Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[N:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[OH:19])=O>CCCCCC>[Cl:2][C:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=1/[CH:17]=[CH:18]\[C:9]#[N:7])=[O:19]
Reactant: O=Nc1ccc2ccccc2c1O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCCCCC
Product: N#C/C=C\c1ccccc1C(=O)Cl

Procedure:
To a rapidly stirring suspension of phosphorus pentachloride (197.5 g) in dry hexane (3.5 liters) is added 167.0 g (0.964 mole) of 2-nitroso-1-naphthol. The mixture is stirred at room temperature for 1 hour after which it is refluxed for 1 hour, cooled slightly and decanted while hot. The residue is boiled with hexane (3.0 liters) for another hour after which the solution is decanted and combined with the first hexane extract. It is evaporated down to dryness. Yield: 200.0 g (crude). This residue is extracted with hexane (2.0 liters), the hexane decanted, cooled, and the resultant crystals are filtered off. The filtrate is used to reestract additional compound from the above residue (the reextraction being repeated four times) with cooling and filtering of the crystals obtained each time. Yield: 79.0 g (42.5%), mp=72°-74°.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[S:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:1][CH2:2][C:3]1[N:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[S:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1COC1CCCCO1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a 1-L round-bottom flask equipped with a magnetic stir-bar and a N2inlet was added Ethyl 4-(hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate (42g, 0.127moles, 1eq) and dry CH2Cl2(300ml) at room temperature. This was followed by the addition of 3,4-dihydro-2H-pyran (14ml, 0.152moles, 1.2eq) as a neat liquid and pyridinium p-toluenesulfonate (6.4g, 25.4mmoles, 20mol %). The reaction mixture was stirred at room temperature overnight (10hrs). The volatiles were then removed in vacuo and the residue was purified by flash silica gel chromatography (10% EtOAc/Hexanes to 30% EtOAc/Hexanes) to yield 34g (64%) of pure title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@H:3]([N:7]1[CH2:15][C:14]2[C:9](=[CH:10][C:11]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:36])[C:24]4[CH:29]=[CH:28][C:27]([N:30]5[CH2:35][CH2:34]O[CH2:32][CH2:31]5)=[N:26][CH:25]=4)=[CH:18][CH:17]=3)=[CH:12][CH:13]=2)[C:8]1=[O:37])[C:4]([OH:6])=[O:5].CC(C)[C@H](N1CC2C(=CC(C3C=CC(NC(=O)C4C=CC(N5CCCC5)=NC=4)=CC=3)=CC=2)C1=O)C(OC)=O>>[CH3:38][CH:2]([CH3:1])[C@H:3]([N:7]1[CH2:15][C:14]2[C:9](=[CH:10][C:11]([C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:36])[C:24]4[CH:29]=[CH:28][C:27]([N:30]5[CH2:31][CH2:32][CH2:34][CH2:35]5)=[N:26][CH:25]=4)=[CH:20][CH:21]=3)=[CH:12][CH:13]=2)[C:8]1=[O:37])[C:4]([OH:6])=[O:5]
Reactant: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(N5CCOCC5)nc4)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(N5CCCC5)nc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(N5CCCC5)nc4)cc3)cc2C1=O
Yield: 67 %

Procedure:
The compound of example 217 was prepared analogous to compound of example 213 by hydrolysis of compound of example 216.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]3=[O:25])[CH2:12][CH2:11]2)=[N:4][CH:5]=[N:6][C:7]=1[NH:8][CH3:9].[CH3:26][C:27]1[N:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][N:28]=1>CN(C=O)C.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[CH3:9][N:8]1[C:33]([C:30]2[CH:29]=[N:28][C:27]([CH3:26])=[N:32][CH:31]=2)=[N:1][C:2]2[C:7]1=[N:6][CH:5]=[N:4][C:3]=2[N:10]1[CH2:11][CH2:12][CH:13]([N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:17]2=[O:25])[CH2:14][CH2:15]1
Reactant: Cc1ncc(C=O)cn1
Reactant: CNc1ncnc(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)c1N
Agent: Cl[Fe](Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncc(-c2nc3c(N4CCC(n5c(=O)[nH]c6ccccc65)CC4)ncnc3n2C)cn1
Temperature: 90 °C
Yield: 51.7 %

Procedure:
To a solution of 1-(1-(5-amino-6-(methylamino)pyrimidin-4-yl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (300 mg, 0.88 mmol) in anhydrous DMF (5 mL) were added 2-methylpyrimidine-5-carbaldehyde (108 mg, 0.88 mmol) and Iron (III) chloride hexahydrate (0.88 g, 0.24 mmol). The dark brown solution was heated to 90° C. for 14 hour in an open air vessel. The reaction mixture was cooled to room temperature and poured over ice (5 g). The resulting mixture was extracted with ethyl acetate (50 mL), the organic layer was washed with brine (10 mL), and dried over MgSO4. The solution was filtered, and concentrated under reduced pressure. The resulting solids were triturated with 15 mL of diethyl ether (15 mL) for 30 min. The precipitate was collected by vacuum filtration to give 201 mg (51% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 9.16 (s, 2H), 8.33 (s, 1H), 7.18-7.11 (m, 1H), 6.98-6.87 (m, 3H), 4.55 (t, 1H), 3.86 (s, 3H), 2.71 (s, 3H), 2.34 (dd, 2H), 1.84 (d, 2H); MS (EI) for C23H23N9O: 442.3 (MH+).
Reaction SMILES: [C:1]([C:4]1[N:5]([CH3:13])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([CH3:3])=[CH2:2].[CH2:14]([N:21]1[C:25](=[O:26])[CH:24]=[CH:23][C:22]1=[O:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([N:21]1[C:25](=[O:26])[CH:24]2[CH:23]([CH2:2][CH:1]([CH3:3])[C:4]3[N:5]([CH3:13])[C:6]4[C:11]([C:12]=32)=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:22]1=[O:27])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Reactant: C=C(C)c1cc2ccccc2n1C
Product: CC1CC2C(=O)N(Cc3ccccc3)C(=O)C2c2c1n(C)c1ccccc21
Yield: 68.6 %

Procedure:
850 mg of 2-isopropenyl-1-methylindole and 980 mg of N-benzylmaleimide were stirred at 110° C. for 30 minutes. The resulting solid was recrystallized from 10 ml of ethanol to obtain 1.22 g (yield: 69%) of N-benzyl-1-methyl-9-methyl-1,2,3,4-tetrahydrocarbazole-3,4-dicarboximide as colorless needles.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].N([O-])=O.[Na+].[N-:14]=[N+:15]=[N-].[Na+]>FC(F)(F)C(O)=O.O>[N:1]([C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccccc1CO
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: [N-]=[N+]=Nc1ccccc1CO
Reaction time: 0.75 h
Yield: 72.3 %

Procedure:
To a solution of 2-aminobenzyl alcohol (12.0 g, 97.4 mmol) in 50 mL of trifluoroacetic acid at 0° C. was added sodium nitrite (7.39 g, 107.2 mmol). This solution was stirred for 45 min and then there was added sodium azide (6.33 g, 97.4 mmol) dropwise as a solution in water. The resulting mixture was stirred at 0° C. for 45 min and then was carefully quenched by slow addition of potassium carbonate. The reaction mixture was diluted with ethyl acetate, washed with brine, dried (MgSO4), filtered through a pad of silica gel and concentrated to afford 10.5 g (72%) of the title compound which was used without further purification. 1H NMR (CDCl3) δ7.33 (m, 2H), 7.14 (m, 2H), 4.59 (s, 2H), 2.69 (broad s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[CH3:27])[C:6]1[N:7]=[C:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[S:9][C:10]=1[C:11]#[N:12])=[O:4].[CH3:28][NH:29][CH3:30]>CN(C)C=O.CCOC(C)=O>[Cl:26][C:22]1[C:21]([CH3:27])=[C:20]([CH2:19][N:5]([C:6]2[N:7]=[C:8]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:9][C:10]=2[C:11]#[N:12])[C:3](=[O:4])[CH2:2][N:29]([CH3:30])[CH3:28])[CH:25]=[CH:24][CH:23]=1
Reactant: Cc1c(Cl)cccc1CN(C(=O)CCl)c1nc(N2CCOCC2)sc1C#N
Reactant: CNC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1CN(C(=O)CN(C)C)c1nc(N2CCOCC2)sc1C#N
Temperature: 120 °C

Procedure:
To a solution of 2-chloro-N-[(3-chloro-2-methylphenyl)methyl]-N-[5-cyano-2-(4-morpholinyl)-1,3-thiazol-4-yl]acetamide (100 mg, 0.235 mmol) (prepared according to the procedures of example 111) in N,N-Dimethylformamide (DMF) (2 mL) was added dimethyl amine (0.588 mL, 1.176 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 mins. The resultant mixture was diluted in EtOAc (100 mL) and washed with H2O (100 ml×2). The organic layer was concentrated to afford the crude product, which was use in next step without further purification. (88%)
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1=[C:17]([Cl:23])[C:18]([O:20][C:21]1=O)=[O:19]>C(O)(=O)C>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([N:12]2[C:21](=[O:20])[C:16]([Cl:15])=[C:17]([Cl:23])[C:18]2=[O:19])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: Nc1ccc(Oc2ccccc2)cc1
Solvent: CC(=O)O
Product: O=C1C(Cl)=C(Cl)C(=O)N1c1ccc(Oc2ccccc2)cc1

Procedure:
A mixture of 28 g of p-phenoxyaniline and 28 g of dichloromaleic anhydride in 200 ml of glacial acetic acid was heated at reflux for 3 hours. Upon subsequent cooling, N-phenoxyphenyl-2,3 -dichloromaleimide crystallized and was collected by filtration. The 46 g (92% of theory) of crude material was washed with petroleum ether and air-dried. An analytical sample was prepared by recrystallization from glacial acetic acid, producing golden flakes of N-(p-phenoxyphenyl)-2,3-dichloromaleimide melting at 180°-181° C.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]([OH:13])=O)[CH:2]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:29]3[CH2:28][CH2:27][CH2:26][NH:25][C:24]=3[CH:23]=[N:22]2)=[CH:17][CH:16]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(=O)(O)[O-].[Na+]>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:29]3[CH2:28][CH2:27][CH2:26][N:25]([C:11](=[O:13])[CH2:10][N:3]4[C:4]5=[N:5][CH:6]=[CH:7][CH:8]=[C:9]5[N:1]=[CH:2]4)[C:24]=3[CH:23]=[N:22]2)=[CH:19][CH:20]=1
Reactant: O=C(O)Cn1cnc2cccnc21
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cn1cnc2cccnc21)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.4 %

Procedure:
A mixture of 2-imidazo[4,5-b]pyridin-3-ylacetic acid (251.7 mg, excess), 1-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[4,3-b]pyridine (42.7 mg, 0.23 mmol), triethyl amine (200 μL, 1.4 mmol), and HATU (87.9 mg, 0.23 mmol) in DMF (1 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with 10 mL of aqueous saturated sodium bicarbonate, and extracted with EtOAc (2×15 mL). The combined organic layers were then washed with water (2×20 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 10% MeOH in EtOAc) to afford the desired product (26.1 mg, 0.07 mmol, 30%). 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J=7.2 Hz 1H), 8.50 (s, 0.8H), 8.25 (s, 0.2H), 8.12 (d, J=5.6 Hz, 1H), 7.45 (m, 2H), 7.28 (m, 1H), 7.15 (m, 2H), 5.46 (s, 0.2H), 5.33 (s, 0.8H), 3.95 (m, 2H), 2.88 (m, 2H), 2.15 (m, 2H); MS: (ES) m/z calculated for C20H17FN6O [M+H]+ 377.1, found 377.1.
Reaction SMILES: [F:1][C:2]1[C:16]([F:17])=[CH:15][C:5]2[NH:6][C:7]([CH2:9][C@@H:10]3[CH2:14][CH2:13][CH2:12][NH:11]3)=[N:8][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:29][C:28]([CH2:30][OH:31])=[N:27][C:26]=2[C:32](O)=[O:33])=[CH:21][CH:20]=1>>[F:1][C:2]1[C:16]([F:17])=[CH:15][C:5]2[NH:6][C:7]([CH2:9][C@@H:10]3[CH2:14][CH2:13][CH2:12][N:11]3[C:32]([C:26]3[N:27]=[C:28]([CH2:30][OH:31])[S:29][C:25]=3[C:22]3[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=3)=[O:33])=[N:8][C:4]=2[CH:3]=1
Reactant: Fc1cc2nc(C[C@@H]3CCCN3)[nH]c2cc1F
Reactant: O=C(O)c1nc(CO)sc1-c1ccc(F)cc1
Product: O=C(c1nc(CO)sc1-c1ccc(F)cc1)N1CCC[C@H]1Cc1nc2cc(F)c(F)cc2[nH]1

Procedure:
The title compound (65 mg) was prepared from 5,6-difluoro-2-(S)-1-pyrrolidin-2-ylmethyl-1H-benzoimidazole, D27 (153 mg) and 5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazole-4-carboxylic acid (205 mg) according to a procedure similar to that for Example 4.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:3][CH2:2]1.[C:28](#[N:31])[CH:29]=[CH2:30]>>[N:27]1[C:19]([NH:18][C@H:16]([C:8]2[N:7]([CH:4]3[CH2:5][CH2:6][N:1]([CH2:30][CH2:29][C:28]#[N:31])[CH2:2][CH2:3]3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH3:17])=[C:20]2[C:24]([NH:23][CH:22]=[N:21]2)=[N:25][CH:26]=1
Reactant: C=CC#N
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCNCC1
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCN(CCC#N)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 32.6 %

Procedure:
A mixture of [(S)-1-(1-piperidin-4-yl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine 113 (75 mg, 0.207 mmol) and acrylonitrile (75 μL, 1.14 mmol) in IMS (3 mL) was stirred in a sealed tube at 70° C. for 3 h. After cooling to RT, the crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined, concentrated in vacuo and purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM), followed by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 20 min gradient 5-60% 0.1% NH4OH in acetonitrile/water) and finally loaded into an Isolute® SCX-2 which was washed with MeOH and the product eluted with 2M NH3/MeOH. The ammonia fractions were combined and concentrated in vacuo affording 126 as a white solid (28 mg, 33%). LCMS: RT 1.67 min [M+H]+ 416.1. 1H NMR (CDCl3, 400 MHz): δ 8.52 (1H, s), 7.96 (1H, s), 7.80-7.73 (1H, m), 7.65-7.59 (1H, m), 7.26-7.08 (3H, m), 5.29 (1H, bs), 4.69-4.57 (1H, m), 3.09 (1H, bd, J=11.28 Hz), 2.90 (1H, d, J=11.11 Hz), 2.76-2.60 (3H, m), 2.37-2.25 (3H, m), 2.30-2.30 (1H, m), 1.98-1.66 (7H, m)
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[N:17]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:16]=[N:15][C:14]=1[C:30]([NH2:32])=[O:31]>CC(C)=O>[C:1]([NH:9][C:10]([NH:12][C:13]1[N:17]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:16]=[N:15][C:14]=1[C:30]([NH2:32])=[O:31])=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NC(=O)c1ncn(OCCCOCc2ccccc2)c1N
Solvent: CC(C)=O
Product: NC(=O)c1ncn(OCCCOCc2ccccc2)c1NC(=S)NC(=O)c1ccccc1
Yield: 95.9 %

Procedure:
Benzoylisothiocyanate (1.0 ml, 7.6 mmol) in acetone (100 ml) was added to a solution of 5-amino-1-(3-benzyloxyprop-1-oxy)imidazole-4-carboxamide (2.0 g, 6.9 mmol) in hot acetone (200 ml). The solution was boiled under reflux for 6 hours, cooled, evaporated under reduced pressure, and the residue chromatographed on silica gel (eluted with chloroform and then chloroform-ethanol, 30:1), yielding the title compound (3.0 g, 96%), IR: υmax (KBr) 3470, 3300, 3130, 1670, 1610, 1535, 1495 cm-1. 1H NMR: δH [(CD3)2SO] 1.93 (2H, quintet, J=6.3 Hz, CH2CH2CH2), 3.54 (2H, t, J=6.3 Hz, CH2OCH2Ph), 4.39 (4H, m, CH2ON, CH2Ph), 7.12 (1H, CONH), 7.25 (6H, m, PhCH2, CONH), 7.54 (2H, t, 2 protons of PhCO), 7.68 (1H, t, 1 proton of PhCO), 8.10 (3H, m, H-2, 2 protons of PhCO), 11.95 (2H, br.s, 2 x NH).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH:5]=[N+]=[N-])[CH3:2].C(OC(OCC)CNC(N)=O)C.[Cl:23][CH2:24][C:25](=[O:49])[C@:26]1([OH:48])[C@:43]2([CH3:44])[C@H:29]([C@H:30]3[C@H:40]([C@@H:41]([OH:45])[CH2:42]2)[C@:38]2([CH3:39])[C:33](=[CH:34][C:35](=[O:46])[CH:36]=[CH:37]2)[CH2:32][CH2:31]3)[CH2:28][C@H:27]1[OH:47]>CO>[Cl:23][CH2:24][C:25](=[O:49])[C@:26]1([OH:48])[C@:43]2([CH3:44])[C@H:29]([C@H:30]3[C@H:40]([C@@H:41]([OH:45])[CH2:42]2)[C@:38]2([CH3:39])[C:33](=[CH:34][C:35](=[O:46])[CH:36]=[CH:37]2)[CH2:32][CH2:31]3)[CH2:28][C@H:27]1[O:47][CH2:5][CH:4]([O:8][CH2:9][CH3:10])[O:3][CH2:1][CH3:2]
Reactant: CCOC(C=[N+]=[N-])OCC
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](O)[C@]2(O)C(=O)CCl
Agent: CCOC(CNC(N)=O)OCC
Solvent: CO
Product: CCOC(CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CCl)OCC
Temperature: 0 °C

Procedure:
A solution of 2,2-diethoxy-1-diazoethane (prepared from 0.0935 mole of N-2,2-diethoxyethyl urea by the method of W. Kirmse and M. Buschhoff, Chem. Ber., 100, 1491 (1967)) in 300 ml of 3:2 ether-pentane is diluted with 100 ml of methanol and cooled to 0°C. 21-Chloro-11β,16α,17-trihydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate is added in portions until nitrogen evolution ceases. The solvent is removed in vacuo to yield the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:35])=[C:24]([N:27]3[C:31](=[O:32])[CH2:30][N:29]([CH3:33])[C:28]3=[O:34])[CH:25]=2)[NH:20][C:19](=[O:36])[C:18]=1[C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[C:39]([CH3:44])[CH:38]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1.C(Cl)Cl>[Cl:35][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][CH2:15][CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[C:18]([C:37]3[CH:42]=[C:41]([CH3:43])[CH:40]=[C:39]([CH3:44])[CH:38]=3)[C:19](=[O:36])[NH:20]2)=[CH:25][C:24]=1[N:27]1[C:31](=[O:32])[CH2:30][N:29]([CH3:33])[C:28]1=[O:34]
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(N4C(=O)CN(C)C4=O)c(Cl)cc3[nH]c2=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3)c3cc(N4C(=O)CN(C)C4=O)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C

Procedure:
To a solution of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-(3-methyl-2,5-dioxoimidazolidin-1-yl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester in 2.0 dry methylene chloride was added a few drops of anisole followed by 1.0 mL of trifluoroacetic acid and the mixture stirred at room temperature. After 1 hour the solvents were removed in vacuo and the resulting residue purified by flash chromatography on silica gel (methylene chloride:ammonium hydroxide:methanol, 96:1:3) to give the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][CH:14]1[C:21](=[O:22])[N:20]2[CH:23]([C:26]([OH:28])=O)[CH2:24][CH2:25][CH:19]2[CH2:18][CH:17]=[CH:16][CH2:15]1)=[O:12].CCN=C=NCCCN(C)C.[NH2:40][CH:41]([CH2:56][C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C:42](=[O:55])[CH2:43][O:44][C:45](=[O:54])[C:46]1[C:51]([CH3:52])=[CH:50][CH:49]=[CH:48][C:47]=1[CH3:53].C(N(CC)CC)C>ClCCl>[C:60]([O:59][C:57]([CH2:56][CH:41]([NH:40][C:26]([CH:23]1[N:20]2[C:21](=[O:22])[CH:14]([NH:13][C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[O:12])[CH2:15][CH:16]=[CH:17][CH2:18][CH:19]2[CH2:25][CH2:24]1)=[O:28])[C:42](=[O:55])[CH2:43][O:44][C:45](=[O:54])[C:46]1[C:47]([CH3:53])=[CH:48][CH:49]=[CH:50][C:51]=1[CH3:52])=[O:58])([CH3:63])([CH3:61])[CH3:62]
Reactant: Cc1cccc(C)c1C(=O)OCC(=O)C(N)CC(=O)OC(C)(C)C
Reactant: O=C(NC1CC=CCC2CCC(C(=O)O)N2C1=O)c1ccc2ccccc2c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1C(=O)OCC(=O)C(CC(=O)OC(C)(C)C)NC(=O)C1CCC2CC=CCC(NC(=O)c3ccc4ccccc4c3)C(=O)N21

Procedure:
To a solution of 6-[(naphthalene-2-carbonyl)-amino]-5-oxo-1,2,3,5,6,7,10,10a-octahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid, (124 mg, 0.33 mmol)in dichloromethane is added EDCI (191 mg, 1 mmol), 2,6-dimethyl-benzoic acid 3-amino-4-tert-butoxycarbonyl-2-oxo-butyl ester, 111, (200 mg, 0.62 mmol), and triethylamine (150 ul). After consumption of the starting material, the reaction is washed with 1N HCl (1×50 ml), water (1×50 ml), and brine (1×50 ml). The CHCl2 is reduced in vacuo. The residue is used directly in the next step without purification. ESI MS 696.1 (M+H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:3])[CH3:2].Cl[CH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]1[C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[N:26][C:27]([Cl:33])=[CH:28][CH:29]=2)[N:24]=1.N12CCCN=C1CCCCC2>CN(C)C=O>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]1[C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[N:26][C:27]([Cl:33])=[CH:28][CH:29]=2)[N:24]=1)=[O:10])(=[O:3])[CH3:2]
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: CC(=O)NCCCCC(=O)O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)NCCCCC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 36.5 %

Procedure:
The procedure is as in Example 24, but starting with 5-acetamidopentanoic acid (5 g) in dimethylformamide (66 cc), 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (6.6 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.7 cc). After recrystallization in acetonitrile, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 5-acetamidopentanoate (3.3 g), m.p. 185° C., is obtained.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([F:14])([F:13])[F:12].[H-].[Na+].[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>CN(C=O)C>[CH3:34][S:35]([N:25]1[C:26]2[C:22](=[C:21]([C:18]3[N:17]=[C:16]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:15])[C:11]([F:12])([F:13])[F:14])=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:4]=4)[O:20][N:19]=3)[CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:24]1)(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: CC(Oc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1C(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Oc1ccc(-c2nc(-c3cccc4c3ccn4S(C)(=O)=O)no2)cc1C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole (80 mg) in DMF (0.80 ml) was added 60% NaH (8.7 mg) at 0° C., followed by stirring at room temperature for 0.5 hour. Methanesulfonyl chloride (21.1 μl) was added thereto at 0° C., followed by stirring at room temperature for 3 hours. To the reaction solution was added water (30 ml), followed by extraction three times with EtOAc (20 ml). The organic layer was combined, washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. The filtrate was purified by silica gel column chromatography (automatic purifier, chloroform:CH3OH=100:0 to 98:2) to obtain 1-(methylsulfonyl)-4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole (15.6 mg) as a white solid.