Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.[C:12]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>CCOCC>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[OH:19])=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccncc1
Reactant: Fc1ccc(Br)cc1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: OC(c1ccccc1)(c1ccncc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
To a suspension of 18.5 g (0.761 mole) of magnesium turnings and several crystals of iodine in 800 ml of anhydrous ether, cooled in an ice bath and under an atmosphere of argon was slowly added a solution of p-bromofluorobenzene in 200 ml of ether. The solution was stirred for 2 hr at 25° C. and 97.02 g (0.530 mole) of 4-benzoylpyridine was added as a solid. An additional 1 liter of anhydrous ether was added, and the solution was stirred at 25° C. for 3 hr. The reaction mixture was poured into an icy, aqueous solution of ammonium chloride. The mixture stood in the hood overnight and a white solid was collected. The solid was dissolved in a mixture of methanol-methylene chloride. The solution was filtered and the solvent was removed in vacuo. The residue was crystallized from chloroform-hexane to give 66.68 g (45%) of title compound as a white, crystalline solid, m.p. 189°-192° C. Part of this was recrystallized from methylene chloride-acetonitrile-hexane, m.p. 190°-192° C.
Reaction SMILES: Cl.S1C=CN=C1.[NH2:7][C:8]1[S:9][C:10]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:12]=1.[H-].[Na+].[C:31]([N:39]=[C:40]=[S:41])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O>CN(C)C=O.C1(C)C=CC=CC=1>[C:31]([NH:39][C:40](=[S:41])[NH:7][C:8]1[S:9][C:10]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[N:12]=1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1ccc(-c2nc(N)sc2-c2ccc(OC)cc2)cc1
Reactant: O=C(N=C=S)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2nc(NC(=S)NC(=O)c3ccccc3)sc2-c2ccc(OC)cc2)cc1
Yield: 150.2 %

Procedure:
A suspension of 2-amino-4,5-bis(4-methoxyphenyl)thiazole thiazole hydrochloride (35.7 g) in a mixture of N,N-dimethylformamide (60 ml) and toluene (60 ml) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil) (4.58 g) in a mixture of N,N-dimethylformamide (60 ml) and toluene (60 ml) for 30 minutes at 0° C. with stirring. The reaction mixture was stirred at the same temperature for 30 minutes. A solution of benzoyl isothiocyanate (9.57 g) in a mixture of N,N-dimethylformamide (30 ml) and toluene (30 ml) was added dropwise to the above-mentioned reaction mixture at 0°~5° C., stirred for 1 hour and continued to stir at 5°~10° C. for 2 hours. Water (200 ml) was added thereto and the resulting mixture was extracted with ethyl acetate (200 ml). The extract was washed with water and brine. The resulting organic layer was dried and evaporated. The residue was crystallized from ethyl acetate to give 2-(3-benzoylthioureido)-4,5-bis( 4-methoxyphenyl)thiazole (41.9 g).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][CH2:9][CH2:10][CH2:11][C:12]1[S:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14]C=1C([O-])=O>C(Cl)Cl.CN(C=O)C>[CH3:7][O:8][CH2:9][CH2:10][CH2:11][C:12]1[S:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COCCCc1sc(-c2ccccc2)nc1C(=O)[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCCc1sc(-c2ccccc2)nc1C(=O)Cl
Reaction time: 0.33 h
Yield: 99.6 %

Procedure:
Oxalyl chloride (67.2 mmol, 5.9 mL) was slowly added to a room temperature solution of 5-(3-methoxypropyl)-2-phenylthiazole-4-carboxylate (22.4 mmol, 6.2 g) in CH2Cl2 (100 mL). 3 drops of DMF were added and the reaction became homogeneous over ˜20 min. The reaction was stirred for 3 h, then concentrated under reduced pressure. The crude product was dissolved in CH2Cl2 (150 mL) and concentrated under reduced pressure. The crude product was dissolved in EtOAc (150 mL), washed with brine (2×100 mL), dried (MgSO4), and concentrated under reduced pressure to give 5-(3-methoxypropyl)-2-phenylthiazole-4-carbonyl chloride as a tan solid (6.6 g, 99% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].Cl.[NH2:31][CH2:32][C:33]1([OH:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:31][CH2:32][C:33]2([OH:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: NCC1(O)CCCCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCC3(O)CCCCC3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 1-aminomethyl-1-cyclohexanol hydrochloride (13 mg, 0.10 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[(1-hydroxycyclohexyl)methylaminomethyl]indol-2-yl}isoindolinone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12](=[O:13])[N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10]([CH3:22])([CH3:21])[CH2:9]2)=[CH:4][C:3]=1[F:23].[OH:24][Li].O>C1COCC1.CO.O>[C:17]([O:16][C:14]([NH:11][C:10]([CH3:22])([CH3:21])[CH2:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:23])[CH:4]=1)[C:12]([OH:24])=[O:13])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1C(=O)C(c2ccc(Cl)c(F)c2)CC1(C)C
Reactant: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(CC(C(=O)O)c1ccc(Cl)c(F)c1)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
tert-Butyl 4-(4-chloro-3-fluorophenyl)-2,2-dimethyl-5-oxopyrrolidine-1-carboxylate (1.168 g, 3.42 mmol, theor.) was dissolved in 4 mL of each: THF, MeOH, water. The LiOH—H2O (574 mg, 13.7 mmol) was added in one sum to the stirring solution. The reaction mixture was allowed to stir to completion overnight. The reaction mixture was concentrated, and the residue was partitioned between ether and water. The aqueous portion was washed again with ether (both discarded) and then treated with 3N HCl solution until a pH of about 2 to about 3 was achieved. The aqueous portion was extracted with ether several times, and the organics were combined. The organic portion was washed with brine, separated, dried over MgSO4, filtered, and concentrated in vacuo to afford 4-(tert-butoxycarbonylamino)-2-(4-chloro-3-fluorophenyl)-4-methylpentanoic acid as a white solid (1.06 g, 86%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([CH:9](O)[CH3:10])=[CH:5][CH:4]=1.O=S(Cl)[Cl:16]>ClCCl>[Cl:16][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:13])([F:12])[F:1])=[N:8][CH:7]=1)[CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1ccc(C(F)(F)F)nc1
Solvent: ClCCl
Product: CC(Cl)c1ccc(C(F)(F)F)nc1
Temperature: 0 °C

Procedure:
To a solution of 0.30 g of 1-(6-trifluoromethyl-pyridin-3-yl)-ethanol in 5 mL of dry dichloromethane was added 0.34 mL of SOCl2. The reaction mixture was refluxed for a half hour and then poured into ice-water, and extracted with dichloromethane. The organic phase was washed with 10% aqueous sodium hydrogen carbonate solution, dried over sodium sulphate and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica, heptanes/ethyl acetate) to give 0.10 g of 5-(1-chloroethyl)-2-trifluoromethyl-pyridine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][C:5]([N+:17]([O-])=O)=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:3]=1>[Fe].C(O)(=O)C>[Cl:1][C:2]1[C:7]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][C:5]([NH2:17])=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:3]=1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)c(Cl)cc1NC1CCOCC1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cc(-c2nc3ccccc3o2)c(Cl)cc1NC1CCOCC1
Yield: 21.8 %

Procedure:
To 2-(4-chloro-2-(tetrahydropyran-4-yl)aminonitrobenzen-5-yl)benzoxazole (see Working Example 112-2) (0.10 g, 0.8 mmol) was added iron powder (0.33 g, 5.8 mmol) and acetic acid (50 mL), and this was heated to reflux for 2 hours. After the reaction solution cooled, this was filtered through Celite and concentrated, and the residue obtained was purified by silica gel column chromatography to yield the title compound (0.06 g, 65% yield) as a reddish-brown solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:24]#[N:25].[Br:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30].Cl.N1C=CC=CC=1.C(OCCO)C>>[Br:26][C:27]1[CH:28]=[C:29]([NH:30][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:24]#[N:25])[CH:31]=[CH:32][CH:33]=1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCN1CCOCC1
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2c(Nc3cccc(Br)c3)c(C#N)cnc2cc1OCCCN1CCOCC1

Procedure:
The method of Example 312 was used as well as 0.3 g of 4-chloro-6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinoline-3-carbonitrile, 0.12 ml of 3-bromo aniline, 0.1 g of pyridine hydrochloride and 4.0 ml of 2-ethoxy ethanol. This afforded an oil which was purified by silica gel flash chromatography utilizing a gradient of methylene chloride/methanol (96:4 to 92:8) to give 0.22 g of the title compound as an off white solid,mp 115-118 C; mass spectrum (ES,m/e): M+H499.
Reaction SMILES: Br[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([Cl:13])[CH:5]=[CH:4][N:3]=1.[CH:14]([Zn]C(C)C)([CH3:16])[CH3:15].O.Cl>O1CCOCC1>[Cl:13][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH:14]([CH3:16])[CH3:15])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC(C)[Zn]C(C)C
Reactant: CCOC(=O)c1c(Cl)ccnc1Br
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(Cl)ccnc1C(C)C
Temperature: 40 °C
Yield: 49.7 %

Procedure:
Ethyl 2-bromo-4-chloropyridine-3-carboxylate (1 g, 3.78 mmol) was dissolved in anhydrous dioxane (30 mL). A solution of diisopropyl zinc (4.5 mL, 4.54 mmol, 1.0 M in toluene) was added dropwise, followed with (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (44 mg, 60 μmol). The mixture was heated at 40° C. overnight, and water followed with 1 N HCl was added. The reaction mixture was extracted 3 times with ethyl acetate, and the combined organic phases were washed with brine and dried over sodium sulfate. After evaporation, the residue was dissolved in DCM and purified on silica gel using 0-15% hexane/ethyl acetate to afford ethyl 4-chloro-2-(propan-2-yl)pyridine-3-carboxylate (428 mg, 50% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][C:5]=1[C:6]([NH:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH:13]=1)=[O:7])([O-])=O>CO.ClCCl.[Pd]>[NH2:1][C:4]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][C:5]=1[C:6]([NH:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:15]=2)[CH:13]=1)=[O:7]
Reactant: O=C(Nc1cn(-c2cccc(C(F)(F)F)c2)cn1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1cn(-c2cccc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 2-nitro-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)benzamide (600 mg, 1.11 mmol, 1.00 equiv, 85%) in methanol/dichloromethane (10/5 mL). The mixture was treated with Pd/C (600 mg) and stirred under an atmosphere of hydrogen overnight at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum to give 450 mg (85%) of product as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[I:15][C:16]1[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:23]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:24][C:16]=2[I:15])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(I)c1
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(I)c1

Procedure:
600 mg of methyl 2-amino-4-(methylsulfonyl)benzoate was added to a solution of 4 mL of H2O and 1 mL of concentrated sulfuric acid. The solution was cooled to 0° C. and a solution of 206 mg of sodium nitrite in 1 mL of H2O was added slowly. The reaction mixture was stirred for 2 h and then a solution of 782 mg of potassium iodide in 2 mL of H2O was added dropwise at 0° C. The reaction was allowed to warm to room temperature and stirred for 5 h. The mixture was extracted with ethyl acetate. The combined organic extracts were washed with saturated Na2S2O3, dried (MgSO4) and evaporated. Purified by silica gel chromatography (5-50% ethyl acetate/hexane) to afford methyl 2-iodo-4-(methylsulfonyl)benzoate. 160 mg of methyl 2-iodo-4-(methylsulfonyl)benzoate was hydrolyzed via Procedure M to give 2-iodo-4-(methylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-iodo-4-(methylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-iodo-4-(methylsulfonyl)benzamide. MS (Q1) 513.0 (M)+.
Reaction SMILES: C([O:9][CH:10]([C@@H:13]1[CH2:17][C@@H:16]([CH2:18][CH:19]=[CH2:20])[C@H:15]([N:21]2[C:25]3[N:26]=[C:27]([NH2:31])[NH:28][C:29](=[O:30])[C:24]=3[S:23][C:22]2=[O:32])[O:14]1)[CH2:11][CH3:12])(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].[NH4+].[Cl-]>CO>[CH2:18]([C@@H:16]1[CH2:17][C@@H:13]([CH:10]([OH:9])[CH2:11][CH3:12])[O:14][C@H:15]1[N:21]1[C:25]2[N:26]=[C:27]([NH2:31])[NH:28][C:29](=[O:30])[C:24]=2[S:23][C:22]1=[O:32])[CH:19]=[CH2:20]
Reactant: C=CC[C@@H]1C[C@@H](C(CC)OC(=O)c2ccccc2)O[C@H]1n1c(=O)sc2c(=O)[nH]c(N)nc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: C=CC[C@@H]1C[C@@H](C(O)CC)O[C@H]1n1c(=O)sc2c(=O)[nH]c(N)nc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.4 %

Procedure:
To a solution of 1-[(2S,4R,5R)-4-allyl-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl]propyl benzoate (compound 26f, 800 mg, 1.75 mmol) in methanol (25 mL) was added K2CO3 (483 mg, 3.5 mmol). After being stirred at room temperature for 12 hours, the reaction was diluted by saturated NH4Cl solution and extracted with DCM. The organic layers were combined and concentrated in vacuo. The residue was purified by preparative HPLC to afford 200 mg of 3-[(2R,3R,5S)-3-allyl-5-(1-hydroxypropyl)tetrahydrofuran-2-yl]-5-amino-6H-thiazolo[4,5-d]pyrimidine-2,7-dione (Example 26). 100 mg of Example 26 was further separated by supercritical fluid chromatography (SFC) to afford 32.0 mg of Example 26-A and 30.8 mg of Example 26-B as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[N:9]([CH:19]2[CH2:24][CH2:23][S:22][CH2:21][CH2:20]2)[C:8]1=[O:25].Br[CH2:32][C:33]#[N:34].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:32][C:33]#[N:34])[CH:14]=2)[N:9]([CH:19]2[CH2:20][CH2:21][S:22][CH2:23][CH2:24]2)[C:8]1=[O:25]
Reactant: N#CCBr
Reactant: COc1ccc(Cn2c(=O)c3cc(O)ccc3n(C3CCSCC3)c2=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3cc(OCC#N)ccc3n(C3CCSCC3)c2=O)cc1OC
Yield: 0.1 %

Procedure:
A mixture of 0.16 g of the compound obtained in Step 3.3, 0.054 g of bromoacetonitrile and 0.243 g of Cs2CO3 in 1 ml of DMF is irradiated in a microwave field for 15 minutes at 100° C. The reaction mixture is evaporated under reduced pressure. The residue is taken up in DCM, washed with water, dried over Na2SO4 and filtered, and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with an EtOAc/DCM mixture from (10/90, v/v) to (20/80, v/v) to give 0.138 mg of the expected product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:17]([O:24]CCO)[C:18]1C=CC=CC=1>>[OH:24][CH2:17][CH2:18][O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(O)cc(N2CCCC2=O)c1
Reactant: OCCOCc1ccccc1
Product: O=C(O)c1cc(OCCO)cc(N2CCCC2=O)c1

Procedure:
Prepared from the methyl ester of 3-hydroxy-5-(2-oxopyrrolidin-1-yl)benzoic acid (D6) by Mitsunobu reaction with 2-benzyloxyethanol, followed by saponification of the methyl ester and hydrogenolytic removal of the benzyl group.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:15]3[N:16]=[C:17]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)[N:18]=[C:19]([C:20]4[CH:21]=[N:22][C:23]([N:26](CC5C=CC(OC)=CC=5)CC5C=CC(OC)=CC=5)=[N:24][CH:25]=4)[C:14]=3[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:59]2[CH:64]=[CH:63][N:62]=[CH:61][CH:60]=2)O1>>[N:62]1[CH:63]=[CH:64][C:59]([C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9]([N:11]3[C:15]4[N:16]=[C:17]([N:45]5[CH2:46][CH2:47][O:48][CH2:49][CH2:50]5)[N:18]=[C:19]([C:20]5[CH:25]=[N:24][C:23]([NH2:26])=[N:22][CH:21]=5)[C:14]=4[CH2:13][CH2:12]3)=[O:10])=[CH:6][CH:7]=2)=[CH:60][CH:61]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)Nc3ccc(I)cc3)cn2)cc1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Product: Nc1ncc(-c2nc(N3CCOCC3)nc3c2CCN3C(=O)Nc2ccc(-c3ccncc3)cc2)cn1

Procedure:
Using 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid (4-iodo-phenyl)-amide (25 mg) obtained in Step A in Example 1-D-65 and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (13 mg) instead of pyridin-3-boronic acid, in the same manner as Step B in Example 1-D-65, 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid-4-pyridin-4-yl-phenyl)-amide was obtained. Further, in the same manner as Step B in Example 1-D-65 according to the above Deprotection method 3, the PMB groups were removed, to obtain the desired compound (D-66) as a colorless solid (8.9 mg, 40%).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:11](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[CH3:11][S:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1cccc(S)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CSc1cccc(C(C)=O)c1
Yield: 77 %

Procedure:
A suspension of 3′-mercaptoacetophenone (Reference compound No. 4-1, 1.5 g, 9.9 mmol), potassium carbonate (1.6 g, 12 mmol) and iodomethane (740 μL, 12 mmol) in N,N-dimethylformamide was stirred at 50° C. for 75 minutes. Water (50 mL) was added to the reaction mixture, extracted with a mixed solvent (50 mL) which consists of hexane and ethyl acetate (3:1). The organic layer was washed with brine (50 mL), dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title reference compound (1.3 g) as a brown oil (Yield 77%).
Reaction SMILES: [N:1]1[C:10]2[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:12][C@@H:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO.C[C@@H](N)C1C=CC=CC=1>[N:1]1[C:10]2[C:9](=[N:20][C@@H:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:12])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=C1CCCc2cccnc21
Solvent: CO
Product: C[C@@H](N=C1CCCc2cccnc21)c1ccccc1
Reaction time: 24 h
Yield: 104.8 %

Procedure:
To a stirred solution of 6,7-dihydro-5H-quinolin-8-one (3.02 g, 20.5 mmol) in dry MeOH (100 mL) was added (R)-(+)-α-methylbenzylamine (2.61 mL, 20.5 mmol) via syringe. The resulting mixture was stirred 24 h, at which point additional (R)-(+)-α-methylbenzylamine (0.26 mL, 2.0 mmol) was added and the reaction was stirred for an additional 24 h. The solvent was removed in vacuo and dried for 3 days at room temperature under reduced pressure (0.1 Torr) to afford 5.38 g (95%) of the title compound as a red/brown solid. [α]D=−126.0 (c 1.04, CHCl3); 1H NMR (CDCl3) δ 1.55 (d, 3H, J=6.9 Hz), 2.17-2.29 (m, 2H), 7.35 (t, 2H, J=7.8 Hz), 4.39 (q, 1H, J=6.6 Hz), 4.72 (t, 1H, J=4.7 Hz), 5.50 (br s, 11H), 7.07 (dd, 1H, J=7.5, 5.1 Hz) 7.20-7.47 (m, 6H), 8.37 (d, 1H, J=2.4 Hz); 3C NMR (CDCl3) δ 21.99, 25.68, 28.29, 53.79, 98.12, 122.43, 126.33, 127.03, 128.92, 132.63, 135.09, 139.47, 146.36, 150.48. ES-MS m/z 251 (M+H).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>C(Cl)Cl>[C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:20])=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1

Procedure:
The conditions to prepare Reference Example 34 are used with 2.0 g of 4-benzoylbenzoic acid and 30 ml of thionyl chloride to give the desired product in a solution of 30 ml of methylene chloride.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].N1C=CC=CC=1.[CH3:17][C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20].O>CC(C)=O>[CH3:17][C:18]([CH3:23])([CH3:22])[C:19]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])=[O:20]
Reactant: O=C(O)c1ccccc1O
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)C(=O)Oc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 105 %

Procedure:
10 g (72.4 mmol) of salicylic acid and 6.1 ml (76 mmol) of pyridine are placed in 100 ml of acetone at −5° C. 9.3 ml (76 mmol) of 2,2-dimethylpropionyl chloride are added and, after stirring at ambient temperature for 2 hours, water is added and the mixture is extracted with dichloromethane. The organic phase is dried over magnesium sulphate, filtered and concentrated. The residue is precipitated from heptane at 0° C. and then filtered off. 16.9 g of 2-(2,2-dimethylpropionyloxy)benzoic acid are obtained in the form of a white powder with a yield of 95%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH:21]=[CH:20]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:28]O>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH:21]=[CH:20]3)=[O:28])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(SCCCCOc2ccc3[nH]c(=O)ccc3c2)cc1
Reactant: OO
Product: CC(C)(C)c1ccc(S(=O)CCCCOc2ccc3[nH]c(=O)ccc3c2)cc1

Procedure:
Prepared analogous to Example 123 from 6-[4-(4-tert. butylphenyl-mercapto)-butoxy]-carbostyril and hydrogen peroxide.