Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=O)(=O)C.[CH3:13][NH:14][NH2:15]>CO>[CH3:13][N:14]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:1]=[N:15]1
Reactant: CC(=O)C1C(=O)CCCCC1=O
Reactant: CNN
Solvent: CO
Product: Cn1ncc2c1CCCCC2=O
Temperature: 0 °C

Procedure:
To an ice-cold solution of 21 grams of 2-acetyl-1,3-cycloheptanedione in 180 ml of methanol was added, dropwise, a solution of 6.2 ml of methylhydrazine in 30 ml of methanol. The resulting reaction mixture was heated at reflux for 1 hour and the solvent was then removed under reduced pressure. The residual material was partitioned between dichloromethane and brine, the aqueous layer was extracted twice with dichloromethane, and the combined organic layers were dried over magnesium sulfate. The solvent was removed under reduced pressure to leave a dark oil which crystallized on standing. The solid was recrystallized from a mixture of ether and hexane to give 5,6,7,8-tetrahydro-1-methyl-4(1H)-cycloheptapyrazolone as a yellow crystalline solid melting at about 95°-97° C.
Reaction SMILES: [CH3:1][Mg]Cl.[CH2:4]1[C:13]2[C:12]3[CH:14]=[CH:15][C:16]([C:18]([C:20]4[N:21]=[CH:22][NH:23][CH:24]=4)=[O:19])=[CH:17][C:11]=3[CH:10]=[CH:9][C:8]=2[O:7][CH2:6][CH2:5]1.[Cl-].[NH4+]>C(OCC)C.C1COCC1>[CH2:4]1[C:13]2[C:12]3[CH:14]=[CH:15][C:16]([C:18]([C:20]4[N:21]=[CH:22][NH:23][CH:24]=4)([OH:19])[CH3:1])=[CH:17][C:11]=3[CH:10]=[CH:9][C:8]=2[O:7][CH2:6][CH2:5]1
Reactant: C[Mg]Cl
Reactant: O=C(c1ccc2c3c(ccc2c1)OCCC3)c1c[nH]cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)(c1ccc2c3c(ccc2c1)OCCC3)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of methylmagnesium chloride in diethyl ether (3M; 3 mL) was added to a solution of (2,3-dihydro-1H-benzo[f]chromen-8-yl)(1H-imidazol-4-yl)ketone (0.50 g) in THF (20 ml) at 0° C. The mixture was stirred at room temperature for 3 h. Aqueous ammonium chloride solution was added to the mixture and extracted with ethyl acetate. The extract was dried and concentrated. The residue was washed with ethyl acetate to give the titled compound (0.49 g) as a colorless solid.
Reaction SMILES: C([N:5]([CH2:10]CCC)CCCC)CCC.[C:14]([NH:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26]C(N=[N+]=[N-])=O)[CH:21]=[CH:22][C:23]=1[CH3:24])(=[O:16])[CH3:15].CCCCCC.C1([O:44]C2C=CC=CC=2)C=CC=CC=1>>[CH3:24][C:23]1[CH:22]=[C:21]2[C:20]([CH:25]=[CH:26][NH:5][C:10]2=[O:44])=[CH:19][C:18]=1[NH:17][C:14](=[O:16])[CH3:15]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CCCCN(CCCC)CCCC
Reactant: CC(=O)Nc1cc(C=CC(=O)N=[N+]=[N-])ccc1C
Solvent: CCCCCC
Product: CC(=O)Nc1cc2cc[nH]c(=O)c2cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of diphenyl ether (250 mL) and tributylamine (11.9 mL, 49.9 mmol) at 220-240° C. is added a slurry of 3-(3-acetylamino-4-methyl-phenyl)-acryloyl azide (12.2 g, 49.9 mmol) in diphenyl ether. After 2 hours, the yellow solution is cooled to room temperature and poured over hexane (800 mL). A brown solid precipitates out and the title product (3.56 g, 16.5 mmol) is obtained as a light yellow solid by recrystallization from DMF/MeOH.
Reaction SMILES: [N+](=[CH2:3])=[N-].[C:4]([NH:12][C@H:13]1[C:20](=[O:21])[N:19]2[C@@H:14]1[O:15][CH2:16][C:17]([OH:29])=[C:18]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCOCC.C(Cl)Cl>[C:4]([NH:12][C@H:13]1[C:20](=[O:21])[N:19]2[C@@H:14]1[O:15][CH2:16][C:17]([O:29][CH3:3])=[C:18]2[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])(=[O:11])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)C1=C(O)CO[C@@H]2[C@@H](NC(=O)c3ccccc3)C(=O)N12
Solvent: CCOCC
Solvent: ClCCl
Product: COC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](NC(=O)c3ccccc3)[C@H]2OC1
Yield: 62 %

Procedure:
A solutin of diazomethane in ether was added to a solution of 260 mg (0.72 mmol) of tert.-butyl (6R, 7R)-7-benzoylamino-3-hydroxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate in 3 ml of anhydrous methylene chloride at room temperature until a yellow coloration remained. The solvent and excess diazomethane were then evaporated off in vacuo and the residue was chromatographed on 18 g of silica gel (toluene:ethyl acetate 2:3). 169 mg (62%) of the title compound were obtained as a colorless rigid foam.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([F:25])([F:24])[F:23])[CH:16]=2)[C:13](=[O:26])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:27])[N:6]=1)[CH2:3][CH3:4].Cl[C:29]1[CH:34]=[CH:33][N:32]=[C:31]2[NH:35][CH:36]=[N:37][C:30]=12.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:37]1[C:30]2[C:31](=[N:32][CH:33]=[CH:34][C:29]=2[NH:1][C@H:2]([C:5]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([F:25])([F:23])[F:24])[CH:16]=3)[C:13](=[O:26])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[F:27])[N:6]=2)[CH2:3][CH3:4])[NH:35][CH:36]=1
Reactant: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(CC(F)(F)F)c1
Reactant: Clc1ccnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CC[C@H](Nc1ccnc2[nH]cnc12)c1nc2cccc(F)c2c(=O)n1-c1cccc(CC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
Under nitrogen, to (S)-2-(1-aminopropyl)-5-fluoro-3-(3-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (38 mg, 0.10 mmol, 1.0 equiv) in t-BuOH (0.5 mL) at 23° C. is added 7-chloro-3H-imidazo[4,5-b]pyridine (23 mg, 0.15 mmol, 1.5 equiv) and diisopropylethylamine (63 μL, 0.36 mmol, 4.0 equiv). After stirring for 48 hr at 120° C. in a sealed tube, the reaction mixture is concentrated in vacuo and the residue is purified by preparative TLC eluting with CH2Cl2/MeOH to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].O>CS(C)=O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 150 °C

Procedure:
A mixture of 2 g (11.6 mmol) 5-chloro-2-nitro-phenylamine, 2.14 g (11.6 mmol) piperazine-1-carboxylic acid tert-butyl ester and 1.3 g (11.6 mmol) 1,4-diazo-bicyclo[2.2.2]octane in 20 ml DMSO was heated to 150° C. for 16 h. The mixture was poured onto 200 ml water and extracted with 250 ml ethyl acetate. The emulsion was filtered through decalite and the aqueous phase was extracted with 2×200 ml. The combined organic phases were washed with 2×100 ml water, dried with MgSO4 and evaporated to dryness. The residue was purified with column chromatography on silica eluting with ethyl acetate/hexane to yield the title compound as a yellow solid. MS(ISP): 321.2 (M−H)−.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3]C([O-])=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:17])C=CC=CC=1.C([N:29]([CH2:32]C)CC)C>C1(C)C=CC=CC=1>[CH3:9][O:8][C:1]([CH2:2][CH2:3][N:29]=[C:32]=[O:17])=[O:7]
Reactant: COC(=O)CCC(=O)[O-]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)CCN=C=O
Reaction time: 3 h
Yield: 52.3 %

Procedure:
In 600 ml of dry toluene was dissolved 26.4 g of monomethyl succinate, followed by the addition of 55 g of diphenylphosphorylazide and 22 g of triethylamine. The mixture was allowed to stand at room temperature with stirring for 3 hours, after which it was washed with water and dried. The solvent was concentrated to about one-third of its original volume and, finally, the mixture was refluxed for 2 hours. After the solvent was completely evaporated off, the residue was distilled under reduced pressure. By the above procedure there was obtained 13.6 g of the above-indicated compound. b.p.8 : 64°-66° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:25])=[CH:20][CH:19]=1>>[C:4](#[N:3])[CH3:5].[O:25]=[C:24]([C:21]1[CH:22]=[CH:23][C:18]([NH:1][C:2]2[N:7]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:19][CH:20]=1)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cc1ccccc1)c1ccc(Br)cc1
Reactant: Nc1nccc(-c2cnc3ccccn23)n1
Product: CC#N
Product: O=C(Cc1ccccc1)c1ccc(Nc2nccc(-c3cnc4ccccn34)n2)cc1
Yield: 10 %

Procedure:
The title compound was prepared from 2-amino-4-(imidazo[1,2-a]pyridin- 3-yl)pyrimidine and benzyl 4-bromophenyl ketone following the general method of Example 2. The crude product was purified by column chromatography on silica gel using chloroform/ethanol, 98:2, as the eluent followed by recrystallization from acetonitrile affording 30 mg (10% yield) of the title compound as an off-white solid: mp (decomp.) 225-228° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.15 (broad s, 2 H), 8.67 (s, 1 H), 8.53 (d, J=5.3 Hz, 1 H), 8.06 (d, J=7.3 Hz, 2 H), 7.95 (d, J=7.3 Hz, 2 H), 7.80 (d, J=8.7 Hz, 1 H), 7.54-7.51 (m, 2 H), 7.32-7.16 (m, 6 H), 4.33 (s, 2 H); 13C NMR (400 MHz, DMSO-d6) δ 195.8, 158.9, 157.2, 156.9, 148.0, 145.1, 138.9, 135.5, 129.7, 129.5, 129.3, 129.2, 128.2, 127.1, 126.3, 120.9, 117.9, 117.3, 113.8, 108.2, 44.3; MS (ESP) m/z 406 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][NH:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[NH:16]([C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])[C@H:17]([C:43](O)=[O:44])[CH2:18][C:19]1[N:23]=[CH:22][N:21]([C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(#N)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][N:6]([C:43](=[O:44])[C@@H:17]([NH:16][C:46]([O:48][CH2:49][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)=[O:47])[CH2:18][C:19]1[N:23]=[CH:22][N:21]([C:24]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:20]=1)[CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9]
Reactant: O=C(N[C@@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)CCNCC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)CCN(CC(=O)OC(C)(C)C)C(=O)[C@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of the compound from Step 1 (0.434 g, 2 mmol) in methylene chloride (10 mL) was added Cbz-His(Trt)-OH (1.062 g, 2 mmol), triethylamine (0.8 mL, 5.7 mmol) and HBTU (0.758 g, 2 mmol) dissolved in acetonitrile (10 mL). The reaction mixture was stirred overnight at room temperature. The solution was concentrated, the residue taken up in ethyl acetate and washed three times with saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo. Chromatography was carried out on silica gel, using 30% hexanes in ethyl acetate as eluent, to give an oil; 1.38 g (94% yield). MS-APCI: M+1=732.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([N:9]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[C:20]2[NH:24][N:23]=[N:22][N:21]=2)[C:10]([NH2:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C([O-])(=O)C.[Na+]>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[C:5]([N:9]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:27](=[O:29])[CH3:28])=[CH:15][C:14]=2[C:20]2[NH:24][N:23]=[N:22][N:21]=2)[C:10]([NH2:12])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: NC(=O)N(c1cccc(C(F)(F)F)c1)c1ccc(N)cc1-c1nnn[nH]1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)Nc1ccc(N(C(N)=O)c2cccc(C(F)(F)F)c2)c(-c2nnn[nH]2)c1
Temperature: 0 °C

Procedure:
To a solution of 3-trifluoromethylphenyl-4-amino-2-(5-tetrazolyl)phenyl urea (0.22 g, 0.6 mmol) in 17% aqueous sodium acetate (5 mL), cooled on an ice bath, was added acetic anhydride (1 mL). The reaction was stirred at 0° C. for another hour. The precipitate was filtered off and re-crystallised from 96% ethanol to give 0.12 g of the desired material. M.p. 280-282° C.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:17])(=[O:16])[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.O1COCO[CH2:19]1>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[C:11]([C:10]1[CH:14]=[C:15]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:17])[O:16][CH2:19]2)([OH:13])=[O:12]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: C1OCOCO1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc2c(c1)COC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
To 153 ml of fuming sulfuric acid, containing about 27% of SO3, 50 g (0.3 m) of terephthalic acid are added, under stirring, at room temperature, then 23 g (0.25 m) of 1,3,5-trioxane are added thereinto in two portions, by cooling to a temperature of 15-18° C. after any addition. At the end of the addition, the mixture is left 30 minutes under stirring at room temperature, then it is heated at 135-145° C. and let under stirring for 2-2.5 hours at this temperature until the end of the reaction. The reaction mixture is cooled to a temperature lower than 3° C., then 100 ml of glacial acetic are added thereto by keeping the temperature at about 25° C. At the end of the addition, the mixture is let to stand 60 minutes under stirring at 20-25° C. and filtered. The wet product is suspended in 1900 ml of water. The suspension is heated up to 25-30° C. under stirring, its pH is adjusted to about 8 by gradual addition of 175 g of sodium bicarbonate. The solid is filtered off on Celite® by washing with hot water (40-45° C.). The pH of the mother liquors is brought to 1.5 by addition of about 125 ml of 37% hydrochloric acid and the obtained precipitate is filtered at 20-25° C. by washing with water until the filtrate reaches a neutral pH. Thus, 32 g of 5-carboxyphthalide with a titer (HPLC)>93% are obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)=[CH2:2].[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]2[O:13][CH2:12][CH2:11][O:8]2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: OCCO
Reactant: C=Cc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1ccc(C2OCCO2)cc1
Temperature: 45 °C
Yield: 96.3 %

Procedure:
In a 250 ml 3-necked round-bottomed flask, 13.72 g of (103 mmol) of 4-vinylbenzaldehyde, 7.08 g (114 mmol) of ethylene glycol and 0.23 g (1.3 mmol) of p-toluenesulfonic acid are added to 100 ml of toluene. The resulting mixture is refluxed at 45° C. under reduced pressure for 3 hours using a water separator. It is then washed twice with 100 ml of water, and the organic phase is dried over magnesium sulfate and concentrated to yield 17.47 g of crude product in the form of a pale yellow oil. The latter is distilled at 80° C./0.05 mbar. Yield: 12.81 g (72.7 mmol, 70.6% of the theoretical yield). 1H-NMR (CDCl3, 100 mHz): δ7.39/s/4H, 6.68/dd (J1 =11 Hz, J2 =18 Hz)/1H, 5.74/s/1H, 5.72 (J1 =18 Hz, J2 =2 Hz)/1H, 5.22/dd (J1 =11 Hz, J2 =2 Hz)/1H, 3.96/m/4H.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH:14]1([NH:17][C:18](=[O:36])[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=3)[CH:20]=2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C(#N)C>[CH:14]1([NH:17][C:18](=[O:36])[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([NH:26][C:27](=[O:35])[C:28]3[CH:29]=[CH:30][C:31]([O:9][CH2:8][C:3]4[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=4)=[CH:32][CH:33]=3)[CH:20]=2)[CH2:16][CH2:15]1
Reactant: Cc1cccnc1CO
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ncccc2C)cc1
Temperature: 80 °C
Yield: 102.2 %

Procedure:
To (3-methylpyridine-2-yl)methanol (157 mg, 1.272 mmol) in DCM (5 mL) was added thionyl chloride (200 μl) and the mixture stirred and heated at reflux for 4 h. The mixture was evaporated to dryness. To the residue was added N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide (197 mg, 0.636 mmol) and potassium carbonate (176 mg, 1.27 mmol) in acetonitrile (5 mL) and the resulting mixture heated at 80° C. for 16 h. The reaction mixture was cooled and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic phase was concentrated under reduced pressure. Precipitation with DCM in diethyl ether gave the title compound as a solid (270 mg); NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.68 (m, 2H), 2.26 (s, 3H), 2.40 (s, 3H), 2.86 (m, 1H), 5.30 (s, 2H), 7.17 (d, 2H), 7.33 (m, 2H), 7.65 (m, 2H), 7.82 (s, 1H), 7.97 (d, 2H), 8.39 (m, 2H), 9.81 (s, 1H); Mass Spectrum: M+H+ 416.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[CH3:8][C:9]1([CH3:21])[S:13][C@@H:12]2[C@H:14]([NH2:17])[C:15](=[O:16])[N:11]2[C@H:10]1[C:18]([OH:20])=[O:19].Cl[C:23]1[C:28]([O:29][C:30](=[O:47])[CH:31]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:32](OC2C=CC=CC=2)=[O:33])=[C:27](Cl)[C:26](Cl)=[C:25](Cl)[C:24]=1Cl>C(Cl)Cl>[CH2:1]([NH+:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[O:29]([C:30]([CH:31]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:32]([NH:17][CH:14]1[C:15](=[O:16])[N:11]2[CH:10]([C:18]([O-:20])=[O:19])[C:9]([CH3:21])([CH3:8])[S:13][C@H:12]12)=[O:33])=[O:47])[C:28]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Oc1ccccc1)C(C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)c1ccccc1
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)S[C@@H]2C(NC(=O)C(C(=O)Oc3ccccc3)c3ccccc3)C(=O)N2C1C(=O)[O-]
Product: CC[NH+](CC)CC
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
11.2 ml. (0.08 moles) or triethylamine are added to a suspension of 8.63 g (0.04 moles) of 6-APA in 120 ml. of methylene chloride. The obtained solution is cooled to 0° C. and 21 g. (0.04 moles) of phenylmalonic acid phenylester pentachlorophenylester are added in small portions so that the temperature of the mixture does not rise above +5° C. The mixture is stirred at 0° to +5° C. for one hour, thereafter the solvent is evaporated in vacuo, and the residue is triturated with 150 ml. of ethyl acetate. The separated crystalline substance is filtered off, and washed with ethyl acetate. 20 g. (90%) of 6-(α-phenoxycarbonyl-phenylacetamido)-2,2-dimethyl-penam-3-carboxylic acid triethylammonium salt are obtained. M.p.: 125°-130° C.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]=[N:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[NH:28][S:29]([C:32]1[CH:33]=[C:34]([S:38]([OH:41])(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30].CN1CCCC1=O.P(Cl)(Cl)([Cl:51])=O>>[S:38]([Cl:51])([OH:41])(=[O:40])=[O:39].[OH:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]=[N:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[NH:28][S:29]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)(=[O:30])=[O:31]
Reactant: CS(=O)(=O)c1cc([N+](=O)[O-])ccc1N=Nc1ccc(O)c2cccc(NS(=O)(=O)c3cccc(S(=O)(=O)O)c3)c12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na]
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1cc([N+](=O)[O-])ccc1N=Nc1ccc(O)c2cccc(NS(=O)(=O)c3ccccc3)c12
Product: O=S(=O)(O)Cl
Temperature: 60 °C
Reaction time: 6 h

Procedure:
126 g of the sodium salt of 3-[5-hydroxy-8-(2-methylsulphonyl-4-nitrophenylazo)-naphthylsulphamoyl]-benzene sulphonic acid are stirred in 700 ml of phosphorus oxychloride and heated to 60° C. At this temperature 20 g of N-methylpyrrolidone are gradually added, whereupon the mixture is stirred at 60° C. for 6 h and thereafter allowed to cool. The precipitate formed is filtered with suction, washed with dichloroethane and dried.
Reaction SMILES: [OH:1][C:2]1([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH2-:21].[Na+].ClCl>C1C=CC=CC=1>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:2]2([O:1][CH2:12][CH2:11][CH2:13][N:21]3[CH2:4][CH2:3][CH2:2][CH2:7]3)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH:16]=1
Reactant: [NH2-]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccnc2)CC1
Agent: ClCl
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(OCCCN2CCCC2)(c2cccnc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
tert-Butyl 4-hydroxy-4-(pyridin-3-yl)piperidine-1-carboxylate (2 g) was dissolved in benzene (20 ml), sodium amide (10 eq.) was added at 25° C. and the mixture was stirred at this temperature for 15 min. The corresponding chlorine compound (1.2 eq.) was then added and the mixture was heated under reflux for 16 h. When the reaction had ended (TLC control), the mixture was cooled to 0° C. and hydrolysis was carried out with ice. The aqueous phase was extracted with ethyl acetate. The organic phase was then washed successively with water and saturated NaCl solution and dried over Na2SO4. The solvent was removed on a rotary evaporator and the crude product obtained was purified by column chromatography (silica gel, MC/methanol, 95:5).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C=O.[ClH:14].N.[CH3:16]O>>[Cl:14][CH2:16][C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:10])([F:11])[F:1])=[CH:5][CH:6]=1
Reactant: Cl
Reactant: FC(F)(F)Oc1ccccc1
Reactant: CO
Agent: C=O
Agent: N
Product: FC(F)(F)Oc1ccc(CCl)cc1
Temperature: 0 °C

Procedure:
200 g of trifluoromethoxybenzene and 48 g of paraformaldehyde were dissolved in 500 ml of methanol, and dry hydrogen chloride gas was introduced at 60° C. for 7 hours. The waste gases were, via a reflux condenser, passed into aqueous ammonia. The reaction mixture was then poured onto 1,000 g of ice and extracted twice with in each case 300 ml of methyl tert-butyl ether. The combined extracts were washed with 100 ml of water and then with 100 ml of sodium bicarbonate solution and subsequently concentrated. The residue was distilled at 18 hPa in a spinning band column. This gave 158.8 g of 4-chloromethyl-1-trifluoromethoxybenzene as a colorless liquid (65% of theory) of b.p. 71-74° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][CH3:25])[CH:19]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1>>[CH2:24]([C:20]1[CH:19]=[C:18]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:32]4[C:27]([F:26])=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:3]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:23]=[CH:22][N:21]=1)[CH3:25]
Reactant: CCc1cc(C2(c3cccc(Br)c3)N=C(N)c3ccccc32)ccn1
Reactant: OB(O)c1cccnc1F
Product: CCc1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)c3ccccc32)ccn1
Yield: 61 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-(2-ethylpyridin-4-yl)-1H-isoindol-3-amine (Example 110) as described in Example 67 Scheme #10, D in 61% yield using 2-fluoropyridine-3-boronic acid. 1H NMR (DMSO-d6) δ 8.28 (d, J=5.31 Hz, 1 H), 8.20-8.11 (m, 1 H), 7.98-7.89 (m, 1 H), 7.79-7.71 (m, 2 H), 7.47-7.28 (m, 7 H), 7.15-7.10 (m, 1 H), 7.06 (dd, J=5.18, 1.64 Hz, 1 H), 6.83 (br s, 2 H), 2.60 (q, J=7.58 Hz, 2 H), 1.08 (t, J=7.58 Hz, 3 H); MS (ESI) m/z 409 [M+1]+.