Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][NH:18][C:19]([CH3:21])([CH3:20])[C:12]2=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:19]([CH3:21])([CH3:20])[C:12]2=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)NCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCn2c(nc(C(=O)NCc3ccc(F)cc3)c(OCc3ccccc3)c2=O)C1(C)C
Temperature: 45 °C

Procedure:
A mixture of 3-(benzyloxy)-N-(4-fluorobenzyl)-9,9-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrazino[1,2-a]pyrimidine-2-carboxamide (prepared as described in Example 3, Step 1) (1 eq.), K2CO3 (2 eq.) and tert-butyl bromoacetate (3 eq.) in DMF was heated for 24 hours at 45° C. and then cooled to room temperature. Solvent was removed under reduced pressure and the residue was taken up in EtOAc and washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to yield the ester. MS (ES) C30H35FN4O5 requires 550. Found: 551 (M+H+).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10]Cl)=[CH:6][CH:5]=1>CC#N>[CH3:1][NH:2][CH2:10][C:7]1[CH:8]=[N:9][C:4]([CH3:3])=[CH:5][CH:6]=1
Reactant: Cc1ccc(CCl)cn1
Reactant: CN
Solvent: CC#N
Product: CNCc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 16.6 g of 40% aqueous MeNH2 solution and 52 ml of CH3CN was cooled with ice and 6.08 g (0.043 mole in terms of pure product) of crude (6-methyl-3-pyridyl)-methyl chloride was added dropwise with constant stirring. After completion of dropwise addition, the mixture was stirred at room temperature for 1.5 hours, at the end of which time the solvent was distilled off. The solid residue was extracted with CH2Cl2 and the CHCl2 layer was dried over MgSO4. The CH2Cl2 was distilled off and the residue was diluted with 70 ml of Et2O and filtered to remove the insoluble matter. Finally the filtrate was concentrated to recover 4.60 g of the title compound as a crude oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][O:19][CH3:20]>CN(C=O)C.O.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH2:18][O:19][CH3:20])=[CH:4][C:3]=1[CH3:9]
Reactant: COCCBr
Reactant: Cc1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc(Cl)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-chloro-3-methylphenol (1 eq.) in DMF (0.7 M) was added K2CO3 (1.2 eq.). The mixture was stirred at 50° C. for 5 min before 1-bromo-2-methoxyethane (1.5 eq.) was added. After 2 h at 70° C., the reaction mixture was cooled down to RT and then diluted with water and ether. The organic phase was separated and washed sequentially with 2 N aq. NaOH, water and brine. The organic extract was dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford the title compound as a yellowish oil.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][S:21][C:22]3[NH:23][CH:24]=[CH:25][N:26]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)(=O)C>C(O)C>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[CH2:20][S:21][C:22]1[NH:26][CH:25]=[CH:24][N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3ncc[nH]3)c2CC1
Solvent: CCO
Solvent: CC(=O)Cl
Product: Cl
Product: Clc1ccc2c(c1CSc1ncc[nH]1)CCNCC2
Yield: 204 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-(1H-imidazol-2-ylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (10.11 g, 25.65 mmol) in absolute ethanol (125 mL). Add acetyl chloride (20.13 g, 256.5 mmol) dropwise. On addition, the reaction mixture exotherms to 40-50° C. Stir the reaction at 50 to 60° C. for 2.5 h. Cool the mixture to 0 to ° 5 C. Filter, wash with ethanol, and dry solid in vacuo to obtain 7-chloro-6-(1H-imidazol-2-ylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride (8.64 g). MS (ES+) m/z: 294.3 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=4[CH3:23])[C:13]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[CH:12][CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)([O-])[O-:32].[K+].[K+].OO.O>CS(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21](=[O:32])[NH2:22])=[CH:17][C:16]=4[CH3:23])[C:13]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:12][CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)CCc1ccc(-c2ccc3c(c2)OCO3)n1-c1ccc(C#N)cc1C
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C(N)=O)ccc1-n1c(CCC(=O)O)ccc1-c1ccc2c(c1)OCO2
Yield: 87 %

Procedure:
To a mixture of ethyl 3-(5-(benzo[d][1,3]dioxol-5-yl)-1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate (100 mg, 0.249 mmol) and potassium carbonate (52 mg, 0.373 mmol) in DMSO (1 mL) was added 30% aqueous H2O2 (28.2 mg, 0.249 mmol). The resultant mixture was stirred at room temperature for 2 h. TLC showed the reaction was completed. Water (7 mL) was added and white solid precipitated. The suspension was centrifuged and the aqueous phase was discarded. The resultant solid was dried in vacuum to afford the amide intermediate as a white solid (85 mg, yield 81%). To the mixture of this intermediate in H2O (0.6 mL) and THF (0.6 mL) was added LiOH H2O (10 mg, 0.238 mmol). The reaction mixture was stirred at room temperature overnight. THF was evaporated in vacuum. The residue was acidified to pH=4 with 5% hydrochloric acid, centrifuged and dried to afford 3-(5-(benzo[d][1,3]dioxol-5-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid as a white solid (46 mg, overall yield 47%).
Reaction SMILES: C[N:2]1[C:8](=O)[O:7][C:5](=O)[C:4]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:3]12.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[NH:15][NH2:16].C(O)C>C(OCC)(=O)C>[CH3:8][NH:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([NH:16][NH:15][C:14]([O:18][CH2:19][CH3:20])=[O:17])=[O:7]
Reactant: CCOC(=O)NN
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)NNC(=O)c1ccccc1NC
Yield: 50.5 %

Procedure:
A mixture of 8.86 g of N-methylisatoic anhydride, 5.73 g of ethyl carbazate and 25 ml of ethanol was heated to reflux for 2 hours. After the reaction mixture was allowed to around room temperature, ethyl acetate was added thereto and the mixture was washed with water two times. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was washed with methyl tert-butyl ether to obtain 5.99 g of N-(2-methylaminobenzoyl)-N′-ethoxycarbonylhydrazine of the formula:
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:2].C([O-])([O-])=[O:18].[K+].[K+].OO>CS(C)=O>[CH:1]([C:3]1[S:7][C:6]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]([NH2:14])=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(Oc2ccc(C=O)s2)cc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(C=O)s2)cc1
Temperature: 0 °C
Yield: 152.5 %

Procedure:
Combine 4-(5-formyl-thiophen-2-yloxy)-benzonitrile (772 mg, 3.36 mmol), K2CO3 (powder, 232 mg, 50 mol %) and DMSO (33 mL). Cool down to 0° C. Add hydrogen peroxide (1.01 mL) dropwise. Stir the resulting reaction mixture for 3 hours. Pour the reaction mixture onto H2O (5 mL). Stir for 5 min till a white precipitate appears, then filter and dry under vacuum to provide 633 mg (76%) of the title compound. Part C would be the reaction of this intermediate with an amine to make the final compound. Example 1 was prepared using Method A; Example 2 used Medthod B.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH3:10]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:10])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: N
Product: Cc1cc(N)nc(N)n1
Temperature: 25 °C

Procedure:
2,4-Diamino-6-methyl pyrimidine was prepared by a modified procedure of Gabriel and Coleman (Ber., volume 34, page 1253, 1901). A mixture of 2-amino-4-chloro-6-methyl pyrimidine (9.0 gm) and alcoholic ammonia (225 ml), were heated in a steel bomb at 180° C for 6 hours. The mixture was then filtered, and the filtrate was evaporated to dryness. The solid residue was dissolved in 60ml hot water. The solution was cooled to room temperature, and 40 gm of potassium hydroxide was then added. The product thus precipitated, was filtered, and crystallized from acetone, m.p. 183° C. Yield: 5.5gm. U.V. spectrum data corresponded to those reported by Curd and Rose (J.C.S., page 98, 1949).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.Br[CH2:34][CH2:35]Cl.[NH:37]1[CH2:44][CH2:43][CH2:42][C@@H:38]1[C:39]([OH:41])=[O:40]>>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[N:18]([CH2:43][CH2:44][N:37]4[CH2:35][CH2:34][CH2:42][C@@H:38]4[C:39]([OH:41])=[O:40])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1
Reactant: ClCCBr
Reactant: O=C(O)[C@H]1CCCN1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(ccn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: O=C(O)[C@H]1CCCN1CCN1C(=O)S/C(=C\c2ccc3c(ccn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C1=O

Procedure:
1-{2-[(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}-D-proline was prepared from [(5Z)-5-({1-[2,4-bis-(trifluoromethyl)benzyl]-1H-indol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 238), 2-bromo-1-chloroethane and (D)-proline following General Procedure G.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:10]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[C:22](=[O:40])[NH:23][C:24](=[O:39])[C:25]=2[C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]([CH:35](OC)[CH3:36])[CH:27]=2)=[CH:13]1)[CH3:11]>Cl.ClCCl>[C:1]1([S:7][CH:35]([N:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:26]([C:25]3[C:24](=[O:39])[NH:23][C:22](=[O:40])[C:21]=3[C:14]3[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:12]([CH:10]([S:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH3:11])[CH:13]=3)=[CH:27]2)[CH3:36])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: COC(C)n1cc(C2=C(c3cn(C(C)OC)c4ccccc34)C(=O)NC2=O)c2ccccc21
Agent: Cl
Solvent: ClCCl
Product: CC(Sc1ccccc1)n1cc(C2=C(c3cn(C(C)Sc4ccccc4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 2 h
Yield: 93.7 %

Procedure:
220 mg of thiophenol and 1 drop of concentrated hydrochloric acid were added to a solution of 150 mg of the product of Example 10 in 40 ml of dichloromethane. The solution was stirred nitrogen for 2 hours. The solvent was evaporated and the residue was recrystallized from diethyl ether/hexane to give 190 mg of 3,4-bis[1-(1-phenylthioethyl)-3-indolyl]-1H-pyrrole-2,5-dione, m.p. 102°-105° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([CH3:13])[CH:4]=1.[OH:14]C1C2C(=CC=CC=2)N=C(C)C=1.ClC1C=CC=C(C(OO)=O)C=1.[OH-].[Na+]>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:13])[N+:6]([O-:14])=[C:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2
Reactant: COc1cc(C)nc2ccccc12
Reactant: Cc1cc(O)c2ccccc2n1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc(C)[n+]([O-])c2ccccc12
Temperature: 40 °C

Procedure:
31 g of 4-methoxyquinaldine (prepared from 4-hydroxyquinaldine by the method of M. Maurin, A. Ch. 4 [11] (1935), 301 and 335) are taken up in 80 ml of chloroform at room temperature, and 42 g of 85% strength m-chloroperbenzoic acid are added a little at a time, with stirring. The mixture is heated at 40° C. for 2 hours and is then cooled to 20° C. and brought to pH 6-7 with about 9 g of NaOH in 50 ml of H2O. The organic phase is separated off, dried with Na2SO4, filtered and concentrated. 34 g of crude product remain, and are recrystallized from toluene with addition of a small amount of solid KOH. 12 g of pure 4-methoxyquinaldine-N-oxide are obtained. Melting point 131°-132° C.
Reaction SMILES: [CH3:1][I:2].[O:3]([C@@H:10]1[CH2:14][N:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][C@H:11]1[OH:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(OCC)C>[I-:2].[OH:22][C@H:11]1[C@H:10]([O:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:14][N+:13]([CH3:1])([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12]1
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1Oc1ccccc1
Reactant: CI
Solvent: CCOCC
Product: C[N+]1(Cc2ccccc2)C[C@@H](O)[C@H](Oc2ccccc2)C1
Product: [I-]
Reaction time: 48 h

Procedure:
A solution of 8.0 g. (56 mmol) of methyl iodide in 30 ml of dry ethyl ether was added dropwise to a stirred solution of 7.0 g. (26 mmol) of trans-4-phenoxy-1-phenylmethyl-3-pyrrolidinol in 70 ml. of dry diethyl ether. The mixture was stirred for two days and then concentrated under reduced pressure. The 10.7 g. of crystalline residue was washed with tetrahydrofuran and dried, and gave 10.4 g. (97%) of white powder, m.p. 122°-27° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[C:7]([CH:12]=[CH2:13])[N:8]=[CH:9][CH:10]=2)[O:5][C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[ClH:38].O1CCOCC1>C(Cl)Cl>[NH2:30][C:26]1([C:23]2[CH:22]=[CH:21][C:20]([C:3]3[C:2](=[O:1])[C:11]4[C:6]([O:5][C:4]=3[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:7]([CH2:12][CH2:13][Cl:38])[N:8]=[CH:9][CH:10]=4)=[CH:25][CH:24]=2)[CH2:27][CH2:28][CH2:29]1.[ClH:38]
Reactant: C=Cc1nccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(CCCl)nccc4c3=O)cc2)CCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 1-(4-(4-oxo-2-phenyl-8-vinyl-4H-pyrano[2,3-c]pyridin-3-yl)phenyl)cyclobutylcarbamate (15 mg, 0.030 mmol) in DCM was added 4 M HCl in 1,4-dioxane (0.05 mL, 2 mmol). The reaction mixture was stirred at RT for 4 h. The solvents were removed in vacuo. The product was chromatographed on a 5 g C18 cartridge {gradient 10 to 50% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to give the title compound as an HCl salt (5 mg, 38%). 1H NMR (500 MHz, CD3OD): δ 8.61 (d, 1H), 7.95 (d, 1H), 7.51-7.30 (m, 9H), 4.15-4.08 (m, 2H), 3.68-3.60 (m, 2H), 2.75-2.67 (m, 2H), 2.55-2.42 (m, 2H), 2.28-2.12 (m, 1H), 1.98-1.88 (m, 1H). LCMS (Method I): RT=4.49 min, [M+2]+=432.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[S:7]1(=[O:14])=[O:13].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:11][C:8]1([CH3:12])[S:7](=[O:14])(=[O:13])[NH:6][CH2:10][CH2:9]1
Reactant: COc1ccc(CN2CCC(C)(C)S2(=O)=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CCNS1(=O)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
To a 0° C. solution of 2-(2,4-dimethoxybenzyl)-5,5-dimethylisothiazolidine-1,1-dioxide (0.220 g, 0.7 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (3.591 mL, 48.3 mmol) and the resulting red solution was stirred at 0° C. for 3 hrs and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (20-80% ethyl acetate/hexanes) to give a clear oil (0.087 g, 86%). 1HNMR (300 MHz, CDCl3) δ 4.61 (br s, 1H), 3.32-3.26 (td, 2H, J=5.1, 7.1 Hz), 2.25-2.20 (t, 2H, J=7.2 Hz), 1.43 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#N.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.Cl.C1C[O:32]CC1>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:32]
Reactant: C1CCOC1
Reactant: N#Cc1ccc(O)cc1Br
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=Cc1ccc(O)cc1Br
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-4-hydroxy-benzonitrile (Intermediate 7, 2000 mg, 10.1 mmol) in DCM (50 mL) and THF (10 mL), at 0° C., diisobutylaluminum hydride 1M in toluene (20.2 ml, 20.2 mmol) was slowly added (10 min) and the reaction mixture was stirred at the same temperature for 1 hour. Then 40 ml of HCl 2M were added and the reaction mixture was warmed at 40° C. for 30 minutes. After cooling ethyl acetate (100 ml) was added and two phases were separated. The organic layer was washed with brine (3×100 ml) dried over sodium sulphate and concentrated under vacuum to give the title compound (1950 mg) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[F:27][C:28]([F:42])([F:41])[C:29]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:30]=1[CH2:31]Br>ClCCl>[F:27][C:28]([F:41])([F:42])[C:29]1[CH:36]=[C:35]([C:37]([F:40])([F:38])[F:39])[CH:34]=[CH:33][C:30]=1[CH2:31][NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:16][CH:17]=1
Reactant: COC(=O)C(C)(C)Oc1ccc(CCN)cc1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
A solution of methyl 2-[4-(2-aminoethyl)phenoxy]-2-methylpropanoate (Biochim. Biophys. Acta 1997, 1339 (2), 321–330) (2 g; 8.44 mmol) in dichloromethane (20 ml) was treated with DIEA (1.47 ml; 8.44 mmol) and 2,4-bis-trifluoromethyl-benzyl bromide (2.59 g; 8.44 mmol). After stirring at rt overnight, the reaction mixture was concentrated and partitioned between ethyl acetate and saturated Na2CO3 solution. The organic phase was washed with Na2CO3 solution and brine, dried over sodium sulfate and concentrated. Purification by flash chromatography on silica gel using an ethyl acetate-hexane mixture (10–50%) afforded the title compound (2.0 g; 51% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][C:20]([CH3:23])([OH:22])[CH3:21])[CH2:15][CH2:14]1)=[O:12])=[CH:5]2.[C:24](OC(=O)C)(=[O:26])[CH3:25].O>O1CCOCC1.C1COCC1>[OH:22][C:20]([CH3:23])([CH3:21])[CH2:19][CH:16]1[CH2:17][CH2:18][N:13]([C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([NH:1][C:24](=[O:26])[CH3:25])=[CH:10][CH:9]=3)=[O:12])[CH2:14][CH2:15]1
Reactant: CC(C)(O)CC1CCN(C(=O)c2cc3cc(N)ccc3[nH]2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc2[nH]c(C(=O)N3CCC(CC(C)(C)O)CC3)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 105 mg of 1-{1-[(5-amino-1H-indol-2-yl)carbonyl]piperidin-4-yl}-2-methylpropan-2-ol in 2 mL of dioxane and 2 mL of THF was added 32 μL of acetic anhydride, followed by stirring at room temperature for 2 hours. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform:methanol=1:0-10:1], and then solidified using ethyl acetate-hexane to obtain 110 mg of N-(2-{[4-(2-hydroxy-2-methylpropyl)piperidin-1-yl]carbonyl}-1H-indol-5-yl) acetamide as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].[Cl:14]N1C(=O)CCC1=O.Cl.C(OCC)(=O)C>C(Cl)(Cl)Cl.CO>[Cl:14][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([C:1]#[N:2])[C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)c(O)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
Methyl 3-cyano-4-hydroxybenzoate (2.00 g) was dissolved in chloroform (15 mL) and methanol (5 mL), and N-chlorosuccinimide (3.62 g) and 4N hydrochloric acid-ethyl acetate (6.8 mL) were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and a mixture of methanol and water in a mixing ratio of 9:1 was added, and then the precipitated crystal was washed with water and isopropyl alcohol to obtain the title compound (1.27 g) as a colorless crystal.
Reaction SMILES: [CH:1]([N:4]1[C:8]([SH:9])=[N:7][C:6]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[N:5]1)([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19]([NH:23][C:24](=[O:27])[CH2:25]Cl)[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCl>[Cl:16][C:17]1[CH:18]=[C:19]([NH:23][C:24](=[O:27])[CH2:25][S:9][C:8]2[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[N:7]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(CCl)Nc1cccc(Cl)c1
Reactant: CC(C)n1nc(-c2ccncc2)nc1S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1nc(-c2ccncc2)nc1SCC(=O)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of the thiol TFA salt from Step A (100 mg, 0.30 mmol), N-(3-Chlorophenyl)-2-chloroacetamide (61 mg, 0.30 mmol), and triethylamine (0.145 mL 1.040 mmol) in dichloromethane (2.0 mL) was stirred at room temperature for 6 h. The solvent was removed by evaporation, and the crude product was purified by HPLC to afford the title compound as a colorless solid, 127 mg (85%). MS (ES): 388 (M+H)+
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:38]=[CH:37][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[CH:31][CH:30]=[N:29]4)=[CH:24][C:23]=3[C:33]([F:36])([F:35])[F:34])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:56][C:57]1[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH:65]2[CH2:67][O:66]2)=[CH:59][CH:58]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[N:28]1([C:25]2[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:18]([N:15]3[CH2:14][CH2:13][CH:12]([NH:11][C:10]4[CH:37]=[CH:38][C:7]([CH2:6][CH2:5][NH:4][CH2:67][C@H:65]([OH:66])[CH2:64][O:63][C:60]5[CH:61]=[CH:62][C:57]([OH:56])=[CH:58][CH:59]=5)=[CH:8][CH:9]=4)[CH2:17][CH2:16]3)=[O:19])=[C:23]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH:32]=[CH:31][CH:30]=[N:29]1
Reactant: NCCc1ccc(NC2CCN(C(=O)NCc3ccc(-n4cccn4)cc3C(F)(F)F)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NCc1ccc(-n2cccn2)cc1C(F)(F)F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 20 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-[4-(1H-pyrazol-1-yl)-2-(trifluoromethyl)benzyl]-1-piperidinecarboxamide formate (0.532 g, 1.0 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.404 g, 1.0 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.18 g, 0.20 mmol)