Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]1=[O:13].[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH3:18].O>CN(C)C=O>[CH2:14]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]1=[O:13])[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCN1C(=O)C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.7 %

Procedure:
A stirred solution of 270 mg of sodium hydride was added to 1.00 g of 2,3-dihydro-1H-indol-2,3-dione in dimethylformamide at room temperature. After the reaction mixture was stirred at room temperature for 10 minutes, 5 ml of a dimethylformamide solution of 2.10 g of pentyl bromide was added dropwise thereto. After the reaction mixture was stirred at room temperature for 20 minutes, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was removed by evaporation. The residue was purified by silica gel column chromatography [ethyl acetate-hexane (1:5)] to afford 1.31 g of 2,3-dihydro-1-pentyl-1H-indol-2,3-dione as orange crystals. Melting point: 50° to 51° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.[OH-].[Na+].[C:14](Cl)(=[O:25])[O:15][CH2:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=1>C(Cl)Cl>[Cl:23][C:21]1[CH:22]=[C:17]([CH:18]=[C:19]([Cl:24])[CH:20]=1)[CH2:16][O:15][C:14]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1)=[O:25]
Reactant: O=C(O)CCC1CCNCC1
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(O)CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3-piperidin-4-yl-propionic acid (1 g, 6.36 mmol) in DCM (20 ml) was added 2M NaOH (9.54 ml, 19.08 mmol) to give a colorless biphasic solution. 3,5-Dichlorobenzyl carbono-chloridate (1.523 g, 6.36 mmol) was added to the reaction mixture and this was stirred at RT for 2 hrs. The mixture was extracted with DCM (2×50 ml), and the organics were dried (MgSO4) and concentrated to give the product as a white solid.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)#[N:33].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:37]3[CH:38]=[CH:39][C:34]([C:32]#[N:33])=[CH:35][CH:36]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCC5)CC4)ccc32)cc1
Yield: 30 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 4-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a off-white foam (30%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[B:15]([O:24]C(C)C)([O:20]C(C)C)[O:16]C(C)C.Cl>CCCCCC.C1COCC1>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([O:16][B:15]([OH:24])[OH:20])=[CH:3][CH:4]=1)[CH3:9]
Reactant: CCc1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1ccc(OB(O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.3 %

Procedure:
To a mixture of 1-bromo-4-ethylbenzene (743 mmol) and 500 ml of THF, was added dropwise 500 ml of a solution of n-butyl lithium (corresponding to 780 mmol) in hexane at −78° C. in 1.6 hours, and stirred at the same temperature for 1.5 hours. To this solution was added dropwise 200 ml of a solution of triisopropyl borate (1,486 mmol) in THF, the solution was gradually warmed up to room temperature, and then the solution was stirred overnight. After 750 ml of 7.3% hydrochloric acid was added and stirred for 30 min, the reaction solution was extracted twice with diethyl ether, washed thrice with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was recrystallized from about 1,000 ml of toluene to give a white solid of 4-ethylphenyl boric acid (515 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:15][CH:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 65.3 %

Procedure:
The N-Boc p-hydroxy phenyl glycine methyl ester from step (300a) (123.0 g, 440 mmol) was combined with benzyl bromide (90.3 g, 528 mmol), potassium carbonate (182 g, 1.3 mol) and acetone (800 mL) under a nitrogen atmosphere. The reaction was heated to reflux for 5 h, allowed to cool to rt, diluted with ethyl acetate (800 mL) filtered to remove the solids and concentrated in vacuo to give a semisolid residue. The product was crystallized from ethyl ether to give the N-Boc p-benzyloxy phenyl glycine methyl ester (106.7 g, 65%) as a white powder. MS (M+H)+=372, (M+NH4)+=389.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:12]([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14][OH:15].[I-].[Na+]>O1CCOCC1>[OH:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][OH:18])[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ClCCCSc1ccccc1
Reactant: OCCNCCO
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Product: OCCN(CCO)CCCSc1ccccc1
Yield: 57 %

Procedure:
A mixture of 8.30 g (44.5 mmols) of 1-chloro-3-phenylthiopropane, 100 ml of diethanolamine, 13.3 g (88.7 mmols) of sodium iodide and 250 ml of dioxan was heated under reflux for 15 hours. The mixture was concentrated under reduced pressure, and an aqueous saturated sodium bicarbonate solution was added to the mixture followed by extraction of the solution with chloroform 5 times. The chloroform layer was drided over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol =25/1) to afford 6.46 g (yield: 57%) of 1-bis(hydroxyethyl)amino-3-phenylthiopropane.
Reaction SMILES: C(N(CC)CC)C.ClC([O:11][CH2:12][CH3:13])=O.[OH:14][CH:15]([C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:31](=[O:32])[CH2:30][CH2:29][C@@H:28]2[CH2:33][CH2:34][CH2:35][C:36]2[S:40][C:39]([C:41]([OH:43])=[O:42])=[CH:38][CH:37]=2)=[CH:23][CH:22]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(O)CO>>[OH:11][CH2:12][CH2:13][O:42][C:41]([C:39]1[S:40][C:36]([CH2:35][CH2:34][CH2:33][C@H:28]2[CH2:29][CH2:30][C:31](=[O:32])[N:27]2[C:24]2[CH:23]=[CH:22][C:21]([CH:15]([OH:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=2)=[CH:37][CH:38]=1)=[O:43]
Reactant: CCCCCC(O)c1ccc(N2C(=O)CC[C@@H]2CCCc2ccc(C(=O)O)s2)cc1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: OCCO
Product: CCCCCC(O)c1ccc(N2C(=O)CC[C@@H]2CCCc2ccc(C(=O)OCCO)s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
Triethylamine (17.5 μL, 0.13 mmol) and ethyl chloroformate (6 μL, 0.063 mmol) were added sequentially to a solution 5-(3-{(S)-1-[4-(1-hydroxyhexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic acid (derived from the faster eluting [HPLC] ester diastereomer, see U.S. Ser. No. 10/599,046 or U.S. Provisional Patent Application No. 60/777,506, filed on Feb. 28, 2006, incorporated by reference herein, 18 mg, 0.042 mmol) in CH2Cl2 (0.6 mL) at 0° C. The mixture was allowed to warm to room temperature. After 30 min at room temperature, ethylene glycol (25 μL, 0.45 mmol) was added. After stirring overnight at room temperature, the reaction mixture was concentrated under a stream of nitrogen. The residue was diluted with EtOAc (20 mL) and washed with H2O (2×5 mL) and brine (5 mL). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→10% MeOH/CH2Cl2, gradient) afforded 8.5 mg (43%) of the title compound (1).
Reaction SMILES: [C:1]([Si:5]([CH3:28])([CH3:27])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[CH2:8][CH2:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:39][O:40][C:41](=[O:52])[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][CH2:50]Br)=[CH:44][CH:43]=1>>[CH3:39][O:40][C:41](=[O:52])[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][CH2:50][N:14]2[C:13](=[O:15])[CH2:12][CH2:11][CH:10]2[CH2:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:28])[CH3:27])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=2)=[CH:44][CH:43]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(CCCBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: COC(=O)c1ccc(CCCN2C(=O)CCC2CCC(Cc2cccc(C(F)(F)F)c2)O[Si](C)(C)C(C)(C)C)cc1
Yield: 84.2 %

Procedure:
Analogous to the procedure described for Example 1A, Step D, 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-trifluoromethyl-phenyl)-butyl]-pyrrolidin-2-one (250 mg, 0.602 mmol) was alkylated with NaHMDS (1M in THF, 0.72 mL, 0.72 mmol) and 4-(3-bromo-propyl)-benzoic acid methyl ester (170 mg, 0.663 mmol) to yield 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-trifluoromethyl-phenyl)-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester (300 mg). MS 592.1 (M+1).
Reaction SMILES: [CH:1]([O:4][CH2:5][C@@H:6]([OH:9])[CH2:7][OH:8])([CH3:3])[CH3:2].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Si:10]([O:8][CH2:7][C@H:6]([OH:9])[CH2:5][O:4][CH:1]([CH3:3])[CH3:2])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)OC[C@@H](O)CO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC[C@@H](O)CO[Si](C)(C)C(C)(C)C

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 34 step iii) using (2S)-3-isopropoxypropane-1,2-diol (0.80 g) (the product from step (ii) in DCM (10 mL), tert-butyldimethylsilyl chloride (1.59 g), triethylamine (1.43 mL) and 4-(dimethylamino)pyridine (50 mg) at 0° C. to give the subtitle compound as a clear, colourless oil. Yield: 1.86 g
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].Br[CH2:16][CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.CC(C)=O>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:16][CH2:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=1[OH:10])(=[O:12])[CH3:13]
Reactant: O=C(O)c1ccc(CCBr)cc1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCCc1c(OCCc2ccc(C(=O)O)cc2)ccc(C(C)=O)c1O

Procedure:
A mixture of 1 g (5.55 mmoles) of 2,4-dihydroxy-3-propylacetophenone, 1.27 g (5.55 mmoles) of para-(β-bromoethyl)benzoic acid, 2.4 g of potassium carbonate, and 50 ml of dry acetone was stirred and refluxed for 3 days. The reaction flask was cooled and the stirred mixture was diluted with H2O and acidified with 6N HCl. Extraction with ethyl acetate and drying with Na2SO4 afforded the crude product after evaporating the ethyl acetate in vacuo. Pure 4-β-(4-acetyl-3-hydroxy-2-propylphenoxy)ethyl benzoic acid was isolated by flash chromatography on silica gel eluting with 5% MeOH/CH2Cl2 containing 0.1% acetic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[SH:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: Sc1ccccn1
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2ccccn2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
The title compound was prepared from the reaction of trifluoro-methanesulfonic acid 4-methyl-2-nitro-phenyl ester (3.50 g, 12.27 mmol) reacting with pyridine-2-thiol (2.046 g, 18.41 mmol), and K2CO3 (2.968 g, 21.48 mmol) in DMF at 100° C. for 16 h the reaction mixture was then cooled to room temperature and diluted with water, extracted with EtOAc Dried over Na2SO4, filtered and concentrated under vacuum giving the title compound (2.52 g, 78%).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[CH3:8][CH:9]([CH2:11][CH:12](O)[CH3:13])[CH3:10].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[C:1]([O:7][CH:12]([CH3:13])[CH2:11][CH:9]([CH3:10])[CH3:8])(=[O:6])[CH2:2][C:3]([O:5][CH:12]([CH3:13])[CH2:11][CH:9]([CH3:10])[CH3:8])=[O:4]
Reactant: O=C(O)CC(=O)O
Reactant: CC(C)CC(C)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)CC(C)OC(=O)CC(=O)OC(C)CC(C)C
Yield: 83.9 %

Procedure:
Malonic acid (72.8 g, 0.7 mol) and 2-methyl-4-pentanol(286 g, 2.8 mol) in 200 ml of toluene are refluxed for 2 hours in the presence of 1.8 ml of concentrated sulfuric acid in a reactor equipped with Dean-Stark apparatus. The water formed is removed azeotropically. The organic phase is washed three times with water and dried over sodium sulfate. This solution is filtered and the solvent is evaporated off. The product obtained distils at 147° C. under 20 hPa. 160 g (79% yield) of bis(1,3-dimethylbutyl) malonate are obtained in the form of a colorless oil, which is used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]2[O:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:4][C:3]=1[O:18][CH3:19].Cl[CH2:21][C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:23]=1>>[CH3:19][O:18][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][CH2:10][CH:11]2[O:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])[CH:6]=[CH:7][C:2]=1[O:1][CH2:21][C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:23]=1
Reactant: ClCc1nc(-c2ccccc2)no1
Reactant: COc1cc(CCCC2OC(=O)NC2=O)ccc1O
Product: COc1cc(CCCC2OC(=O)NC2=O)ccc1OCc1nc(-c2ccccc2)no1

Procedure:
In substantially the same manner as in Working Example 9, 5-[3-(4-hydroxy-3-methoxyphenyl)propyl]-2,4-oxazolidinedione was reacted with 5-chloromethyl-3-phenyl-1,2,4-oxadiazole to obtain 5-[3-[3-methoxy-4-(3-phenyl-1,2,4-oxadiazol-5-ylmethoxy)phenyl]propyl]-2,4-oxazolidinedione, which was recrystallized from ethyl acetate-hexane to give colorless prisms, m.p.110-111° C.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]1([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:15][CH2:14][CH2:13][CH2:12]1.BrC1C(NCCNC(=O)OC(C)(C)C)=NC(Cl)=NC=1>>[Br:1][C:2]1[C:3]([NH:10][C:11]2([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:12][CH2:13][CH2:14][CH2:15]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC1(N)CCCC1
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: CC(C)(C)OC(=O)NCCNc1nc(Cl)ncc1Br
Product: CC(C)(C)OC(=O)NCC1(Nc2nc(Cl)ncc2Br)CCCC1

Procedure:
tert-butyl N-[[1-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclopentyl]methyl]carbamate is synthesized by treating 5-Bromo-2,4-dichloropyrimidine with tert-butyl N-[(1-aminocyclopentyl)methyl]carbamate using similar experimental conditions as described for the synthesis of tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate. LCMS (ESI) 405 (M+H)
Reaction SMILES: [OH:1][C:2]([CH3:16])([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.[C:17]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:18][C:19](O)=[O:20].C1CCN2C(=NCCC2)CC1.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:24]([O:23][C:17]([C:18]1[C:19](=[O:20])[O:1][C:2]([CH3:16])([CH3:15])[C:3]=1[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=[O:22])[CH3:25]
Reactant: CC(C)(O)C(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: CCOC(=O)CC(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C1=C(c2ccc(S(C)(=O)=O)cc2)C(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 62.6 %

Procedure:
A mixture of 2-hydroxy-2-methyl-1-(4-(methylsulfonyl) phenyl)propan-1-one (2.87 g, 11.8 mmol), ethyl hydrogen malonate (2.02 g, 15.3 mmol), CMC (6.51 g, 15.4 mmol) and DMAP (0.35 g, 2.8 mmol) was dissolved in 100 mL of CH2Cl2. The mixture was stirred for 14 h at room temperature, then DBU (4 mL, 27 mmol) was added, stirred 1 h, then partitioned-between CH2Cl2 and 1M HCl. The organic layer was washed with brine, filtered through cotton and evaporated. Purification by flash chromatography (90% ether/Hex) provided 2.50 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[O:27]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:32][C:29]4[CH:30]=[CH:31][O:27][CH:28]=4)[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Reactant: O=Cc1ccoc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccoc3)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.045 mmol) was reacted with 3-furaldehyde to provide 19 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].O>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C(Cl)CCCBr
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(CCCBr)OCc1ccccc1
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a solution of 4-bromobutyryl chloride (Aldrich Chemical Company, Wisconsin), (10.27 g, 55.4 mmol) in 100 mL of dichloromethane was added benzyl alcohol (Aldrich Chemical Company, Wisconsin), (6.29 g, 58.1 mmol), followed by potassium carbonate (8.3 g, 60 mmol) in four portions. After 2 hours, water was added, and the layers were separated. The organic layer was washed with water, brine, and dried over magnesium sulfate. Evaporation of the solvent gave the title compound (11.87 g, 83% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.36 (m, 5H), 5.14 (s, 2H), 3.46 (t, J=6.4 Hz, 2H), 2.56 (t, J=7.2 Hz, 2H), 2.20 (quin, J=6.6 Hz, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2[O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([C:26]([F:29])([F:28])[F:27])[CH:18]=1)(=[O:3])[NH2:2]>O1CCCC1.CO.[C].[Pd]>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([C:26]([F:28])([F:29])[F:27])[CH:18]=1)(=[O:3])[NH2:2]
Reactant: COc1cc2nccc(Oc3ccc([N+](=O)[O-])c(C(F)(F)F)c3)c2cc1C(N)=O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(N)c(C(F)(F)F)c3)c2cc1C(N)=O
Yield: 107.9 %

Procedure:
After dissolving 6-carbamoyl-4-(3-trifluoromethyl-4-nitrophenoxy)-7-methoxyquinoline (0.60 g) in tetrahydrofuran (10 ml) and methanol (10 ml), the solution was subjected to catalytic reduction with palladium-carbon (600 mg) for 10 hours under a hydrogen atmosphere to obtain the title compound (0.60 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:6][CH:7]=1.Cl[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=3)[CH2:22][CH2:23]2)=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCNCC1
Reactant: N#Cc1cc(Cl)ccn1
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#Cc1cc(N2CCC(CNc3ccccc3C(=O)Nc3ccc(Cl)cn3)CC2)ccn1
Yield: 46.3 %

Procedure:
Using a similar procedure to that described in Example 52, N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (100 mg, 0.29 mmol), 4-chloro-2-cyanopyridine (80 mg, 0.58 mmol), triethylamine (59 mg, 0.58 mmol), and ethanol (2 mL) yielded 60 mg (46%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1F)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.COC(C1C=C[C:52]2[N:53](C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O.NCC1C=CC(B(O)O)=CC=1>>[NH2:53][CH2:52][C:43]1[CH:2]=[CH:3][C:4]([C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:21]5[N:25]([CH:26]6[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]6)[C:24]6[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=6[N:22]=5)[CH:17]=4)[N:12]=3)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=2)=[CH:41][CH:42]=1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Agent: NCc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(CN)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 46 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 4-aminomethylphenylboronic acid (49 mg, 0.2625 mmol) to produce the title compound (48 mg, 46% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[C:5](=[NH:36])[CH:6](P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:2].[C:38](=O)=[O:39]>>[CH2:1]([O:3][C:4](=[O:37])[CH:5]([N:36]=[C:38]=[O:39])[CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH3:2]
Reactant: CCOC(=O)C(=N)C(CCNC(=O)OC(C)(C)C)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C=O
Product: CCOC(=O)C(CCCNC(=O)OC(C)(C)C)N=C=O
Temperature: 50 °C

Procedure:
The reaction solution from Example 9 is placed in a Parr® bomb and carbon dioxide (22 g, 0.5 mol) is condensed into the bomb. The bomb is sealed and heated to 50° C. for 12 hours. The bomb is cooled and vented to atmospheric pressure. The solution is transferred from the bomb to a flask and used as is in the next reaction (Example 11).