Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([C:15]([OH:17])=[O:16])([CH3:14])[CH2:6][CH2:5]2.[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([O:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([C:15]([OH:17])=[O:16])([CH3:14])[CH2:6][CH2:5]2)(=[O:21])[CH3:20]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)O)O2
Temperature: 30 °C
Reaction time: 2 h

Procedure:
Dissolve 50 grams (0.2 mol) of (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)carboxylic acid in 150 cm3 of anhydrous pyridine. Add dropwise 9.4 cm3 (0.1 mol) of acetic anhydride under a stream of nitrogen. Stir for 2 hours at a temperature of 30° C. After cooling, pour the mixture onto some ice, extract the resulting product with diethyl ether, and wash the organic phase with a 0.2N hydrochloric acid solution, and then with water until neutral. After evaporation of the solvent, an oily mass is collected which crystallises after trituration in diisopropyl ether.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][CH:10]=[CH:11][CH:12]=1.[CH2:13]([CH:15]1[O:17][CH2:16]1)Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:17]1[CH2:16][CH:15]1[CH2:13][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Oc1ccccc1-c1ccc[nH]1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1c[nH]c(-c2ccccc2OCC2CO2)c1
Yield: 48.6 %

Procedure:
7.0 g of 2-(hydroxyphenyl)-pyrrole, 7.3 g of epibromohydrin and 11.4 g of dry potassium carbonate in 50 ml of acetone are refluxed for 7 hours. After the mixture has cooled, it is filtered and the filter residue is washed with acetone. The combined filtrates and freed from solvent by distilling off the latter. The residue is twice chromatographed on silica gel, using methylene chloride as the eluant, and thereby gives 4.6 g (48% of theory) of 2-[2- (2,3-epoxypropoxy)-phenyl]-pyrrole as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[O:8])=[CH:5][N:6]=1.[Cl:16][C:17]1[CH:34]=[CH:33][CH:32]=[CH:31][C:18]=1[C:19]([C:21]1SC(N=CN(C)C)=NC=1)=[O:20]>Cl>[NH2:1][C:2]1[S:3][C:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[O:8])=[CH:5][N:6]=1.[Cl:16][C:17]1[CH:34]=[CH:33][CH:32]=[CH:31][C:18]=1[C:19](=[O:20])[CH3:21]
Reactant: CN(C)C=Nc1ncc(C(=O)c2ccccc2Cl)s1
Agent: Cl
Agent: Nc1ncc(C(=O)c2ccccc2Cl)s1
Product: CC(=O)c1ccccc1Cl
Temperature: 70 °C
Reaction time: 1 h

Procedure:
(2-Amino-thiazol-5-yl)-(2-chloro-phenyl)-methanone The crude N′-[5-(2-chloro-benzoyl)-thiazol-2-yl]-N,N-dimethyl-formamidine was dissolved in 10% aqueous hydrochloric acid (150 mL) and heated to 70° C. for 4 hours. The precipitate was filtered, washed with ether, and then suspended in a 10% aqueous sodium carbonate solution (250 mL). The suspension was stirred for 1 hour and the precipitate was filtered, washed with ether, and dried in air to give (2-amino-thiazol-5-yl)-(2-chloro-phenyl)-methanone as a brown solid (8.5 g, 36 mmol, 55% from 1-(2-chloro-phenyl)-ethanone). ESI-MS m/z calc. 238.0, found 239.3 (M+1)+ 1H NMR (DMSO): δ: 7.252 (s, 1 H), 7.420-7.553 (m, 4 H), 8.345 (s, 2 H).
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:43]1[CH2:48][CH2:47][O:46][CH2:45][CH:44]1[C:49]1[C:57]2[S:56][C:55]([NH2:58])=[N:54][C:53]=2[C:52]([O:59][CH3:60])=[CH:51][CH:50]=1>C1COCC1.C(Cl)(Cl)Cl>[O:43]1[CH2:48][CH2:47][O:46][CH2:45][CH:44]1[C:49]1[C:57]2[S:56][C:55]([NH:58][C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[O:9])=[N:54][C:53]=2[C:52]([O:59][CH3:60])=[CH:51][CH:50]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: O=C(O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)C3CCCCC3)nc12

Procedure:
From cyclohexanecarboxylic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+19.2° (c=1.05, CHCl3), ES-MS m/e (%): 377 (M+H+, 100).
Reaction SMILES: [F:1][CH:2]([F:36])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([NH:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[C:28]([F:35])[CH:27]=4)=[O:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.FC(F)O[C:40]1C=CC(S(Cl)(=O)=O)=C[CH:41]=1>>[CH2:40]([O:31][C:30](=[O:32])[C:29]1[CH:33]=[CH:34][C:26]([NH:25][C:23]([C:20]2[CH:21]=[C:22]3[C:17]([CH2:16][CH2:15][CH2:14][N:13]3[S:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:1])[F:36])=[CH:5][CH:6]=3)(=[O:12])=[O:11])=[CH:18][CH:19]=2)=[O:24])=[CH:27][C:28]=1[F:35])[CH3:41]
Reactant: O=C(Nc1ccc(C(=O)O)c(F)c1)c1ccc2c(c1)N(S(=O)(=O)c1ccc(OC(F)F)cc1)CCC2
Reactant: O=S(=O)(Cl)c1ccc(OC(F)F)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2ccc(OC(F)F)cc2)CCC3)cc1F

Procedure:
4-{[1-(4-Difluoromethoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-2-fluoro-benzoic acid, m/z (ES+): 521.17 (M+H+.), was prepared in analogy to example 48, steps 1 to 5. Step 4 was performed using 4-difluoromethoxy-benzenesulfonyl chloride, yielding 4-{[1-(4-difluoromethoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3]1.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:22][C:23]#[N:24]>>[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1/[C:22](=[CH:11]/[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)/[C:23]#[N:24]
Reactant: N#CCc1nc2ccccc2s1
Reactant: Cn1cc(C=O)c2ccccc21
Product: Cn1cc(/C=C(\C#N)c2nc3ccccc3s2)c2ccccc21
Yield: 100.3 %

Procedure:
1-Methylindole-3-carboxaldehyde (79 mg) was condensed with 2-benzothiazoleacetonitrile (87 mg) through Method B (production step 3), to thereby yield the target product (yield: 157 mg, 99%).
Reaction SMILES: C(O)(=O)C.O.[CH3:6][O:7][C:8]([CH2:10][O:11][C:12]1[CH:44]=[CH:43][C:15]([CH2:16][CH:17]2[S:21][C:20](=[O:22])[N:19](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:18]2=[O:42])=[CH:14][CH:13]=1)=[O:9]>O1CCOCC1>[CH3:6][O:7][C:8]([CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][CH:17]2[S:21][C:20](=[O:22])[NH:19][C:18]2=[O:42])=[CH:43][CH:44]=1)=[O:9]
Reactant: COC(=O)COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 85.6 %

Procedure:
1700 ml of acetic acid and then 400 ml of water were added at room temperature to a suspension of 344 g of 5-(4-methoxycarbonylmethoxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 20) in 400 ml of 1,4-dioxane and the resulting mixture was stirred for 5 hours at 80° C. At the end of this time, the reaction mixture was freed from the solvent by evaporation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel using a 1:2 by volume mixture of ethyl acetate and hexane, a 2:1 by volume mixture of ethyl acetate and hexane and then ethyl acetate as eluents, to give 161.7 g of the title compound, melting at 100°-106° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4](=[O:16])[O:5][C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][C:8]=1[OH:9].[H-].[Na+].[C:19](Cl)(=[O:23])[C:20](Cl)=O.[C:25]1(CC(O)=O)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>C1COCC1>[OH:9][C:8]1[CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:16])[C:3]=1[NH:2][C:19](=[O:23])[CH2:20][C:27]1[CH:26]=[CH:25][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1cccc2ccccc12
Reactant: Nc1c(O)cc(-c2ccccc2)oc1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Cc1ccc2ccccc2c1)Nc1c(O)cc(-c2ccccc2)oc1=O

Procedure:
The title compound was prepared by Method E using 3-amino-4-hydroxy-6-phenyl-2H-pyran-2-one hydrochloride (0.200 g, 0.835 mmol), THF (9 mL), 60% sodium hydride (0.037 mL, 0.918 mmol), oxalyl chloride (0.080 mL, 0.918 mmol), 2-naphthalyl acetic acid (0.170 g, 0.918 mmol). m.p. dec. 227° C.; 1H NMR (250 MHz, DMSO-d6) δ4.17 (s, 2 H), 6.84 (s, 1 H), 7.50 (m, 6 H), 7.83 (m, 4 H), 7.93 (d, 1 H), 8.17 (d, 1 H), 9.58 (s, 1 H).
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([NH:15][C@@H:16]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:18]([CH2:28][NH:29][CH3:30])[CH2:17]2)=[O:14])=[N:5]1)([CH3:3])[CH3:2].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>>[CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([NH:15][C@@H:16]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[C@H:18]([CH2:28][N:29]([CH3:30])[S:32]([CH3:31])(=[O:34])=[O:33])[CH2:17]2)=[O:14])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CNC[C@@H]1C[C@H](NC(=O)c2nn(C(C)C)c3ccccc23)CN1C(=O)OC(C)(C)C
Product: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CN(C)S(C)(=O)=O)N(C(=O)OC(C)(C)C)C2)c2ccccc21

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 17 from tert-butyl (2S,4S)-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}-2-[(methylamino)methyl]pyrrolidine-1-carboxylate (step 1 of Example 26) and methanesulfonyl chloride.
Reaction SMILES: O[C:2]1[O:3][C:4]2[C:9]([C:10](=[O:19])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH3:20].N1C=CC=CC=1.[C:27]([O:30]C(=O)C)(=[O:29])[CH3:28]>>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:10](=[O:19])[C:9]3[C:4](=[C:5]([CH3:20])[C:6]([O:30][C:27](=[O:29])[CH3:28])=[CH:7][CH:8]=3)[O:3][CH:2]=2)=[CH:13][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc2c(=O)c(-c3ccc(O)cc3)c(O)oc12
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(=O)c(-c3ccc(O)cc3)coc2c1C
Temperature: 25 °C

Procedure:
Hydroxy-3-(4-hydroxy-phenyl)-8-methyl-chromen-4-one (35.18 g) were combined into a round bottom flask (1 L). Pyridine (38 ml, 2 equivalents) and acetic anhydride (576 ml, 47 equivalents) were added to the round bottom flask while stirring at room temperature. The reaction was monitored by HPLC and was completed instantaneously. There was a change in colour observed, the reaction mixture was dark brown initially and went bright orange with tan brown floccular particles upon stirring. The reaction mixture was poured into chilled, distilled H2O (4 L) and was left stirring at room temperature for 30 minutes. An off-white solid was collected by suction filtration. 1HNMR of the solid in d-CDCl3 indicated it was Acetic acid 3-(4-hydroxy-phenyl)-8-methyl4-oxo-4H-chromen-7-yl ester with >95% purity The solid was dried on a freeze dryer for 24 hours. When dry, the solid was weighed (31.80 g, 69%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]#[CH:17])=[CH:14][C:13]([C:18]3[CH:19]=[N:20][C:21]([N:24]4[CH2:29][CH2:28][C:27]([CH3:35])([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]4)=[N:22][CH:23]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[N:36]([CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])=[N+:37]=[N-:38].C(N(C(C)C)C(C)C)C>CN(C=O)C.O.[Cu]I>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[N:38]=[N:37][N:36]([CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH:17]=3)=[CH:14][C:13]([C:18]3[CH:23]=[N:22][C:21]([N:24]4[CH2:25][CH2:26][C:27]([CH3:35])([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:29]4)=[N:20][CH:19]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: C#Cc1cc(-c2cnc(N3CCC(C)(C(=O)OCC)CC3)nc2)cc2nc(NC(=O)NCC)sc12
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(-c3cn(C[Si](C)(C)C)nn3)c2s1

Procedure:
Ethyl 1-[5-[2-(ethylcarbamoylamino)-7-ethynyl-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (115 mg, 0.233 mmol), (azidomethyl)trimethylsilane (150 mg, 1.169 mmol), Copper(I)Iodide (8.9 mg, 0.0467 mmol), N-ethyl-N-isopropylpropan-2-amine (30.1 mg, 0.233 mmol) in 2 mL of DMF were stirred at rt for 24 hours. The reaction was diluted with 10 mL of water, filtered and washed with water then dried to yield the desired compound as a beige solid, 95 mg, 65.5 yield %.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1OC)[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[NH2:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>CO>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([NH:26][CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22]
Reactant: NCc1cccnc1
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Solvent: CO
Product: COC12C(CO)C3=C(C(=O)C(C)=C(NCc4cccnc4)C3=O)N1CC1NC12
Product: NC(=O)O
Reaction time: 16 h
Yield: 146.2 %

Procedure:
To a solution of 115 mg mitomycin A (0.33 mmol) in 5 ml of anhydrous methanol, 71 mg 3-aminomethylpyridine (0.66 mmol) was added and the mixture was stirred. The progress of the reaction was checked by TLC and appeared to be complete in 16 hours. The solvent was removed by evaporation under reduced pressure. The residue was chromatographed using silica-gel as adsorbent. The fraction obtained by eluting the column with a mixture of chloroform and ethyl acetate (1:1 by volume) was evaporated to give 107 mg (76% yield) of the desired product as purple-colored crystals having a melting point of 116°-118° after recrystallization from chloroform-hexane and providing the following analysis:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:10]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:11])[CH:6]=[C:7]([F:9])[CH:8]=1.C1C=C([O:23]O)C(C(O)=O)=C(C(O)=O)C=1.C([O-])(O)=O.[Na+]>CO.C(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:4]=[C:5]([C:10]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:11])[CH:6]=[C:7]([F:9])[CH:8]=1)=[O:23]
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Reactant: CSc1cc(F)cc(C(=O)c2nccs2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CS(=O)c1cc(F)cc(C(=O)c2nccs2)c1
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 144.4 %

Procedure:
To a solution of sulfide from Step 1 (0.76 g, 2.99 mmol) in MeOH (1.5 mL) and CH2Cl2 (6 mL) at 0° C. was added the magnesium salt of monoperoxyphthalic acid (1.11 g, 1.80 mmol). The mixture was stirred at 0° C. for 1.25 h and then sat. aqueous NaHCO3 was added. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic layers were washed with H2O and dried over anhydrous MgSO4. Evaporation of the solvent and chromatography using toluene:EtOAc (25:75) gave 0.70 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=1)[CH2:6][C:5]2=[O:19].[OH:20]C1C=C(C=CC=1)C=O>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:20])[CH:13]=1)[CH2:6][C:5]2=[O:19]
Reactant: O=Cc1cccc(O)c1
Reactant: O=C1CC(c2ccc(F)cc2)Oc2ccc(O)cc21
Product: O=C1CC(c2cccc(O)c2)Oc2ccc(O)cc21

Procedure:
6-Hydroxy-2-(3-hydroxyphenyl)chroman-4-one was prepared as described for 6-hydroxy-2-(4-fluorophenyl)chroman-4-one in Example 2(a) but starting from 3-hydroxybenzaldehyde. The product was recrystallised from ethanol. 1H NMR (400 MHz, d6-DMSO) δ: 9.50 (bs, 1H), 9.41 (bs, 1H), 7.22-7.17 (m, 1H), 7.11 (d, 1H, J 3.0 Hz), 7.03 (dd, 1H J 3.0, 8.9 Hz), 6.64 (d, 1H, J 8.9 Hz), 6.92-6.90 (m, 2H), 6.76-6.73 (m, 1H), 5.46 (dd, 1H J 2.9, 12.7 Hz), 3.09 (dd, 1H, J 12.7, 16.9 Hz), 2.75 (dd, 1H, J 2.9, 16.9 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]1([C:15]#[C:16][C:17]2[CH:31]=[CH:30][C:20]([C:21]([C:23]3[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=3)=[O:22])=[CH:19][CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O.CC(N(C)C)=O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:26]1[CH:27]=[CH:28][C:23]([C:21]([C:20]2[CH:30]=[CH:31][C:17]([C:16]#[C:15][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:18][CH:19]=2)=[O:22])=[CH:24][CH:25]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(C#Cc2ccccc2)cc1
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1cccc(Oc2ccc(C(=O)c3ccc(C#Cc4ccccc4)cc3)cc2)c1
Temperature: 142 °C
Yield: 95 %

Procedure:
In a 500 mL flask equipped with nitrogen inlet, overhead stirring assembly, Dean-Stark trap, and reflux condenser were placed 3-aminophenol (18.5 g, 0.17 mol), 4-phenylethynyl-4'-fluorobenzophenone (43.2 g, 0.14 mol), potassium carbonate (22 g, 0.16 mol), toluene (30 mL), and DMAc (200 mL). The mixture was heated to 142° C. for 8 h, then cooled to room temperature. The reaction mixture was poured into water and the resulting light yellow powder was collected by filtration. Recrystallization from water/acetone (50/50) (v) and sodium dithionite (0.5 g) afforded 51.8 g (95% yield) of the desired product: m.p. 137°-139° C. IR (KBr); 3414 and 3342 cm-1 (NH2); 3040, 1596, and 1499 cm-1 (aromatic C--H); 2216 cm-1 (C≡C), and 1646 cm-1 (C=O): Mass Spec. m/e (relative intensity): M+, 389.4 (100); FW=389.44 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12](O)=[O:13])=[N:9][C:8]([C@@H:15]([NH:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]3[C:19]=1[N:20]=[CH:21][N:22]3[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH3:16])=[CH:7]2.CN(C=O)C.C(Cl)(=O)C([Cl:44])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]([Cl:44])=[O:13])=[N:9][C:8]([C@@H:15]([NH:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]3[C:19]=1[N:20]=[CH:21][N:22]3[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH3:16])=[CH:7]2
Reactant: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C(=O)O)n4)ncnc32)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C(=O)Cl)n4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carboxylic acid 10 (160 mg, 0.327 mol, 1 eq) and DMF (0.1 mL) in DCM (10 mL), oxalyl chloride (83.1 mg, 0.654 mmol, 2 eq) was added and the resulting mixture was stirred at RT for 1 h. The mixture was concentrated in vacuo to afford the product (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carbonyl chloride 11. The product obtained was used directly in the next step without purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][OH:4].[Na].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Br)[N:9]=1>CCOC(C)=O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:4][CH2:3][CH:2]([CH3:5])[CH3:1])[N:9]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC(C)CO
Agent: [Na]
Solvent: CCOC(C)=O
Product: CC(C)COc1cccc(Br)n1
Reaction time: 0.25 h

Procedure:
To 2-methylpropan-1-ol (1 mL), was added sodium (36 mg, 1.56 mmol). The mixture was stirred at 70° C. until sodium was ˜75% consumed, then 1 mL THF and the mixture was stirred an additional 15 min. To this mixture, 2,6-dibromopyridine (250 mg, 1.06 mmol). The mixture was stirred at 90° C. for 2 h, then was diluted with EtOAc. The organic phase was washed with water (2×) and brine, dried (Na2SO4) and concentrated. The crude material was purified by flash chromatography (0 to 10% EtOAc/hexanes gradient) to afford 185 mg of Intermediate 162.1 as a colorless oil. LCMS (2 min gradient) RT=1.98 min, 230.2 (M+H)+.
Reaction SMILES: N[C:2]1[CH:12]=[CH:11][C:10]2[CH:9]3[CH2:13][CH:5]([CH2:6][N:7]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:8]3)[C:4]=2[CH:3]=1.N([O-])=O.[Na+].[ClH:24]>O.Cl[Cu]>[Cl:24][C:2]1[CH:12]=[CH:11][C:10]2[CH:9]3[CH2:13][CH:5]([CH2:6][N:7]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:8]3)[C:4]=2[CH:3]=1
Reactant: Nc1ccc2c(c1)C1CC2CN(C(=O)C(F)(F)F)C1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(N1CC2CC(C1)c1cc(Cl)ccc12)C(F)(F)F
Temperature: 60 °C
Yield: 95 %

Procedure:
1-(4-Amino-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (460 mg, 1.7 mmol) was dissolved in H2O (3 mL) and concentrated HCl solution(1 mL) then cooled to 0° C. and treated with a solution of sodium nitrite (NaNO2) (275 mg) in H2O (1 mL) dropwise. To the resulting solution was added a CuCl (202 mg, prepared as described above, 2.04 mmol) in concentrated HCl solution (2 mL) over 10 minutes (gas evolution observed). The resulting solution was warmed to 60° C. for 15 minutes, then was cooled to room temperature and extracted with EtOAc (4×30 mL). After drying over Na2SO4, the solution was filtered and concentrated to an oil which was filtered through a Silica pad to remove baseline material eluting with 50% EtOAc/hexanes to give an oil (470 mg, 95% ).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O.[NH2:15][C:16]1[S:17][C:18]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[C:19]([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:15][C:16]2[S:17][C:18]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[O:7])[CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: Nc1nc(-c2ccco2)c(N2CCOCC2)s1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccnc(Cl)c1
Yield: 53.7 %

Procedure:
2-Chloroisonicotinic acid (5.00 g, 31.7 mmol) was added to thionyl chloride (40 mL), followed by stirring under heating and reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane (1 mL). The resulting solution was added to a pyridine (16 ml) solution of 2-amino-4-(2-furyl)-5-morpholinothiazole (880 mg, 5.00 mmol) obtained in Step 1 of Example 29, and then N,N-dimethylaminopyridine (48.8 mg, 0.400 mmol) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:3 to ethyl acetate) to afford the entitled Compound 39 (1.05 g, 66%)
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:28])[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][N:9]2[C:12]2[CH:17]=[C:16]([N+:18]([O-])=O)[C:15]([F:21])=[CH:14][C:13]=2[F:22])=[CH:4][C:3]=1[F:29].Cl[CH2:31]Cl.[CH2:33]([OH:35])[CH3:34].Cl>[Pd].N1C=CC=CC=1>[CH:33]([O:35][CH:3]([CH3:4])[CH3:2])([CH3:31])[CH3:34].[NH2:18][C:16]1[CH:17]=[C:12]([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:29])=[C:2]([Cl:1])[N:11]=3)[C:6](=[O:28])[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8]2)[C:13]([F:22])=[CH:14][C:15]=1[F:21]
Reactant: CCOC(=O)c1cn(-c2cc([N+](=O)[O-])c(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Reactant: ClCCl
Reactant: CCO
Agent: [Pd]
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)OC(C)C
Product: CCOC(=O)c1cn(-c2cc(N)c(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Reaction time: 8 h

Procedure:
Ethyl 7-chloro-6-fluoro-1-(2,4-difluoro-5-nitrophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (3.0 g) was added to a mixture of 50 ml of dichloromethane, 30 ml of ethanol, and 2 ml of conc. hydrochloric acid together with 280 mg of 10% palladium on carbon whereupon hydrogenation was carried out overnight at room temperature. Pyridine (2 ml) was added to the reaction solution, which was concentrated in vacua. To the residue were added 80 ml of chloroform and 10 ml of distilled water. The chloroform layer was separated, dried over anhydrous magnesium sulfate and then concentrated in vacua. Ethanol (8 ml) was added to the residue whereupon the solution was allowed to stand at room temperature. The precipitate was collected by filtration and washed with ethanol and then with diisopropyl ether to give 1.95 grams of the title compound.