Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[H-].[Na+].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[CH:21][CH:22]=2)[N:17]=[CH:16][N:15]=1>C1COCC1.CN(C=O)C>[CH3:28][O:27][CH2:26][CH2:25][O:24][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([CH:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]3=[O:10])=[N:15][CH:16]=[N:17]2)=[CH:22][CH:21]=1
Reactant: COCCOc1ccc2c(Cl)ncnc2c1
Reactant: O=C1Cc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCOc1ccc2c(C3C(=O)Nc4ccccc43)ncnc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.5 %

Procedure:
A solution of oxindole (319 mg, 2.4 mmol) in THF (3 ml) was added dropwise under nitrogen to sodium hydride (58 mg, 2.4 mmol, pre-washed with hexane) and the mixture stirred for 20 minutes at ambient temperature. A solution of 4-chloro-7-(2-methoxyethoxy)quinazoline (191 mg, 0.8 mmol) in DMF (3 ml) was added and the mixture then heated at 70° C. for 1 hour. The mixture was allowed to cool and the solvent removed by evaporation. The mixture was partitioned between water and ether. The aqueous phase was separated and adjusted to pH7 with 2M hydrochloric acid. The resulting solid was collected by filtration and washed with water and ethanol. This solid was then suspended in ether, recollected by filtration, washed with ether and dried under vacuum to give 7(2-methoxyethoxy)-4-(oxindol-3-yl)quinazoline (200 mg, 75%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:18]([CH3:19])=[C:17]([C:20]#[N:21])[C:8]2[N:9]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:11][C:7]=2[C:6]=1[F:22])=O.[C:23]([NH2:26])(=[S:25])[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[C:20]([C:17]1[C:8]2[N:9]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:11][C:7]=2[C:6]([F:22])=[C:5]([C:3]2[N:26]=[C:23]([CH3:24])[S:25][CH:2]=2)[C:18]=1[CH3:19])#[N:21]
Reactant: CC(N)=S
Reactant: Cc1c(C(=O)CBr)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Cc1nc(-c2c(C)c(C#N)c3nc(C(=O)N(C)C)oc3c2F)cs1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 65.1 %

Procedure:
Under nitrogen atmosphere, a toluene (100 ml) suspension of 6-bromoacetyl-4-cyano-7-fluoro-N,N,5-trimethyl-1,3-benzoxazole-2-carboxamide (I-128) (3.80 g, 10.3 mmol), thioacetamide (931 mg, 12.4 mmol) and cesium carbonate (4.36 g, 13.4 mmol) was stirred at 100° C. for 45 minutes. After cooling, the reaction liquid was filtered through Celite, the obtained filtrate was washed with water and saturated brine. Next, the organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica, gel column chromatography, and the eluate with n-hexane/ethyl acetate (1:1, v/v) gave the entitled compound (2.31 g, 65%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[Al](C)C.[O:13]1[C@@H:23]2[C:14]31[C@H:19]([CH2:20][CH2:21][CH2:22]2)[CH2:18][O:17][CH2:16][CH2:15]3.[OH-].[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C@@H:23]2[CH2:22][CH2:21][CH2:20][C@@H:19]3[C@:14]2([OH:13])[CH2:15][CH2:16][O:17][CH2:18]3)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: C1C[C@@H]2COCCC23O[C@H]3C1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O[C@]12CCOC[C@@H]1CCC[C@H]2Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-fluoroaniline (0.119 g, 1.07 mmol) in CH2Cl2 (1 mL) at 0° C. was added trimethylaluminum (2M in toluene, 0.535 mL) dropwise. The mixture was warmed to rt and stirred for 30 min. A mixture of cis and trans octahydrooxireno[e]isochromene (0.033 g, 0.214 mmol) in CH2Cl2 (1 mL) was then added and the mixture was stirred at rt overnight. The reaction mixture was cooled to 0° C. and treated with 50% NaOH (1 mL) then water (1 mL). It was diluted with more water and extracted 3× with CH2Cl2. The combined organics were dried, filtered and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (500 MHz, CDCl3) δ 6.92 (t, 2H, J=8.8 Hz), 6.71 (dd, 2H, J=4.2 Hz, 8.8 Hz), 3.81-3.87 (m, 1H), 3.61 (dd, 1H, J=4.6 Hz, 11.2 Hz), 3.50 (t, 1H, J=11.0 Hz), 3.32 (s, 1H), 2.15-2.26 (m, 1H), 1.89-2.07 (m, 2H), 1.59-1.69 (m, 2H), 1.45-1.58 (m, 1H), 1.20-1.37 (m, 4H). HRMS (ES) m/z M+H calc'd.: 266.1551. found: 266.1549
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][C:7]([PH:15]([C:17]1(Cl)[CH:22]=[CH:21][CH:20]=[CH:19][CH2:18]1)=[O:16])([Cl:14])[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9]>C(OCC)C.C(Cl)CCC>[Cl:14][C:7]([P:15]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16])([Cl:6])[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)OC(=O)C(Cl)(Cl)[PH](=O)C1(Cl)C=CC=CC1
Reactant: CCNCC
Solvent: CCCCCl
Solvent: CCOCC
Product: CCN(CC)P(=O)(c1ccccc1)C(Cl)(Cl)C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 11.7 g of diethylamine in 100 ml of diethylether is added dropwise to a solution of 27.1 g of 1-methylethyl 2,2-dichloro-[(1-chloro)phenylphosphinyl]-acetate in 200 ml of ether at 0°. After stirring at room temperature for 1 hour, the solution is washed with water and with 10% sodium bicarbonate solution, then dried over MgSO4 and stripped to give a dark oil. The reaction product is dissolved in n-butyl chloride, washed with water, contacted with activated carbon, dried over MgSO4 and stripped to give substantially pure 1-methylethyl 2,2-dichloro-[(diethylamino)phenylphosphinyl]acetate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:12].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:41][C:42]([F:48])([F:47])[C:43]([F:46])([F:45])[F:44])(=O)=O>CC(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:41][C:42]([F:48])([F:47])[C:43]([F:46])([F:45])[F:44])=[C:3]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)F)C(F)(F)F
Reactant: O=C(c1cc([N+](=O)[O-])ccc1O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1cc([N+](=O)[O-])ccc1OCC(F)(F)C(F)(F)F)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 99 %

Procedure:
To a refluxing solution of 50 mg of (2-hydroxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone in acetone (2 mL) containing potassium carbonate (35 mg) was added 2,2,3,3,3-pentafluoropropyl trifluoromethanesulfonate (54 mg) over 10 min. The reaction mixture was refluxed for 20 hours before being concentrated in vacuo and purified by column chromatography (SiO2, CH2Cl2/MeOH) to yield the title compound as a colorless solid (66 mg). MS (m/e): 569.0 (M+H+, 100%).
Reaction SMILES: S(Cl)(Cl)=O.F[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:15])[CH:7]=1.[CH3:16][S-:17].[Na+]>CO>[CH3:15][C:8]1[CH:7]=[C:6]([S:17][CH3:16])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: C[S-]
Reactant: Cc1cc(F)ccc1C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: CSc1ccc(C(=O)O)c(C)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (2 mL, 27.4 mmol) was added dropwise to a solution of 4-fluoro-2-methyl-benzoic acid (1.25 g, 8.11 mmol) in methanol (10 mL). The reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated in vacuo and methyl 4-fluoro-2-methylbenzoate was used in the next step without further purification. Methyl 4-fluoro-2-methylbenzoate was dissolved in DMF (5 mL) and sodium thiomethoxide (1.1 g, 15.7 mmol) was added and the reaction mixture was heated to 80° C. for 2 hours. The reaction mixture was then partitioned between 1M hydrochloric acid and ethyl acetate. The layers were separated and the organic layer was washed with 1M hydrochloric acid, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 2-methyl-4-(methylthio)benzoic acid which was carried to the next step without further purification. 2-Methyl-4-(methylthio)benzoic acid was suspended in acetic acid (10 mL) and hydrogen peroxide (5 mL of 30% w/w) was added and the reaction mixture was heated to 80° C. for 2 hours. The reaction mixture was concentrated in vacuo, then partitioned between 0.2 M HCl (25 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous extracted with ethyl acetate (50 mL). The combined organics washed with brine (20 mL), dried over MgSO4 and concentrated in vacuo. The resulting solid was rinsed with ether (2×10 mL) and dried in vacuo to give 2-methyl-4-methylsulfonyl-benzoic acid (0.87 g, 50%) as a white solid. ESI-MS m/z calc. 214.0. found 215.5 (M+1)+; Retention time: 0.48 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 7.99 (d, J=8.1 Hz, 1H), 7.87 (s, 1H), 7.82 (d, J=8.0 Hz, 1H), 3.25 (s, 3H), 2.59 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1>>[OH:22][CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[N+:10]([O-:12])=[O:11])[C:5]#[N:6])=[CH:15][CH:16]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: N#Cc1ccc([N+](=O)[O-])c(Cl)c1
Product: N#Cc1ccc([N+](=O)[O-])c(Nc2ccc(CCO)cc2)c1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 3-chloro-4-nitrobenzonitrile (Tsuji, K. Chem. Pharm. Bull. 1992, 40, 2399) and 4-aminophenylethyl alcohol.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:10]=1[CH:11]=O.[Cl-].C([O:27][C:28]1[CH:53]=[CH:52][C:31]([CH2:32][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:30][CH:29]=1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[OH:27][C:28]1[CH:53]=[CH:52][C:31]([CH2:32][CH2:11][C:10]2[O:9][C:8]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:7][C:6]=2[CH2:5][O:4][CH2:3][O:2][CH3:1])=[CH:30][CH:29]=1
Reactant: c1ccc(COc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2)cc1
Reactant: COCOCc1nc(-c2ccccc2)oc1C=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOCc1nc(-c2ccccc2)oc1CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.7 %

Procedure:
A mixture of 4-methoxymethoxymethyl-2-phenyl-1,3-oxazole-5-carbaldehyde (3.00 g), 4-benzyloxybenzyltriphenylphosphonium chloride (6.58 g), potassium carbonate (1.84 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give a colorless oil from a fraction eluted with ethyl acetate-hexane (1:4, v/v). A mixture of the obtained colorless oil, 5% palladium on carbon (5.00 g) and tetrahydrofuran (200 mL) was stirred under a hydrogen atmosphere at room temperature for 3 hrs. After removing palladium on carbon by filtration, the filtrate was concentrated. The obtained crystals were collected by filtration to give 5-[2-(4-hydroxyphenyl)ethyl]-4-methoxymethoxymethyl-2-phenyl-1,3-oxazole (3.24 g, yield 79%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 102-103° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([CH3:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]([C:17]([O:19][CH3:20])=[O:18])[C:4]=2[CH:3]=1.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24]Cl.O>O1CCCC1>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([CH3:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:17]([O:19][CH3:20])=[O:18])([CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])[C:4]=2[CH:3]=1
Reactant: COC(=O)C1c2ccccc2N(C)c2ccc(Cl)cc21
Reactant: CN(C)CCCl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1(CCN(C)C)c2ccccc2N(C)c2ccc(Cl)cc21
Temperature: 45 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
3.9 gm of 2-chloro-9-methoxycarbonyl-10-methyl-acridane were dissolved in 10 cc of tetrahydrofuran and 5 cc of hexamethyl phosphortriamide and the solution was heated to 45°C and 3.4 gm of potassium tert.-butylate were added thereto. After stirring the mixture for 1 hour at 45°-47°C, 4.5 gm of β-dimethylaminoethyl chloride were added thereto and the mixture was stirred for 16 hours at 46°-48°C. After cooling the mixture, 150 cc of water were added and the mixture was extracted with ether. The organic phases were washed with an aqueous solution of sodium chloride, dried over magnesium sulfate, treated with charcoal, filtered and evaporated to dryness to obtain 4.2 gm of raw 2-chloro-9-methoxycarbonyl-9-(β-dimethylaminoethyl)-10-methyl-acridane.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[CH3:13].[NH2:14][C:15]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[C:16]=1[C:17]([NH2:19])=[O:18].OS([O-])=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]2[NH:19][C:17](=[O:18])[C:16]3[C:15](=[CH:23][C:22]([O:24][CH3:25])=[CH:21][C:20]=3[O:26][CH3:27])[N:14]=2)=[CH:7][C:6]=1[CH3:13]
Reactant: Cc1cc(C=O)ccc1OCCO
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OCCO)c(C)c3)nc2c1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(2-hydroxy-ethoxy)-3-methylbenzaldehyde (1.46 g, 8.08 mmol) and 2-amino-4,6-dimethoxybenzamide (1.58 g, 8.08 mmol) in N,N-dimethylacetamide (20 mL) were added NaHSO3 (58.5 wt %, 2.20 g, 12.12 mmol) and p-toluenesulfonic acid monohydrate (0.38 g, 2.02 mmol). The reaction mixture was stirred at 110° C. for 16 hours, then cooled to room temperature. N,N-dimethylacetamide was removed under reduced pressure. The residue was triturated with water (50 mL). The resulting slurry was filtered and solid was washed with water, ether, and hexanes to obtain 2-[4-(2-hydroxy-ethoxy)-3-methyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one as a beige solid. Yield: 2.75 g (95%).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[C:29]([F:31])[C:28]([O:32][CH2:33][CH:34]3[CH2:36][CH2:35]3)=[C:27]([F:37])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH2:16][C:17]([NH:19][C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH:26]=[C:27]([F:37])[C:28]([O:32][CH2:33][CH:34]5[CH2:36][CH2:35]5)=[C:29]([F:31])[CH:30]=4)[N:24]=3)=[O:18])[C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14]
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Reactant: O=C(CBr)Nc1nc(-c2cc(F)c(OCC3CC3)c(F)c2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3cc(F)c(OCC4CC4)c(F)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (50 mg, 0.279 mmol) with 2-bromo-N-{4-[4-(cyclopropylmethoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl}acetamide (135 mg, 0.334 mmol) in the presence of NaH (16 mg, 0.666 mmol) in dry DMF (5.0 mL) to give 39 mg of the product as an off-white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 0.24-0.30 (m, 2H), 0.50-0.56 (m, 2H), 1.15-1.21 (m, 1H), 3.17 (s, 3H), 3.39 (s, 3H), 3.97 (d, J=7.5 Hz, 2H), 5.32 (s, 2H), 6.23 (s, 2H), 7.35 (s, 1H), 7.60-7.66 (m, 2H), 7.77 (s, 1H), 12.68 (br s, 1H); APCI-MS (m/z) 502.13 (M+H)+.
Reaction SMILES: [C:1]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:14]([OH:17])[CH:15]=[CH2:16].C(OOC(C)(C)C)(C)(C)C>>[OH:17][CH2:14][CH2:15][CH2:16][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:1]1=[O:13]
Reactant: C=CCO
Reactant: O=C1CCCCCCCCCCC1
Agent: CC(C)(C)OOC(C)(C)C
Product: O=C1CCCCCCCCCCC1CCCO

Procedure:
From a double-walled vessel made of glass, whose temperature is thermostatically controlled at 100° C. and which is fitted with a magnetic stirrer and serves as the storage container for the cyclododecanone, 400 g/h are pumped to a mixing column which is kept at a temperature of 100° C. 21.4 g/h of a mixture of allyl alcohol (12.2 g/h) and di-tert-butyl peroxide (9.2 g/h) are continuously metered into the feedline of the mixing column.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=O)[O:4][C:2]2=[O:3].[CH3:13][NH2:14]>O1CCCC1>[CH3:13][N:14]1[C:2](=[O:3])[C:1]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:4]
Reactant: CN
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: C1CCOC1
Product: Cn1c(=O)[nH]c2ccccc2c1=O

Procedure:
6 g isatoic anhydride was stirred in 100 ml dry tetrahydrofurane (THF) and methylamine was passed through the mixture for 5 min. The resulting solution was evaporated and the residue was again dissolved in THF (100 ml) and charged with 15 ml 30% phosgene solution in toluene. The mixture was heated to reflux and additional 15 ml phosgene solution was added. After 4 hours reflux the mixture was cooled and evaporated to dryness. The residue was treated with water and the crystals were collected by filtration. The yield was 3.5 g. M.p. 240.4° -240.5° C. In the same manner, from the appropriate substituted isatoic anhydrides, the following compounds were synthesized:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:8][C:9]1[C:10]([I:41])=[C:11]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C:12]([I:35])=[C:13]([C:33]=1[I:34])[C:14]([NH:16][CH:17]([CH:23]([O:29][C:30](=[O:32])[CH3:31])[CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH2:18][O:19][C:20](=[O:22])[CH3:21])=[O:15])=[O:7])(=[O:3])[CH3:2].[C:42]([O:45][CH2:46][CH2:47]Br)(=[O:44])[CH3:43]>>[C:42]([O:45][CH2:46][CH2:47][N:8]([C:9]1[C:10]([I:41])=[C:11]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C:12]([I:35])=[C:13]([C:33]=1[I:34])[C:14]([NH:16][CH:17]([CH:23]([O:29][C:30](=[O:32])[CH3:31])[CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH2:18][O:19][C:20](=[O:22])[CH3:21])=[O:15])[C:6](=[O:7])[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:44])[CH3:43]
Reactant: CC(=O)OCCBr
Reactant: CC(=O)OCC(=O)Nc1c(I)c(COC(C)=O)c(I)c(C(=O)NC(COC(C)=O)C(COC(C)=O)OC(C)=O)c1I
Product: CC(=O)OCCN(C(=O)COC(C)=O)c1c(I)c(COC(C)=O)c(I)c(C(=O)NC(COC(C)=O)C(COC(C)=O)OC(C)=O)c1I

Procedure:
5-(Acetoxyacetamido)-3-acetoxymethyl-N-(1,3,4-triacetoxybut-2-yl)-2,4,6-triiodobenzamide was alkylated with 2-bromoethyl acetate according to the procedure in Example 25a. Yield of crude product=97%.
Reaction SMILES: [Si:1]([C:8]1[C:13]([Cl:14])=[C:12]([F:15])[N:11]=[C:10]([C:16]([C:18]2[C:19](F)=[N:20][CH:21]=[CH:22][CH:23]=2)=O)[C:9]=1[F:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Ca+2].O.[NH2:32][NH2:33]>O1CCOCC1>[Si:1]([C:8]1[C:13]([Cl:14])=[C:12]([F:15])[N:11]=[C:10]([C:16]2[C:18]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:33][N:32]=2)[C:9]=1[F:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)c1c(F)c(C(=O)c2cccnc2F)nc(F)c1Cl
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)c1c(F)c(-c2n[nH]c3ncccc23)nc(F)c1Cl
Yield: 89.7 %

Procedure:
[4-[tert-butyl(dimethyl)silyl]-5-chloro-3,6-difluoro-2-pyridyl]-(2-fluoro-3-pyridyl)methanone (294.86 g, 762.2 mmol) was dissolved in dioxane (2.212 L) and calcium carbonate (152.5 g, 1.524 mol) was added. The reaction was cooled in an ice bath and hydrazine hydrate (190.8 g, 185.4 mL, 3.811 mol) was added dropwise over 15 minutes via cannula to the yellow suspension keeping the internal temperature below 10° C. During addition, the internal temperature dropped to 7.1° C. and the colour changed from light yellow to mango orange. The resulting mixture was allowed to warm to ambient overnight. Lc/Ms after this time indicated the reaction was complete. The reaction mixture was filtered through a pad of Celite, washing copiously with dichloromethane (ca 2.5 L). Water (400 ml) was added to the filtrate followed by a saturated solution of sodium bicarbonate (400 mL). The organic phase separated and washed again with a saturated aqueous sodium bicarbonate (350 mL). The combined aqueous layers were back-extracted with dichloromethane (2×400 ml). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was slurried in petroleum ether, filtered and dried (81 g). The Celite was further washed with dichloromethane/methanol 7:1 (3×800 ml) and with 4 L of dichloromethane/methanol 4:1 until no remaining compound was observed on TLC. The filtrate was concentrated in vacuo. The residual solid was triturated with Petroleum ether as described above (185 g). The solids were combined and dried at 40° C. under vacuum. This gave the title compound as an off-white solid (260.5 g, 89%); 1H NMR (CDCl3) 0.63 (6H, d), 1.07 (9H, s), 7.44 (1H, m), 8.76 (1H, m), 9.07 (1H, m), 13.31 (1H, brs); 19F NMR (decoupled) −104.7, −73.8; MS ES (+) 381.1 (M+1).
Reaction SMILES: S(Br)([Br:3])=O.[C:5]([C:8]12[CH2:17][CH:13]([CH2:14][CH2:15][CH2:16]1)[CH:12]1[CH2:18][CH:9]2[CH2:10][CH2:11]1)(O)=[O:6]>C1C=CC=CC=1>[Br:3][C:5]([C:8]12[CH2:17][CH:13]([CH2:14][CH2:15][CH2:16]1)[CH:12]1[CH2:18][CH:9]2[CH2:10][CH2:11]1)=[O:6]
Reactant: O=C(O)C12CCCC(C1)C1CCC2C1
Reactant: O=S(Br)Br
Solvent: c1ccccc1
Product: O=C(Br)C12CCCC(C1)C1CCC2C1
Yield: 75.5 %

Procedure:
3 g of thionyl bromide was added dropwise with stirring to 2.0 g (10.3 mmoles) of 1-carboxytricyclo[4.3.1.12,5 ]undecane dissolved in 20 ml of anhydrous benzene at room temperature. The mixture was heated under reflux for 1.5 hours. After cooling, the excess thionyl bromide and benzene were distilled off under reduced pressure. The residue obtained was distilled under reduced pressure to afford 2.0 g (yield: 75.5%) of 1-bromocarbonyltricyclo[4.3.1.12,5 ]undecane having a boiling point of 116° C. (1 mmHg).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11](=O)[CH:10]=[C:9]2[CH2:18][C:19]([OH:21])=[O:20].[CH3:22]O>ClCCl>[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[CH2:11][CH:10]=[C:9]2[CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: Cn1c(=O)cc(CC(=O)O)c2cc(Cl)ccc21
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)CC1=CCN(C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 85 %

Procedure:
11 ml (147 mmol) of thionyl chloride are added dropwise over approximately 30 minutes to a stirred suspension of 12.5 g (49 mmol) of 6-chloro-1-methyl-2-oxo-1,2-dihydro-4-quinolineacetic acid in 150 ml of methanol. The mixture is stirred for 17 hours at room temperature and the solvent is driven off under vacuum. The residue is dissolved in 400 ml of dichloromethane, and then washed with saturated aqueous sodium bicarbonate solution and then with water. After drying over sodium sulphate, the organic phase is filtered and the filtrate is condensed. 11.16 g of expected product are obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24]([C:26]2[CH:27]=[C:28]3[C:32](=[C:33]([CH3:35])[CH:34]=2)[N:31]([CH3:36])[CH2:30][C:29]3([CH3:38])[CH3:37])=[O:25])[CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:36][N:31]1[C:32]2[C:28](=[CH:27][C:26]([C:24]([C:20]3[N:21]=[CH:22][N:23]=[C:18]([N:1]4[CH2:2][CH2:3][CH:4]([N:7]5[C:15]6[C:10](=[N:11][CH:12]=[CH:13][CH:14]=6)[NH:9][C:8]5=[O:16])[CH2:5][CH2:6]4)[CH:19]=3)=[O:25])=[CH:34][C:33]=2[CH3:35])[C:29]([CH3:38])([CH3:37])[CH2:30]1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2c1N(C)CC2(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc2c1N(C)CC2(C)C
Temperature: 40 °C
Reaction time: 8 h

Procedure:
38 mg (0.17 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 55 mg (0.17 mmol) (6-chloro-pyrimidin-4-yl)-(1,3,3,7-tetramethyl-2,3-dihydro-1H-indol-5-yl)-methanone and 0.050 mL (0.29 mmol) DIPEA were combined in 2 mL DMF and stirred overnight at 40° C. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.