Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:36][CH3:37])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][C:28]=1[CH3:35])=[O:26])[CH3:19]>C(O)C.N1CCCCC1>[CH2:36]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[NH:12][C:11]2=[O:17])[NH:29][C:28]=1[CH3:35])=[O:26])[CH3:37]
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Reactant: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.9 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)-amide (69.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-fluoro-phenyl)2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2.4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)amide as a yellow solid (57.3 mg, 47%).
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].C([Li])CCC.[F:13][C:14]([F:34])([F:33])[C:15]1[CH:32]=[CH:31][CH:30]=[CH:29][C:16]=1[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26])=[O:18]>O1CCCC1.CCCCCC>[OH:18][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:26])([F:27])[F:28])([C:16]1[CH:29]=[CH:30][CH:31]=[CH:32][C:15]=1[C:14]([F:33])([F:34])[F:13])[CH2:2][C:1]#[N:4]
Reactant: O=C(c1ccccc1C(F)(F)F)c1ccccc1C(F)(F)F
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#CCC(O)(c1ccccc1C(F)(F)F)c1ccccc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.02 h

Procedure:
A stirred solution of diisopropylamine (4.02 mL) in dry tetrahydrofurane (30 mL) under argon was treated dropwise with 1.6M n-butyl lithium in hexane (18 mL). The reaction was kept at -5° C. during the addition and for 15 minutes thereafter, then it was cooled to -78° C. and a solution of 2,2'-bis(trifluoromethyl)benzophenone (8.0 g) in tetrahydrofurane was added at such a rate that the reaction temperature did not exceed -65° C. The mixture was stirred at -78° C. for 1 minutes, then it was allowed to slowly equilibrate to room temperature over 30 minutes. After the solvents were removed under reduced pressure, the residue was treated with water (100 mL) and the resulting solid was filtered off, washed with water and dried. Crystallization of the solid from dichloromethanehexane furnished 7.72 g of 3-hydroxy-3,3-bis[2-(trifluoromethyl)phenyl]-propanenitrile, mp 168°-170° C. A sample was recrystallized from the same solvent system to give the analytical specimen, mp 171°-172° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:24]
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(C(=O)Nc2ccc3[nH]c4c(c3c2)CC(N(C)C)CC4)c1
Yield: 58.6 %

Procedure:
Beginning with 10.6 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.8 μL (0.063 mMol) 3-methoxybenzoyl chloride, 9.8 mg (59%) of the title compound were recovered as a brown foam.
Reaction SMILES: Cl.[O:2]=[C:3]1[N:7]2[CH2:8][CH2:9][N:10]([C:12]([NH:14][CH2:15][CH2:16][NH:17][CH2:18][CH:19]=[CH2:20])=[O:13])[CH2:11][CH:6]2[C:5]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:4]1.C(=O)([O-])O.[Na+].C(N(CC)CC)C.[C:45](OC(=O)C)(=[O:47])[CH3:46]>C(OCC)(=O)C>[C:45]([N:17]([CH2:18][CH:19]=[CH2:20])[CH2:16][CH2:15][NH:14][C:12]([N:10]1[CH2:9][CH2:8][N:7]2[C:3](=[O:2])[O:4][C:5]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:6]2[CH2:11]1)=[O:13])(=[O:47])[CH3:46]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCNCCNC(=O)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CCN(CCNC(=O)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1)C(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To tetrahydro-3-oxo-1,1-diphenyl-N-[2-[(2-propenyl)amino]ethyl]-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxamide hydrochloride (0.13 g, 0.29 mmol) was added a 0.5 M aqueous sodium hydrogen carbonate solution (20 mL), and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL). Triethylamine (58 mg, 0.57 mmol) and acetic anhydride (32 mg, 0.31 mmol) were sequentially added thereto, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added ethyl acetate, and the resulting mixture was washed with a 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from diisopropyl ether to obtain the title compound (90 mg, yield 68%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:10]O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([NH2:21])[CH3:20]>>[CH2:19]([N:21]([CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCCCC1
Reactant: CCN
Product: CCN(CC(CC1CCCCC1)NC(=O)OC(C)(C)C)CC(CC1CCCCC1)NC(=O)OC(C)(C)C

Procedure:
The product from Example 15A and ethylamine were processed as described in Example 7B to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH2:19][OH:20].CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C>[C:23]([O:22][C:18](=[O:21])[CH2:19][O:20][C:2]1[CH:17]=[CH:16][C:5]([C:6](=[O:7])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][N:3]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(Nc1ccc(F)cc1)c1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Temperature: 70 °C
Yield: 7.6 %

Procedure:
A suspension of 6-bromo-N-(4-fluorophenyl)nicotinamide (0.112 g, 0.38 mmol), tert-butyl glycolate (0.1 g, 0.76 mmol), and potassium tert-butoxide (0.85 g, 0.76 mmol) in THF (10 mL) was heated in a sealed tube at 70° C. After 6 h the reaction mixture was diluted with ethyl acetate and washed with water bicarbonate and dried over sodium sulfate. Removal of the solvents provided a solid. Purification by reverse phase chromatography gave 0.010 g (8%) of the titled product as a white solid; MS (EI) m/z 345.21 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23]([OH:25])=[O:24].O[CH2:27][CH2:28][NH:29][C:30]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:31].C1(N=C=NC2CCCCC2)CCCCC1.C(#N)C>CCOCC>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([N:10]2[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=3)[C:3]([CH2:22][C:23]([O:25][CH2:27][CH2:28][NH:29][C:30]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[O:31])=[O:24])=[C:2]2[CH3:1])=[O:12])=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: O=C(NCCO)c1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Solvent: CCOCC
Product: COc1ccc2c(c1)c(CC(=O)OCCNC(=O)c1cccnc1)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
A reaction of indomethacin (1.79 g, 5.00 mmol) and the product of Example 91 (0.830 g, 5.00 mmol) was carried out, using dicyclohexylcarbodiimide (1.10 g, 5.50 mmol) as the coupling agent and acetonitrile as the solvent. The first two reactants were dissolved completely and the solution was then cooled to 0° C. The dicyclohexylcarbodiimide was added and the mixture was stirred overnight. The reaction was allowed to continue for 48 hours. The precipitate (1.2 g) was removed by vacuum filtration. The solvent was removed from the filtrate under reduced pressure leaving an oily residue. The product was solidified by stirring with anhydrous ether. It was filtered, air-dried and recrystallized from ethanol/ether. The final product was vacuum filtered, washed with ether, and air dried. The product weighed 1.65 g, giving a 65.2% yield: mp 123°-125° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([OH:13])=O)=[CH:8][C:9]=1[Br:10])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH2:55][CH2:56][C:57]1[CH:58]=[C:59]([OH:63])[CH:60]=[CH:61][CH:62]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:13])[NH:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([OH:63])[CH:58]=2)=[CH:8][C:9]=1[Br:10])=[O:4]
Reactant: COC(=O)c1sc(C(=O)O)cc1Br
Reactant: NCc1cccc(O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1Br
Temperature: 25 °C
Reaction time: 15 h
Yield: 58.5 %

Procedure:
To a solution of 3-Bromo-thiophene-2,5-dicarboxylic acid 2-methyl ester (204 mg, 0.76 mmol) in anhydrous DMF (7 mL) was added triethylamine (0.32 mL, 2.28 mmol), HBTU (0.43 g, 1.14 mmol), HOBT (123 mg, 0.91 mmol), and 3-Aminomethyl-phenol (110 mg, 0.91 mmol). The mixture was stirred at room temperature 15 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-50% EtOAc in hexane to afford the desired product (0.1647 g, 59% yield).
Reaction SMILES: [C:1]([C:5]1O[C:7]([O:10]CC)=[CH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15]>>[CH2:18]([O:17][C:13](=[O:16])[C:14]1[C:7]([OH:10])=[CH:8][N:9]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:15]=1)[CH3:19]
Reactant: C=CC(=O)OCC
Reactant: CCOc1cnc(C(C)(C)C)o1
Product: CCOC(=O)c1cc(C(C)(C)C)ncc1O
Temperature: 100 °C
Yield: 51.1 %

Procedure:
2-tert-Butyl-5-ethoxy-oxazole (16.6 g, 98.1 mmol) was dissolved in freshly distilled ethyl acrylate (11.7 mL, 108 mmol). The solution was heated in a sealed tube to 100° C. for 24 h. Upon cooling, the remaining starting materials were distilled away from the product which was further purified by filtration through a plug of silica-gel (methylene chloride) and concentrated to provide 2-tert-butyl-5-hydroxy-isonicotinic acid ethyl ester (11.2 g, 54%) as a pale yellow oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([CH2:10][O:11][CH2:12]Cl)=[CH:5][N:4]=1.Cl.[Cl:15][C:16]1[CH:17]=[N:18][C:19](=[O:22])[NH:20][CH:21]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([CH2:10][O:11][CH2:12][N:20]2[CH:21]=[C:16]([Cl:15])[CH:17]=[N:18][C:19]2=[O:22])=[CH:5][N:4]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: CSc1ncc(COCCl)c(C)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ncc(COCn2cc(Cl)cnc2=O)c(C)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Methylthio-4-methyl-5-(chloromethyloxymethyl)pyrimidine (see Preparation 11) (2.7 mmol) in dichloromethane (5 ml) was added dropwise with stirring at room temperature to a solution of 5-chloropyrimidin-2-one hydrochloride (2.7 mmol) and triethylamine in dichloromethane (0.76 ml). The mixture was stirred for 24 hours at room temperature before the solvent was distilled off. The residue was triturated with water, extracted into chloroform and the dried (MgSO4) solution evaporated. yield 0.55 g (65%). 1H NMR (CDCl3): δ2.42 (4-Me), 2.55 (SMe), 4.65 (CH2Pyr), 5.32 (CH2O), 7.80 and 8.42 (H-4, H-6, J 3 Hz), 8.20 (H-6').
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][CH2:26][C@@H:25]([NH:28]C(=O)OC(C)(C)C)[C:24]4=[O:36])=[CH:19][CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>C(Cl)Cl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[NH2:28][C@@H:25]1[CH2:26][CH2:27][N:23]([C:20]2[CH:21]=[CH:22][C:17]([N:13]3[CH2:12][C@H:11]([CH2:10][NH:9][C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:8])[O:15][C:14]3=[O:16])=[CH:18][CH:19]=2)[C:24]1=[O:36]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N3C[C@H](CNC(=O)c4ccc(Cl)s4)OC3=O)cc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CCN(c2ccc(N3C[C@H](CNC(=O)c4ccc(Cl)s4)OC3=O)cc2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
97 mg (0.181 mmol) of tert-butyl (3R)-1-{4-[(5S)-5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-2-oxo-3-pyrrolidinylcarbamate are suspended in 4 ml of methylene chloride, 1.5 ml of trifluoroacetic acid are added and the mixture is stirred at room temperature for 1 hour. The mixture is then concentrated under reduced pressure and the residue is purified on an RP-HPLC (acetonitrile/water/0.1% TFA gradient). Evaporation of the appropriate fraction gives 29 mg (37% of theory) of the target compound of melting point 241° C. (decomp.).
Reaction SMILES: C[C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]CC.O>C1C=CC=CC=1>[CH2:2]([O:3][CH2:4][C@H:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCOC[C@@H](O)CO
Temperature: 25 °C
Yield: 73 %

Procedure:
40 grams of (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol, 80 grams of powdered potassium hydroxide and 100 grams of hexadecyl bromide were stirred in 350 ml benzene and refluxed for 7 hours, while removing the water formed by azeotropic distillation. The volume of the solvent was gradually reduced to about 50 ml. The reaction mixture was cooled to room temperature, 300 ml of ice-cooled water was added, and the mixture was extracted 4 times with 150 ml dichloromethane. The combined organic phase was washed with water and the solvent was removed under reduced pressure. The obtained residue was dissolved in 500 ml of a 90:10:5 (v/v) mixture of methanol:water:concentrated hydrochloric acid, and the resulting solution was refluxed for 2 hours. After cooling to room temperature, 200 ml water was added. The product was extracted thrice with 200 ml chloroform, and washed consecutively with 200 ml water, 200 ml of a saturated aqueous sodium carbonate solution, and again with 200 ml water. The solvent was removed under reduced pressure and the product was crystallized from 450 ml petroleum ether at 4° C., yielding 69.93 grams of pure (S)-1-hexadecyl-sn-glycerol. The yield was 73%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:19][C:13]3[CH:14]=[N:15][C:16]([NH2:18])=[CH:17][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1COCC1.N1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:19][C:13]3[CH:14]=[N:15][C:16]([NH:18][C:26]([CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[O:27])=[CH:17][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1cc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c2cn1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c2cn1)C1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.8 %

Procedure:
To a stirring solution of 8 (0.116 g, 0.45 mmol) in dry THF and Pyridine (10 ml/0.300 ml), cyclohexanecarbonyl chloride (0.100 ml, 0.68 mmol) was added and stirred at room temperature for 4 h. The reaction was quenched by the addition of water and the yellow solid was filtered, air-dried and dissolved in EtOAc and passed through a bed of SiO2 gel. Elution with EtOAc afforded the desired product 9 (0.095 g, 58%). 1H NMR (DMSO-d6, 500 MHz): δ 13.49 (1H, s), 10.38 (1H, s, NH), 8.76 (1H, s), 8.41 (4H, dd, J=15 and 5 Hz); 8.34 (1H, s), 2.53 (1H, m), 1.80-1.20 (10, m); MS m/z: 366 (M+1), 364 (M−1). The product was used for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:13])[CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:4](=[O:6])[C:3]4[CH:7]=[C:8]([N:11]([CH3:13])[CH3:12])[CH:9]=[CH:10][C:2]=4[Cl:1])[CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: CN(C)c1ccc(Cl)c(C(=O)O)c1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: CN(C)c1ccc(Cl)c(C(=O)N2CCN(c3ccc(C(=O)NCCC4CC4)nn3)CC2)c1

Procedure:
Following the procedure of Example 9, making variations only as required to use 2-chloro-5-dimethylaminobenzoic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)-amide, the title compound was obtained as a white solid (53% yield). 1H NMR (300 MHz, CDCl3) δ 8.04, 7.96, 7.39, 6.94, 6.66, 6.55, 4.14-3.32, 2.93, 1.52, 0.75-0.69, 0.48-0.42, 0.11-0.05. MS (ES+) m/z 457.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:20]2[CH:21]=[CH:22][NH:23][C:19]=2[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[NH:23][CH:22]=[CH:21][C:20]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2[nH]ccc21
Product: CC1c2cc[nH]c2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[Cl:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([O:9][C:12]2[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:11]=2[Cl:10])[CH:4]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: Nc1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(Cl)cc1Oc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-amino-5-chlorophenol (11.0 g), 2-chloro-1-fluoro-4-nitrobenzene (1.5 g) and potassium carbonate (2.8 g) in dry DMF (20 ml) was stirred room temperature for 1 h then heated at 60° C. for 2 h. The mixture was partitioned between water/ethyl acetate, the organics separated, washed with water, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 10% ethylacetate/isohexane, yield 1.96 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[NH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>CO>[CH3:17][O:16][C:14]([C:13]1[CH:18]=[CH:19][C:10]([NH:9][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:11][CH:12]=1)=[O:15]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=Cc1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(NCc2cccnc2)cc1
Temperature: 0 °C

Procedure:
Alternately, 3-pyridinecarboxaldehyde ((61.6 g, 0.575 moles, 1 eq) and methyl 4-aminobenzoate (1-03.87 g, 0.687 moles, 1.2 eq) with p-toluenesulfonic acid (2.19 g, 0.012 moles, 0.02 eq) were refluxed in methanol (25 volumes) for 2 hours. The reaction mixture was cooled to 0° C. and sodium borohydride (67.6 g, 1.787 moles, 3.5 eq) added slowly then it was allowed to warm to ambient overnight. The reaction was concentrated, dissolved with dichloromethane and washed with water then brine, and evaporated to give the title compound.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][C:33]1([CH3:40])[O:37][C@@H:36]([CH2:38]O)[CH2:35][O:34]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:32][C:33]1([CH3:40])[O:37][C@@H:36]([CH2:38][O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:35][O:34]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC1(C)OC[C@H](CO)O1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](CON2C(=O)c3ccccc3C2=O)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
A 3-L round-bottomed flask equipped with mechanical stirrer and additional funnel was charged with N-hydroxyphthalimide (68.0 g, 0.416 mol) and tetrahydrofuran (1.2 L) under nitrogen atmosphere. To this solution was added triphenylphosphine (109.2 g, 0.416 mol) and the product of Example 31, Step B, (S)-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (55.0 g, 0.416 mol). The mixture was cooled to 3° C. to 5° C. and diethyl azodicarboxylate (85.2 mL, 0.541 mol) was added dropwise, while keeping the inner temperature below 15° C. The reaction mixture was warmed to ambient temperature, and stirred for 18 hours. The tetrahydrofuran was evaporated under reduced pressure. To the remaining orange solid was added dichloromethane (0.5 L) and the mixture was stirred for 1 hour. The white solid (Ph3PO) was filtered and washed with dichloromethane (0.1 L). The solvent was removed and ethanol (0.5 L) was added to the resulting solid. The mixture was stirred for 2 hours at 3° C. to 5° C. The white solid was filtered, washed with a small amount of cold EtOH, and dried in vacuum oven at 40° C. to give (R)-2-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-isoindole-1,3-dione (112.5 g, 97%) as a white solid: 1H NMR (CDCl3): δ 1.33 (s, 3 H), 1.99 (s, 3 H), 3.96 (m, 1 H), 4.15 (m, 2 H), 4.30 (m, 1 H), 4.48 (m, 1 H), 7.59 (m, 2 H), 7.84 (m, 2 H); MS (APCI+)=278 (M++1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](OB(O)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1(=[O:24])[CH2:23][CH2:22][CH:21]=[CH:20]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:21]2[CH2:22][CH2:23][C:19](=[O:24])[CH2:20]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=CCC1
Reactant: OB(O)Oc1ccc(OCc2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Product: O=C1CC[C@H](c2ccc(OCc3ccccc3)cc2)C1
Yield: 91.3 %

Procedure:
4-Benzyloxyphenylboric acid (3.42 g, 15 mmol), cyclopentenone (1.1 mL, 13 mmol) and (S)-BINAP were used as ligands and treated in a similar manner to (Step 1) of (Example 3) to give the title compound (3.16 g, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCc1cccc(Br)c1
Product: O=C(NCc1cccc(Br)c1)c1ccccc1
Yield: 98 %

Procedure:
In a manner similar to that of Example 1(d), 15 by reacting 7 g (32 mmol) of 3-bromobenzylamine with 4 ml (35 mmol) of benzoyl chloride, 9.1 g (100%) of expected product are obtained.