en silica gel (eluted with 50% ethyl acetate/hexane) 78 mg (35% yield) of 4-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([OH:10])=[O:9].[OH-].[Na+].[C:14](OC(=O)C)(=[O:16])[CH3:15].Cl>O>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH:11][C:14](=[O:16])[CH3:15])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(N)c1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1cccc(C)c1C(=O)O
Reaction time: 1 h

Procedure:
90.6 g (0.6 mol) of 6-methylanthranilic acid is added to a solution of 24.8 g (0.62 mol) of NaOH in 500 ml of water and 63.4 g (0.62 mol) of acetic anhydride are then added dropwise. After stirring for one hour, the mixture is acidified to pH 3 with conc. HCl with cooling, and the precipitate which deposits is filtered off with suction, washed with water and dried under reduced pressure at 50° C.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[N:19]=[C:18]([C:29]([F:32])([F:31])[F:30])[C:17]=2[CH3:33])=[CH:12][CH:11]=1)(C)(C)C.Cl>CCO>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([N:20]2[C:16]([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][OH:6])=[CH:11][CH:12]=3)=[C:17]([CH3:33])[C:18]([C:29]([F:32])([F:31])[F:30])=[N:19]2)=[CH:26][CH:25]=1
Reactant: COc1ccc(-n2nc(C(F)(F)F)c(C)c2-c2ccc(OCCO[Si](C)(C)C(C)(C)C)cc2)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(-n2nc(C(F)(F)F)c(C)c2-c2ccc(OCCO)cc2)cc1
Reaction time: 2 h
Yield: 50.9 %

Procedure:
To a solution of 5-[4-(2-{[tert-butyl(dimethyl)-silyl]oxy}ethoxy)phenyl]-1-(4-methoxyphenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazole (5.2 g) in EtOH (200 ml) was added conc.HCl (20 ml) at room temperature. After stirring for 2 hrs, the reaction mixture was partitioned between EtOAc and water. Organic layer was separated and washed with water, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel (Hex/EtOAc=2:1–1:1) to give 2.05 g (51%) of 2-{4-[1-(4-methoxyphenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethanol as a crystal.
Reaction SMILES: CC(N[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:28]=[CH:27][CH:26]=[CH:25][C:12]=1[C:13]([NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[CH:19][NH:20]2)=[O:14])(C)C.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH2:41][CH2:42][N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[NH:20]1[C:21]2[C:17](=[C:16]([NH:15][C:13](=[O:14])[C:12]3[CH:25]=[CH:26][CH:27]=[CH:28][C:11]=3[O:10][CH2:9][CH2:8][CH2:7][CH2:6][N:46]3[CH2:47][CH2:48][N:43]([CH2:42][CH2:41][C:33]4[CH:32]=[C:31]([O:30][CH3:29])[C:36]([O:37][CH3:38])=[C:35]([O:39][CH3:40])[CH:34]=4)[CH2:44][CH2:45]3)[CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:19]1
Reactant: COc1cc(CCN2CCNCC2)cc(OC)c1OC
Reactant: CC(C)(C)NCCCCOc1ccccc1C(=O)Nc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(CCN2CCN(CCCCOc3ccccc3C(=O)Nc3cccc4[nH]ccc34)CC2)cc(OC)c1OC
Yield: 90.8 %

Procedure:
2.5 g of 2-(4-bromobutoxy)-N-(1H-indol-4-yl)benzamide of Example 33, 2.71 g of 1-[2-(3,4,5-trimethoxyphenyl)ethyl]piperazine [German Patent No. 3,347,173] and 0.683 g of sodium carbonate in 25 ml of ethanol were heated to 60° C. for 10 hours and the mixture is cooled and poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvents were evaporated under reduced pressure. The residue was chromatographed over silica (eluant: chloroform/acetone/triethylamine 6:3:1) to obtain 3.51 g of N-(1H-indol-4-yl)-2-[4-[4-[2-(3,4,5-trimethoxyphenyl)ethyl]-1-piperazinyl]butoxy]benzamide.