Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19](Cl)[N:18]=1>CS(C)=O>[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19]([O:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[N:18]=1
Reactant: OCc1ccc(F)cc1
Reactant: Clc1cncc(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Fc1ccc(COc2cncc(Cl)n2)cc1

Procedure:
4-Fluorobenzylalcohol (200 μL, 1.85 mmol) and potassium tert-butoxide (122.1 mg, 1.00 mmol) in anhydrous DMSO (1 mL) were reacted with 2,6-dichloropyrazine (156.8 mg, 1.05 mmol) as described in Example 19B to afford the title compound. MS (DCI/NH3) m/z 239 (M+H)+.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C1([N+]([O-])=O)C=CC=CC=1.[Cl:14][C:15]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18].[Cl:25][C:26]1[CH:27]=[C:28]([O:33][CH3:34])[CH:29]=[C:30]([Cl:32])[CH:31]=1>CCOCC>[Cl:25][C:26]1[CH:27]=[C:28]([O:33][CH3:34])[CH:29]=[C:30]([Cl:32])[C:31]=1[C:17]([C:16]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:15]=1[Cl:14])=[O:18]
Reactant: COc1cc(Cl)cc(Cl)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCOCC
Product: COc1cc(Cl)c(C(=O)c2ccc(Cl)cc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
Anhydrous AlCl3 (4.5 g, 33.9 mmol) was placed in a round bottom flask and PhNO2 (150 mL) was added. At −78° C. 2,4-dichlorobenzoyl chloride (4.7 mL, 33.9 mmol) and 3,5-dichloro anisole (5.0 g, 28.2 mmol) were added. The reaction mixture was kept at the same temperature for 1 h and warmed to rt over 24 h. The reaction mixture was diluted with Et2O (50 mL) at 0° C. and quenched with 1N NaOH (˜30 mL). The reaction mixture was stirred vigorously until a white precipitate had been formed. The precipitates were filtered and washed with CH2Cl2 (50, 30, and 20 mL). The combined organic solvents were dried (Na2SO4), filtered, and concentrated under vacuum at ˜10 mmHg. Purification by silica gel chromatography (4:1, hexanes:CHCl3) to provide (2,6-dichloro-4-methoxyphenyl)(2,4-dichlorophenyl)methanone (8.3 g, 85%) as a white powder. 1H NMR (300 MHz, CDCl3): δ 7.68 (d, J=8.2 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.37 (dd, J=8.1, 2.1 Hz, 1H), 6.95 (s, 2H), 3.87 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 197.6, 163.8, 142.0, 138.3, 137.7, 136.4, 130.3, 129.9, 127.8, 122.9, 118.4, 117.9, 114.6, 56.1; IR (film): 1619 cm−1, 1584, 1553, 1400, 1309; HRMS (FAB): C14H8Cl4O2 (M+Na1) calcd. 370.91761, found 370.91765.
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20].N12CCN(CC1)CC2.O>CN(C)C=O>[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:19](=[O:20])[N:18]([CH3:17])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:7][CH:6]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C(Nc1ccc(O)nc1)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)Oc1ccc(NC(=O)c2ccccc2)cn1)c1ccccc1
Yield: 67.2 %

Procedure:
A solution of N-(6-hydroxy-pyridin-3-yl)-benzamide (0.64 g, 3.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.51 g, 3.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.34 g, 3.00 mmol) in dimethylformamide (15 ml) was stirred at room temperature for 1 hour. Water was added and the precipitates were collected by suction. The solids were dissolved in dichloromethane and the solution was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was dissolved in ethyl acetate and filtered over a short pad of silica. Evaporation of the solvent in vacuo yielded the title compound (0.70 g, 68% yield) as a thick oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N+:8]1([O-:27])[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccccn1
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)[N+]1([O-])Cc1ccccn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.3 %

Procedure:
2-(2-Pyridylmethyl)-1H-isoindole-1,3(2H)-dione (7.5 g, 32 mmol) and 3-chloroperbenzoic acid (77%, 14.3 g, 64 mmol) were dissolved in chloroform (250 ml), and the mixture was stirred at room temperature for 20 hrs. The solvent was evaporated, and the residue was washed with ethyl acetate to give the titled compound (8.0 g, 99%) as white crystals.
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[CH:19][C:20]([N+:24]([O-])=O)=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1)[C:3](=[O:11])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H][H]>[Pd].C1COCC1.CCO>[NH2:24][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[N:14]([CH2:13][CH2:12][N:2]([CH3:1])[C:3](=[O:11])[O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:15][CH2:16][CH2:17]2
Reactant: CN(CCN1CCCc2cc([N+](=O)[O-])ccc21)C(=O)Oc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(CCN1CCCc2cc(N)ccc21)C(=O)Oc1ccccc1

Procedure:
A suspension of phenyl methyl(2-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)ethyl)carbamate (500 mg, 1.41 mmol) and palladium on activated carbon (10%, 75 mg, 0.07 mmol) in a 1:1 mixture of THF/EtOH (20 mL) was stirred under a balloon of hydrogen for 4.5 hours. The suspension was filtered through a pad of celite. The filter pad was rinsed with 25 mL methanol and the filtrate was concentrated to give a dark viscous oil. The crude product was used without further purification (460 mg, quantitative). 1H-NMR (CDCl3) δ 7.39-7.34 (m, 2H), 7.22-7.17 (m, 1H), 7.12-7.08 (m, 2H), 6.61-6.42 (m, 3H), 3.61-3.45 (m, 4H), 3.26 (t, J=6.0 Hz, 2H), 3.20 (brs, 2H), 3.13 and 3.06 (2×s, 3H), 2.70 (t, J=6.3 Hz, 2H), 1.96-1.87 (m, 2H). MS (ESI): 326.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[C:9]1[C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:21]=[N:20][C:19]=1[O:30][CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:51][N:52]([CH3:56])[CH2:53][CH2:54]O.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:54][CH2:53][N:52]([CH3:56])[CH3:51])[CH:15]=2)[CH:10]=[C:9]1[C:18]1[CH:23]=[C:22]([C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)[N:21]=[N:20][C:19]=1[O:30][CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)CCO
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(O)cc2n1C(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(OCCN(C)C)cc2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 43 %

Procedure:
100 mg 6-hydroxy-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester and 175 mg triphenylphosphine are dissolved in 7 mL toluene and 2 mL THF. After dropwise addition of 84 μL 2-dimethylaminoethanol and 123 μL diethyl azodicarboxylate, the reaction mixture is stirred at room temperature for 5 hours. The solvent is removed in vacuo and the residue is dissolved in dichloromethane. The organic phase is washed with water and the aqueous phase is extracted twice with dichloromethane. The combined organic phases are dried over MgSO4 and concentrated in vacuo. Purification by HPLC afforded 35 mg (43%) 6-(2-dimethylaminoethoxy)-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.[F:19][C:20]1[C:25]([C@H:26]2[N:34]3[C@@H:29]([CH2:30][CH2:31][CH:32](P(=O)(OCC)OCC)[C:33]3=[O:35])[CH2:28][CH2:27]2)=[CH:24][CH:23]=[C:22]([F:44])[N:21]=1.C(O)C>O1CCCC1>[F:19][C:20]1[C:25]([C@H:26]2[N:34]3[C@@H:29]([CH2:30][CH2:31]/[C:32](=[CH:8]\[C:7]4[CH:10]=[CH:11][C:12]([N:13]5[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]5)=[C:5]([O:4][CH3:3])[CH:6]=4)/[C:33]3=[O:35])[CH2:28][CH2:27]2)=[CH:24][CH:23]=[C:22]([F:44])[N:21]=1
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CC[C@@H](c3ccc(F)nc3F)N2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(/C=C2\CC[C@H]3CC[C@@H](c4ccc(F)nc4F)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
Lithium hydroxide (0.106 g) was added to a mixed solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (0.24 g) and diethyl [(3S,8aR)-3-(2,6-difluoropyridin-3-yl)-5-oxooctahydroindolizin-6-yl]phosphonate (1.0 g) in tetrahydrofuran (4 mL)-ethanol (16 mL), and the reaction solution was stirred under shading at room temperature for 12 hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 0.42 g of the title compound as a colorless solid. The property values of the compound are as follows.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[NH:10][CH2:11][C@@H:12]([OH:29])[C@@H:13]([NH:21]C(OC(C)(C)C)=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:31].O1CCOCC1>C1COCC1>[ClH:31].[CH2:1]([O:8][C:9](=[O:30])[NH:10][CH2:11][C@@H:12]([OH:29])[C@@H:13]([NH2:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: N[C@@H](Cc1ccccc1)[C@H](O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A solution of ((2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-carbamic acid benzyl ester (D103) (31.5 g, 76.1 mmol, 1 equiv) in THF (300 ml) was treated with 4N HCl solution in dioxan (40 ml, 160 mmol, 2.1 equiv). The resulting solution was stirred at room temperature for 2 h then concentrated in vacuo. The residue was triturated with Et2O/iso-hexane to give ((2R,3S)-3-amino-2-hydroxy-4-phenyl-butyl)-carbamic acid benzyl ester hydrochloride (D104) (22.1 g, 83%) as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3([CH3:17])[O:16][CH2:15][CH2:14][O:13]3)=[CH:8][C:7]=2[C:18]2[C:19]3[NH:26][C:25]([CH3:27])=[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:3][CH2:2]1.Cl[CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3([CH3:17])[O:13][CH2:14][CH2:15][O:16]3)=[CH:8][C:7]=2[C:18]2[C:19]3[N:26]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:25]([CH3:27])=[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C4(C)OCCO4)ccc3OCC3CC3)ncnc12
Reactant: C[Si](C)(C)CCOCCl
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(C4(C)OCCO4)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-[2-(cyclopropylmethoxy)-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a13) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is obtained as yellow viscous oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].[Cl:21][CH2:22][CH2:23][CH2:24]Cl>CN(C)C=O>[Cl:21][CH2:22][CH2:23][CH2:24][O:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:14])[CH3:13]
Reactant: ClCCCCl
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1OCCCCl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 98.1 g (0.5 mol) of N-(2-hydroxy4-nitrophenyl)acetamide (RN 121-88-0) and 69.2 g (0.5 mol) of potassium carbonate in 500 ml of dimethylformamide was heated with stirring at 50° C.; 113.0 g (1 mol) of 1,3-dichloropropane (RN 142-28-9) were then added and heating was continued at 50° C. for one hour.
Reaction SMILES: [C:1]([CH2:4][N:5]([C:10]1[CH:15]=[CH:14][C:13]([NH:16]/[C:17](=[C:24]2\[C:25](=[O:33])[NH:26][C:27]3[C:32]\2=[CH:31][CH:30]=[CH:29][CH:28]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[S:6]([CH3:9])(=[O:8])=[O:7])([OH:3])=O.[NH4+].O[N:36]1C(=O)CCC1=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[NH2:36][C:1]([CH2:4][N:5]([C:10]1[CH:11]=[CH:12][C:13]([NH:16]/[C:17](=[C:24]2\[C:25](=[O:33])[NH:26][C:27]3[C:32]\2=[CH:31][CH:30]=[CH:29][CH:28]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:15]=1)[S:6]([CH3:9])(=[O:8])=[O:7])=[O:3]
Reactant: O=C1CCC(=O)N1O
Reactant: CS(=O)(=O)N(CC(=O)O)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)N(CC(N)=O)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 18 from (Z)-3-{1-[4-(N-carboxymethyl-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone, N-hydroxysuccinimide-ammonium salt, TBTU and triethylamine in DMF.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].CN(C)C=O.[H-].[Na+].Br[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[N:7]([CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCCc1ccccc1
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nn(CCc2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
To a mixture of 4′-[(3-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile (1.00 g) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.60 g), and the mixture was stirred at room temperature for 30 min. To the mixture was added (2-bromoethyl)benzene (2.22 g), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.72 g, 55%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:20])[NH:18][CH3:19])=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:21]([O:25][C:26](=[O:29])[CH2:27]Br)([CH3:24])([CH3:23])[CH3:22].O>CN(C)C=O>[C:3]([O:7][C:8]([N:10]([CH2:27][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:29])[C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:20])[NH:18][CH3:19])=[CH:15][CH:16]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CNC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(N(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 41.9 mg) was added to a solution of N-(tert-butoxycarbonyl)-4-methylcarbamoylaniline (250 mg) in dimethylformamide (2.5 ml) in ice water bath under nitrogen and stirred for 30 minutes under same condition. To the mixture was added tert-butylbromoacetate (234 mg) and stirred at ambient temperature for 20 hours. The reaction mixture was poured into water and extracted with chloroform. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethyl acetate--n-hexane to give N-(tert-butoxycarbonyl)-N-(tert-butoxycarbonylmethyl)-4-methylcarbamoylaniline (280 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[C:15](OC(=O)C)(=[O:17])[CH3:16]>CO>[C:15]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: NCCCCCO
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)NCCCCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-amino-1-pentanol (0.650 g, 6.31 mmol) in methanol (15 mL) is cooled to 0° C. and treated with triethylamine (1.62 mL, 11.6 mmol) followed by acetic anhydride (0.891 mL, 9.45 mmol). The reaction mixture is stirred at room temperature overnight. Additional triethylamine (1.6 mL, 11.6 mmol) and acetic anhydride (0.9 mL, 9.5 mmol) is added at room temperature and the solution is stirred 16 h further. Concentration in vacuo and flash chromatography affords 5-acetamido-1-pentanol. To a solution of 5-acetamido-1-pentanol (22.2 mmol) in dry dichloromethane (50 mL) is added 2,6-di-tert-butyl-4-methylpyridine (4.6 g, 22.2 mmol) and triflic anhydride (3.7 mL, 22.2 mmol) at 0° C. The reaction is stirred at room temperature for 20 min, poured into water, and extracted with dichloromethane. The combined extracts are dried over anhydrous sodium sulfate and concentrated in vacuo and to afford 5-acetamido-1-pentyl triflate (30) which is used without further purification.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH2:29]>CCOCC>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH:29][C:13](=[O:15])/[CH:12]=[CH:11]/[CH2:10][CH2:9][C:8]#[C:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)/C=C/CCC#Cc1ccccc1
Reactant: COc1cccc(CN)c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1cccc(CNC(=O)/C=C/CCC#Cc2ccccc2)c1

Procedure:
7-phenylhept-2E-en-6-ynoic acid (100 mg) was converted to the acid chloride as described in Example 2(a). The acid chloride was treated with triethylamine (73 ul) and 3-methoxybenzylamine (77 ul) in ether (2 ml). The product was recovered as described in Example 1 and purified by chromatography on silica, eluting with ether:hexane (1:1) to yield N-(3-methoxybenzyl)-7-phenylhept-2E-en-6-ynamide as a colourless solid, m.p. 96.3°-98.9°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:33][C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[C:26]5=[O:34])[C:20]=4[CH3:35])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1.[N:36]([CH:39]([CH3:41])[CH3:40])=[C:37]=[O:38]>C1COCC1>[CH:39]([NH:36][C:37](=[O:38])[NH:1][CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:33][C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[C:26]5=[O:34])[C:20]=4[CH3:35])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)([CH3:41])[CH3:40]
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(CN)ccc4c23)cccc1N1Cc2ccccc2C1=O
Reactant: CC(C)N=C=O
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(CNC(=O)NC(C)C)ccc4c23)cccc1N1Cc2ccccc2C1=O
Yield: 16.4 %

Procedure:
A solution of 7-(aminomethyl)-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (Example 33-1, 30 mg, 0.065 mmol) and 2-isocyanatopropane (0.019 mL, 0.195 mmol) in THF (3 mL) was stirred at 40° C. overnight. The mixture was concentrated and purified by preparative HPLC. The appropriate effluent fractions were concentrated and partitioned between EtOAc and NaHCO3 (aq). The organic phase was dried and concentrated to provide 7-((3-isopropylureido)methyl)-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide as a white solid (5.8 mg, 14%). 1H NMR (400 MHz, methanol-d4) δ 7.84 (1H, d, J=7.7 Hz), 7.77 (1H, d, J=7.5 Hz), 7.53-7.63 (2H, m), 7.38-7.51 (4 H, m), 7.30 (1H, dd, J=7.2, 1.7 Hz), 6.93-6.99 (2H, m), 6.85 (1H, dd, J=8.3, 1.4 Hz), 4.79-4.91 (2H, m), 4.33 (2H, s), 3.69-3.78 (1H, m), 1.79 (3H, s), 1.03 (6H, d, J=6.4 Hz). Mass spectrum m/z 546.3 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:45]1[CH:50]=[CH:49][C:48]([CH2:51]O)=[CH:47][CH:46]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1.O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:51][C:48]4[CH:49]=[CH:50][N:45]=[CH:46][CH:47]=4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1
Reactant: Oc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Reactant: OCc1ccncc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: c1ccc(-c2nn3c(c2-c2ccnc4cc(OCc5ccncc5)ccc24)CCC3)nc1
Temperature: 75 °C

Procedure:
4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ol (0.100 g, 0.305 mmol), triphenylphosphine (0.080 g, 0.305 mmol), and 4-pyridylcarbinol (0.033 g, 0.305 mmol) are combined in toluene (1.0 mL) and treated with diisopropylazodicarboxylate (0.062 g, 0.305 mmol). The resulting mixture is heated at 75° C. for 18 hours. The mixture is diluted with tetrahydrofuran and heated at 75° C. for 24 h. The mixture is placed on a 10 g SCX resin column which is washed sequentially with dichloromethane (120 mL), methanol (60 mL), and 4:1 dichloromethane/2 N ammonia in methanol (125 mL). The latter fraction is concentrated in vacuo and the residue chromatographed on SiO2 (9:1 ethyl acetate:2N ammonia in methanol) to yield the desired product as a tan solid, 0.035 g (27%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.[C:14]([CH2:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)#[N:15]>>[C:14]([CH2:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[N:7]=[C:6]([NH:21][C:20]3[CH:22]=[CH:23][C:17]([CH2:16][C:14]#[N:15])=[CH:18][CH:19]=3)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=2)=[CH:19][CH:18]=1)#[N:15]
Reactant: N#CCc1ccc(N)cc1
Reactant: CCOC(=O)c1cnc(Cl)nc1Cl
Product: CCOC(=O)c1cnc(Nc2ccc(CC#N)cc2)nc1Nc1ccc(CC#N)cc1

Procedure:
In like manner to N2,N4-bis(3-hydroxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine, 2,4-dichloro-5-ethoxycarbonylpyrimidine and 4-cyanomethylaniline were reacted to yield N2,N4-bis(4-cyanomethylphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 8.72 (s, 1H), 7.64 (m, 4H), 7.32 (d, 2H, J=8.7 Hz), 7.21 (d, 2H, J=8.4 Hz), 4.3 (q, 2H, J=7.0 Hz), 3.97 (s, 2H,), 3.89 (s, 2H), 1.32 (3H, J=7 Hz); LCMS: ret. time: 30.83 min.; purity: 90%; MS (m/e): 413 (MH+).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([OH:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].CC(N(C)C)=O.[H-].[Na+]>C(O)(=O)C>[CH2:10]([O:20][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCO
Reactant: O=C(O)c1ccc(Br)o1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: CCCCCCCCCCOc1ccc(C(=O)O)o1
Reaction time: 42 h

Procedure:
A mixture of 30.0 g (0.157 mole) of 5-bromofuroic acid, 75.4 g (0.471 mole) of decanol and 1000 ml of dried dimethyl acetamide is stirred at room temperature after which 15.0 g (0.628 mole) of sodium hydride is added. The mixture is refluxed with stirring for 42 hours after which the mixture is poured into a water-ice mixture, acidified with acetic acid and extracted with ether. The ether layer is washed several times with water and salt water, then dried over sodium sulfate, filtered and evaporated on a steam bath replacing the ether with hexane and allowing the mixture to crystallize. The solid obtained is recrystallized from methanol to give 5-decyloxy-2-furoic acid, M.P. 124°-126° C.