Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[NH2:13].C(N(CC)CC)C.[F:22][C:23]([F:38])([F:37])[C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:27](Cl)=[O:28].C(=O)([O-])N>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[NH:13][C:27](=[O:28])[C:26]1[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=[C:24]([C:23]([F:22])([F:37])[F:38])[CH:25]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1N
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: NC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc([N+](=O)[O-])cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
To a solution of 2-amino-4-nitro-benzoic acid methyl ester (5.00 g, 25.5 mmol) in methylene chloride (75 mL) was added triethylamine (4.13 g, 40.8 mmol) followed by 3,5-bis-trifluoromethyl-benzoyl chloride (8.46 g, 30.6 mmol). This mixture was allowed to stir overnight at ambient temperature. Work-up of an aliquot of the reaction mixture revealed incomplete reaction. Additional 0.5 equivalents of the acid chloride (2.3 mL) and triethylamine (1.8 mL) were added and the mixture was refluxed overnight. The reaction mixture was allowed to cool and filtered. The filtrate was partitioned against brine, the layers were separated, and the aqueous layer was extracted with one portion of ethyl acetate. The organics were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The resultant paste was dissolved in methylene chloride (25 mL) and the product was precipitated out by the addition of hexanes (175 mL). The precipitate was isolated by filtration and determined to be a mixture of the desired amide (mono-acylated) product and the carbamate (di-acylated) side product. The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (15/85 gradient to 30/70) to give 2-(3,5-bis-trifluoromethyl-benzoylamino)-4-nitro-benzoic acid methyl ester (3.7 g, 33%) as an off-white solid. 1H NMR (400 MHz, CDCl3); δ 12.40 (bs, 1H), 9.78 (d, 1H), 8.50 (s, 2H), 8.31 (d, 1H), 8.11 (s, 1H), 8.00 (dd, 1H), 4.07 (s, 3H). 1H NMR (400 MHz, DMSO-d6); δ 9.04 (d, 1H), 8.43 (dd, 1H), 8.34 (s, 4H), 8.24 (s, 1H), 8.22 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]([CH:18]=[CH:19][C:20]([OH:22])=O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=1)[C:27]([NH:29][NH:30][CH:31]([CH3:33])[CH3:32])=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[F:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10](/[CH:18]=[CH:19]/[C:20]([N:30]([CH:31]([CH3:33])[CH3:32])[NH:29][C:27](=[O:28])[C:26]3[CH:34]=[CH:35][CH:36]=[C:24]([F:23])[CH:25]=3)=[O:22])=[CH:9][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)n1cc(C=CC(=O)O)c2ccc(F)cc21
Reactant: CC(C)NNC(=O)c1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)N(NC(=O)c1cccc(F)c1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2cc(F)ccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing 3-(1-(tert-butoxycarbonyl)-6-fluoro-1H-indol-3-yl)acrylic acid (200.0 mg, 0.66 mmol), 3-fluoro-N′-isopropylbenzohydrazide (192.8 mg, 0.98 mmol) and HATU (376.6 mg, 0.98 mmol) dissolved in DMF (5.0 ml), N,N-diisopropylethylamine (DIPEA)(0.16 ml, 0.98 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (50% EtOAc) for refinment and dried so that white (E)-tert-butyl 6-fluoro-3-(3-(2-(3-fluorobenzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (180.0 mg, 56.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C@@H:10]2[CH2:15][CH2:14][C@H:13]([O:16]C(=O)C3C=CC([N+]([O-])=O)=CC=3)[CH2:12][CH2:11]2)[C:6]1=[O:28].C([O-])([O-])=O.[K+].[K+]>CO>[Cl:1][C:2]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C@H:10]2[CH2:11][CH2:12][C@@H:13]([OH:16])[CH2:14][CH2:15]2)[C:6]1=[O:28]
Reactant: O=C(O[C@H]1CC[C@@H](N2CCC(Cc3ccc(Cl)cc3Cl)C2=O)CC1)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C1C(Cc2ccc(Cl)cc2Cl)CCN1[C@H]1CC[C@@H](O)CC1
Reaction time: 8 h

Procedure:
Dissolve cis-4-nitro-benzoic acid 4-[3-(2,4-dichloro-benzyl)-2-oxo-pyrrolidin-1-yl]-cyclohexyl ester (Example 16) (3.58 g, 7.29 mmol) in MeOH (200 mL). Add 2M K2CO3 (50 nL) and stir the reaction mixture overnight. Add water (200 mL) and extract the aqueous layer with ethyl acetate (3×300 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 50-100% of EtOAc-Hexane) to give 1.54 g (62%) of the title compound as a white solid. Mass spectrum (ion spray): m/z=342.0, 344.0 (M+1).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(O)C.C(=O)([O-])[O-].C([N:21](C(C)C)CC)(C)C>C(#N)C>[N:5]1[C:4]2[S:8][CH:9]=[CH:10][C:3]=2[C:2]([NH2:21])=[N:7][CH:6]=1
Reactant: Clc1ncnc2sccc12
Reactant: CCN(C(C)C)C(C)C
Agent: *CC(*)C
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CCO
Product: Nc1ncnc2sccc12

Procedure:
An amine (VIII) is added to a solution of the 4-chlorothieno[2,3-d]pyrimidine (VII) in either ethanol or a mixture of acetonitrile and a base (for example an alkaline carbonate or diisopropylethylamine) in a closable bottle. The bottle is closed with a polypropylene cap, and heated overnight in a conventional oven at a temperature comprised between 40° and 120° C., preferably between 60 and 85° C. After cooling, the solvent is removed under reduced pressure, and the residue is purified by flash chromatography to provide the final thieno[2,3-d]pyrimidin-4-ylamine (I).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:16]([OH:18])=O)[NH:7]2.[NH:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:16]([N:19]1[CH2:25][CH2:24][CH2:23][N:22]([C:16]([C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=4)=[O:18])[CH2:21][CH2:20]1)=[O:18])[NH:7]2
Reactant: C1CNCCNC1
Reactant: COc1cc2[nH]c(C(=O)O)cc2c(OC)c1OC
Product: COc1cc2[nH]c(C(=O)N3CCCN(C(=O)c4cc5c(OC)c(OC)c(OC)cc5[nH]4)CC3)cc2c(OC)c1OC

Procedure:
4,5,6-Trimethoxyindole-2-carboxylic acid (290 mg) and homopiperazine (58 mg) were reacted in the same manner as in Preparation Example 37 to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2F)(=[O:28])=[O:27])=[CH:22][N:21]=1>CN(C)C=O.C(OCC)(=O)C>[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])(=[O:28])=[O:27])=[CH:22][N:21]=1
Reactant: O=S(=O)(c1ccc(/C=C/c2ccc(F)cc2F)nc1)c1ccccc1F
Reactant: CN(C)CCCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)CCCOc1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2F)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-(dimethylamino)-1-propanol (17 μL, 0.14 mmol) was dissolved in N,N-dimethylformamide (1 mL) and sodium hydride (60% dispersion in mineral oil; 6 mg, 0.14 mmol) added. After stirring at room temperature under nitrogen for 10 minutes, a solution of 2-[(E)-2-(2,4-difluorophenyl)vinyl]-5-[(2-fluorophenyl)sulfonyl]pyridine (Example 1, 50 mg, 0.13 mmol) in N,N-dimethylformamide (1 mL) was added and the reaction stirred at room temperature under nitrogen for 3.5 days. The reaction was diluted with ethyl acetate and washed with water (×4) and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 5% methanol/0.5% ammonia/dichloromethane, to give the title compound which was dissolved in ethyl acetate and treated with ethereal HCl to give the hydrochloride salt (42 mg, 66%). δH (400 MHz, MeOD): 9.10 (1H, d, J=2.2 Hz), 8.29 (1H, dd, J=2.3, 8.4 Hz), 8.12 (1H, dd, J=1.6, 7.9 Hz), 7.98 (1H, d, J=16.2 Hz), 7.83 (2H, q, J=7.9 Hz), 7.75-7.67 (1H, m), 7.38 (1H, d, J=16.3 Hz), 7.23 (1H, t, J=7.7 Hz), 7.18 (1H, d, J=8.3 Hz), 7.08-7.02 (2H, m), 4.22 (2H, t, J=5.7 Hz), 3.40 (2H, t, J=7.8 Hz), 2.97 (6H, s), 2.28-2.22 (2H, m); m/z (ES+) 459 [MH+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)[CH2:5][C:6]1[C:7]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:8]=2[S:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:13][CH:12]=1.C([Li])CCC>C1COCC1>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:7]2[C:6]([CH2:5][C:4]3[CH:3]=[CH:2][C:33]([CH2:34][N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:32][CH:31]=3)=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][CH2:23][CH2:24]4)=[CH:13][CH:12]=3)[S:9][C:8]=2[CH:25]=1
Reactant: COc1ccc2c(Cc3ccc(CN4CCCC4)c(Br)c3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2c(Cc3ccc(CN4CCCC4)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Temperature: -60 °C
Reaction time: 0.33 h
Yield: 41.5 %

Procedure:
To a solution of 3-[3-bromo-4-[(1-pyrrolidinyl)methyl]benzyl]-6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (100 mg, 0.16 mmol) in THF (2 mL) at −60° C. under argon was added a solution of n-butyllithium in hexanes (1.6 M, 0.2 mL) and the mixture was stirred at −60° C. for 20 min. The reaction was quenched with 0.5 mL of MeOH and allowed to warm up to ambient temperature. The mixture was then concentrated under reduced pressure and fractionated by flash chromatography with Et3N:MeOH:EtOAc (3:3:94) to afford the product (35 mg, 40%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[Br-].[C:18]([C:21]1[CH:46]=[CH:45][C:24]([CH2:25][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:23][CH:22]=1)([OH:20])=[O:19]>C(O)C>[C:18]([C:21]1[CH:46]=[CH:45][C:24](/[CH:25]=[CH:13]/[C:12]2[CH:15]=[CH:16][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:10][CH:11]=2)=[CH:23][CH:22]=1)([OH:20])=[O:19]
Reactant: O=C(O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccc(OCCCCCCO)cc1
Agent: [Br-]
Solvent: CCO
Product: O=C(O)c1ccc(/C=C/c2ccc(OCCCCCCO)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
0.43 g (62 mmole) of Li was dissolved in 180 ml of ethanol under a nitrogen atmosphere. Then 6.9 g (31 mmole) of 4-(6-hydroxyhexyloxy)-benzaldehyde (15) and 14.8 g (31 mmole) of (4-carboxy-benzyl)-triphenylphosphonium bromide (14) were added. The mixture was stirred for two hours at room temperature. The precipitate was collected on a filter and washed with 50 ml of ethanol. Then the solid was mixed with 1.5 ml of concentrated hydrochloric acid and 35 ml of ethanol. It was stirred for 30 min and the product was collected on a filter. After washing with 50 ml of ethanol and drying in a dessicator 4.1 g of the product were obtained (yield 38%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N+:12]([O-:15])=[C:11]([CH3:16])[CH:10]=2)=[CH:5][CH:4]=1.Br.C(N(CC)CC)C.ClC1C=CC=C(C(OO)=O)C=1>CO.C(OCC)(=O)C.O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][N+:12]([O-:15])=[C:11]([CH3:16])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cc[n+]([O-])c(C)c2)cc1
Agent: Br
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(-c2ccc(O)cc2)cc[n+]1[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.3 %

Procedure:
A solution of 4-(4-methoxyphenyl)-2-methylpyridine 1-oxide (384 mg) in a 48% aqueous solution of hydrobromic acid (2.08 mL) is heated under reflux for 4 hours. The mixture is allowed to cool back to room temperature, water and ethyl acetate are added and the two phases separated by decantation. The aqueous phase is concentrated under reduced pressure. The residue is dissolved in chloroform (4 mL); triethylamine (1 equivalent) is added followed by metachloroperbenzoic acid (1 equivalent). The mixture is stirred for two hours at room temperature; a few drops of methanol are added to dissolve the reactants and stirred again for one hour at room temperature. Concentration under reduced pressure affords 55 mg of 4-(4-hydroxyphenyl)-2-methylpyridine 1-oxide as a yellow oil used without further purification.
Reaction SMILES: C([C@@:8]1([NH2:15])[CH2:12][C@H:11]([CH2:13][OH:14])[CH:10]=[CH:9]1)(OC(C)(C)C)=O.[ClH:16]>CO>[ClH:16].[NH2:15][C@@H:8]1[CH2:12][C@H:11]([CH2:13][OH:14])[CH:10]=[CH:9]1
Reactant: CC(C)(C)OC(=O)[C@]1(N)C=C[C@@H](CO)C1
Agent: Cl
Solvent: CO
Product: N[C@H]1C=C[C@@H](CO)C1
Yield: 95 %

Procedure:
87.8 g of (1R, 4 S)-1-BOC-amino-4-hydroxymethyl-2-cyclopentene were dissolved in 270 ml of 2 N HCl and 1340 ml of methanol. The mixture was boiled under reflux for 4.5 h. After distillation of the methanol, the residue was dissolved in 800 ml of water. The aqueous solution was extracted twice with 340 ml of ethyl acetate. The aqueous phase was completely evaporated (50° C./60 mbar). The solid was dried at 50° C. in vacuo, suspended in 150 ml of diethyl ether, filtered off and washed twice with 50 ml of diethyl ether. Drying resulted in the title compound in a yield of 95% (58.4 g).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18]#[N:19])[CH:14]=[CH:15][CH:16]=1>>[C:18]([CH2:17][C:13]1[CH:12]=[C:11]([NH:10][C:7]([C:5]2[O:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])[CH:16]=[CH:15][CH:14]=1)#[N:19]
Reactant: N#CCc1cccc(N)c1
Reactant: O=C(O)c1ccc(Br)o1
Product: N#CCc1cccc(NC(=O)c2ccc(Br)o2)c1

Procedure:
5-Bromo-furan-2-carboxylic acid (1.68 g, 8.80 mmol) was coupled to aniline (80) (1.16 g, 8.80 mmol), using Method C. The residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [O:1]1[CH2:12][C@@H:2]1[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH3:13]>CCO.CO.[OH-].[NH4+]>[NH2:13][CH2:12][C@@H:2]([OH:1])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N
Reactant: c1ccc(COC[C@H]2CO2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: NC[C@@H](O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A solution of (2R)-benzyl 2-epoxypropyl ether, 6 (21.0 g, 0.128 mol) in EtOH (100 mL) was added slowly to a solution of 7.0 M ammonia in MeOH (100 mL) and 28% aq. ammonium hydroxide (210 mL) at rt. The reaction vessel was tightly capped and stirred at rt for 23 h. The completed reaction was concentrated in vacuo, and the crude product was azeotroped to dry twice with toluene (100 mL) to provide (R)-1-amino-3-(benzyloxy)propan-2-ol, 23 (23 g) as waxy solid containing approximately 15% of dimer. The crude was used for next reaction without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C@H:23]([N:30]([C:38](=[O:40])[CH3:39])[C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=4)[CH2:22][C@@H:21]3[CH3:41])=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:9]=1)=[O:4].C(O)C.[OH-].[Na+]>O1CCCC1>[C:38]([N:30]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C@H:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]([C:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:7]3[O:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=3)=[CH:13][CH:14]=2)=[O:19])[C@@H:21]([CH3:41])[CH2:22]1)(=[O:40])[CH3:39]
Reactant: COC(=O)c1ccc(COc2ccc(C(=O)N3c4ccccc4[C@H](N(C(C)=O)c4ccc(Cl)cc4)C[C@@H]3C)cc2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCc3ccc(C(=O)O)o3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(2S,4R)-5-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxymethyl)-furan-2-carboxylic acid methyl ester (0.145 g, 0.25 mmol) was hydrolyzed to the acid by dissolving in tetrahydrofuran and ethanol and sodium hydroxide (1N) was added. The mixture was stirred at room temperature 4 hours. The mixture was cooled to rt, acidified to form a white precipitate. The solid was filtered to give (2S,4R)-5-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxymethyl)-furan-2-carboxylic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][C:18]([O:21]C(=O)C)=[CH:17][C:15]=4[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1>CO.[OH-].[Na+].CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:15]=4[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)Oc1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: Oc1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1
Reaction time: 24 h
Yield: 82.8 %

Procedure:
To a suspension of 7-chloro-2-(5-acetoxybenzofuran-2-yl)quinoline (16.7 g) in methanol (400 ml), 1N aqueous sodium hydroxide (50 ml) was added at ambient temperature. The mixture was stirred for 1 day. After the solvent was removed under reduced pressure, the residue was suspended with water, and adjusted to pH 6-7 with diluted aqueous hydrochloric acid. After the resulting suspension was stirred at ambient temperature for 1 hour, the precipitates were collected by filtration, washed with water and dried in vacuo to give crude material (15 g). The crude material was dissolved in N,N-dimethylformamide (200 ml) at 80° C., and the resulting solution was allowed to stand at ambient temperature. The resulting crystals were filtered off and washed with N,N-dimethylformamide. The filtrate was poured into Water (500 ml). The resulting precipitates were collected by filtration, washed with water and dried in vacuo to give 7-chloro-2-(5-hydroxybenzofuran-2-yl)quinoline (12.1 g).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]([O:15]C)=O)#N.CC(C[AlH]CC(C)C)C.Cl.C1C[O:30]CC1>>[OH:15][CH2:13][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][CH:12]=[C:3]2[CH:1]=[O:30]
Reactant: C1CCOC1
Reactant: COC(=O)c1cccc2c(C#N)cccc12
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Product: O=Cc1cccc2c(CO)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a cooled (0° C.) solution of methyl 5-cyano-1-naphthylcarboxylate (1 g, 5 mmol) in 20 mL anhydrous THF was added DIBAL (1M in hexane, 20 mL, 20 mmol) via syringe. The mixture was then kept between 50-60° C. overnight. The mixture was then cooled to room temperature. The mixture was poured into a cold (0° C.) solution of 2 N HCl (100 mL). The product was extracted with ether (2×). The organic layer was washed with brine, dried over MgSO4 and concentrated. Silica gel column chromatography using hexane/ethyl acetate (2/1) gave the 0.85 g (91%) of the product.
Reaction SMILES: [I-:1].[Na+].C([Sn](CCCC)(CCCC)[C:8]1[CH:9]=[C:10]([N:14]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]2=[O:20])[CH:11]=[CH:12][CH:13]=1)CCC.CC1C=CC(S(NCl)(=O)=O)=CC=1.S(=O)(O)[O-].[Na+]>O.C(Cl)Cl.CCOC(C)=O.CCCCCC>[I:1][C:8]1[CH:9]=[C:10]([N:14]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]2=[O:20])[CH:11]=[CH:12][CH:13]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(N2C(=O)C=CC2=O)c1
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1C=CC(=O)N1c1cccc(I)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a stirred solution of sodium iodide (32 mg, 0.21 mmol) in H2O (100 μL), was added N-(m-tri-n-butylstannylphenyl)maleimide as described above (0.1 g, 0.21 mmol) in CH2Cl2 (2 mL), followed by a solution of chloramine-T (59 mg, 0.21 mmol) in H2O (2 mL). Reaction progress was followed by TLC on silica gel GHLFC plates (EtOAc/hexane, 1:3), starting material 4 Rf 0.65. The reaction mixture was stirred at room temperature for 30 minutes. The mixture initially turned yellow from the formation of I+. The solution rapidly became lighter until a colorless solution resulted. To this was added 2 mL of 5% aqueous sodium bisulfite and the resulting mixture was extracted with dichloromethane (4×10 mL). The dichloromethane extracts were dried (MgSO4), and the solvent was removed in vacuo to give the desired product N-(m-iodophenyl)maleimide (60 mg/ 95%): TLC (EtOAc/hexane, 1:3) Rf 0.42; mp 154°-155° C. 1H NMR (CDCl3), δ); 7.1-7.7 (multiplets, 4H, 4 aryl CH); 6.8 (singlet, 2H, 2 CHC=O).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][CH:22]2[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:35][C:36]1[CH:44]=[CH:43][C:39]([C:40]([NH2:42])=[O:41])=[CH:38][CH:37]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:24]1[CH2:25][CH2:26][CH2:27][CH:22]([NH:21][C:4]2[C:5]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=4)(=[O:13])=[O:12])[C:6]=3[N:7]=[C:2]([NH:35][C:36]3[CH:44]=[CH:43][C:39]([C:40]([NH2:42])=[O:41])=[CH:38][CH:37]=3)[N:3]=2)[CH2:23]1
Reactant: NC(=O)c1ccc(N)cc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCCN(C(=O)OC(C)(C)C)C4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCCNC4)nc(Nc4ccc(C(N)=O)cc4)nc32)cc1
Temperature: 116 °C
Reaction time: 20 h
Yield: 14.4 %

Procedure:
A mixture of tert-butyl 3-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (251 mg, 0.496 mmol), 4-aminobenzamide (102 mg, 0.750 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) in nBuOH (4 mL) was stirred at 116° C. in a sealed tube for 20 h. It was concentrated in vacuo. The residue was purified by HPLC to give 4-(4-(piperidin-3-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide (36 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][CH:13]1[CH2:18][C@H:17](O)[C@@H:16]([CH:20]([CH3:22])[CH3:21])[CH2:15][CH2:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH:15]2[CH:16]([CH:20]([CH3:22])[CH3:21])[CH2:17][CH2:18][CH:13]([CH3:12])[CH2:14]2)=[O:10])=[CH:6][CH:7]=1
Reactant: CC1CC[C@H](C(C)C)[C@@H](O)C1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1CCC(C(C)C)C(OC(=O)Cc2ccc(O)cc2)C1

Procedure:
2.9 kg of p-hydroxyphenylacetic acid and 1.95 kg of (+)-menthol are heated to boiling for 16 hours with 40 g of p-toluenesulphonic acid in 25 l of toluene; about 300 ml of water are separated in this process. The toluene solution is washed with 10 l of saturated NaHCO3 solution and 10 l of water and concentrated to dryness in vacuo. The title compound is obtained as 5.4 kg of oily residue (98-100% of theory) having a purity of 91.8% (HPLC surface area percentage). For analytical purposes, the (+)-menthylhydroxyphenylacetate was recrystallised twice from n-hexane.