Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][CH2:10][CH:11]([CH3:13])[CH3:12].[CH3:14][C:15]1[C:19]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[C:18]([CH3:32])[O:17][N:16]=1>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[S:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:20][C:19]2[C:15]([CH3:14])=[N:16][O:17][C:18]=2[CH3:32])=[CH:27][CH:26]=1)(=[O:29])=[O:30]
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CNc1c(F)cccc1F
Solvent: c1ccncc1
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)N(CC(C)C)c2c(F)cccc2F)cc1
Reaction time: 16 h

Procedure:
To a solution of (2,6-difluorophenyl)(2-methylpropyl)amine (80 mg, 0.432 mmol) in pyridine (1 mL) was added 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (156 mg, 0.518 mmol) and the reaction stood at room temperature, in air, for 16 hours. The solvent was removed in vacuo and the crude then passed through a sulfonic acid (SCX) SPE (solid phase extraction) cartridge eluting with methanol followed by 2M ammonia/methanol solution. The product-containing fractions were concentrated in vacuo and the crude then passed through an aminopropyl (NH2) SPE cartridge eluting with methanol followed by 2M ammonia/methanol solution. The appropriate fractions were combined and concentrated in vacuo, then further purified by MDAP (Method F) to give the required product, 0.6 mg. LCMS (M+18) 468, RT 1.28 mins.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:29])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][N:20]=3)=[CH:14][CH:13]=2)[CH2:9][C:10]=1[OH:11])(=O)[CH2:2][CH3:3].Cl.[CH2:31]([O:33][NH2:34])[CH3:32].C([O-])(=O)C.[Na+]>C(Cl)Cl.C(O)C>[CH2:31]([O:33][N:34]=[C:1]([C:5]1[C:6](=[O:29])[CH2:7][CH:8]([C:12]2[CH:13]=[CH:14][C:15]([S:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][N:20]=3)=[CH:16][CH:17]=2)[CH2:9][C:10]=1[OH:11])[CH2:2][CH3:3])[CH3:32]
Reactant: CCC(=O)C1=C(O)CC(c2ccc(Sc3ccc(S(C)(=O)=O)cn3)cc2)CC1=O
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2ccc(Sc3ccc(S(C)(=O)=O)cn3)cc2)CC1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a slurry of 4.60 g (0.0107 mol) of 2-propionyl-3-hydroxy-5-(4-(5-(methylsulfonyl)-2-pyridylthio)phenyl)cyclohex-2-en-1-one in 100 mL of methylene chloride and 100 mL of 95 percent ethanol was added 1.35 g (0.0139 mol) of ethoxyamine hydrochloride and 1.31 g (0.0160 mol) of anhydrous sodium acetate. The slurry was stirred at ambient temperature for 12 hours and diluted with 100 mL of methylene chloride and washed thrice with 150 mL portions of water. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo leaving 4.8 g (94.7 percent of theoretical) of the crude product. The product was purified by column chromatography using 5:95 acetone:methylene chloride as eluent and then trituration with diethyl ether affording 2.60 g (51.3 percent of theoretical) of the above named title compound, melting at 125.5°-128.5° C.; 1H NMR (CDCl3): δ 1.05-1.40 (m, 6H, CH3CH2 -- and CH3CH2O--), 2.55-3.55 (m, 11H, ring protons, CH 3 SO2 --, CH3CH2 --), 4.10 (q, 2H, CH3CH2O--), 6.9-8.85 (m, 7H, ArH), 15.0 (broad s, br, 1H, OH).
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[F:25][C:26]1[CH:27]=[C:28]([SH:32])[CH:29]=[CH:30][CH:31]=1>C(#N)C>[F:25][C:26]1[CH:27]=[C:28]([S:32][CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]2)[CH:29]=[CH:30][CH:31]=1
Reactant: Fc1cccc(S)c1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Sc2cccc(F)c2)CC1
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
A mixture of tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.0 g, 3.58 mmol), K2CO3 (0.742 g, 5.37 mmol), and 3-fluorobenzenethiol (0.363 mL, 4.30 mmol) in ACN (7.5 mL) was stirred at 23° C. for 5 min. The reaction mixture was stirred at 80° C. for 17 h, cooled to 23° C. and partitioned between EtOAc and water. The layers were separated, the organic phase was washed with brine, dried over Na2SO4, filtered, rinsed with EtOAc, and dried in vacuo gave tert-butyl 4-((3-fluorophenyl)thio)piperidine-1-carboxylate (1.115 g, 100%) as a yellow oil. ESI-MS m/z [M+H]+ 255.9.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.II.[I:15](O)(=O)=O>C(O)C.O>[F:1][C:2]1[C:3]([OH:12])=[C:4]([I:15])[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1
Reactant: [O-][I+2]([O-])O
Reactant: O=C1COc2cc(O)c(F)cc21
Agent: II
Solvent: O
Solvent: CCO
Product: O=C1COc2c1cc(F)c(O)c2I
Reaction time: 2 h
Yield: 385.3 %

Procedure:
A solution of 5-fluoro-6-hydroxybenzofuran-3(2H)-one (0.190 g, 1.13 mmol) in ethanol (5 mL) was added with iodine (0.115 g, 0.452 mmol) at room temperature. The reaction mixture was added dropwise with a solution of iodic acid (0.0396 g, 0.226 mmol) in water (2 mL), and the mixture was stirred for 2 hours. The reaction mixture was added with water (30 mL), and the precipitated solid was collected by filtration, and dried under reduced pressure to obtain 5-fluoro-6-hydroxy-7-iodobenzofuran-3(2H)-one (0.256 g, 77%).
Reaction SMILES: Cl[CH2:2][CH:3]([CH3:22])[CH2:4][O:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25].[CH:29]([NH2:32])([CH3:31])[CH3:30]>CC(C)=O>[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25].[CH:29]([NH:32][CH2:2][CH:3]([CH3:22])[CH2:4][O:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:31])[CH3:30]
Reactant: CC(CCl)COC1c2ccccc2C(=O)N1c1ccccc1
Reactant: CC(C)N
Agent: O=C(O)C(=O)O
Solvent: CC(C)=O
Product: CC(CNC(C)C)COC1c2ccccc2C(=O)N1c1ccccc1
Temperature: 2 °C

Procedure:
A solution of 3-(3-chloro-2-methylpropoxy)-2-phenyl-isoindolin-1-one (24.7 g.) in isopropylamine (250 cc.) is heated in an autoclave at 120° C. for 24 hours. After cooling, the reaction mixture is concentrated to dryness under reduced pressure and the residue is then taken up in a 5N aqueous solution of sodium hydroxide (30 cc.) water (200 cc.) and diethyl ether (200 cc.). The ether solution is washed three times with distilled water (total 150 cc.) and is extracted four times with a 2N aqueous solution of methanesulphonic acid (total 200 cc.). The acid solution is washed three times with diethyl ether (total 150 cc.) and is then rendered alkaline by adding 10N sodium hydroxide solution (50 cc.). The oil which separates out is extracted four times with diethyl ether (total 200 cc.). The organic extracts are combined, washed five times with distilled water (total 250 cc.), dried over anhydrous magnesium sulphate and concentrated to dryness under reduced pressure. The residue obtained (22.2 g.) is dissolved in acetone (130 cc.). A solution of oxalic acid (6.2 g.) in acetone (30 cc.) is added to the solution obtained. After cooling for 3 hours at 2° C., the product which has crystallised is filtered off and washed twice with acetone (total 20 cc.) and then with diethyl ether (30 cc.). After drying, 3-(3-isopropylamino-2-methylpropoxy)-2-phenyl-isoindolin-1-one hydrogen oxalate (26.6 g.), which melts at 150° C., is obtained.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1.[CH2:31]([C:35]1[CH:36]=[CH:37][C:38]([CH:41]=O)=[N:39][CH:40]=1)[CH2:32][CH2:33][CH3:34].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:31]([C:35]1[CH:36]=[CH:37][C:38]([CH2:41][NH:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([CH2:12][N:11]([CH2:10][C:2]3[NH:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:1]=3)[CH:21]3[C:30]4[N:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:24][CH2:23][CH2:22]3)=[CH:18][CH:17]=2)=[N:39][CH:40]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCc1ccc(C=O)nc1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCc1ccc(CNCc2ccc(CN(Cc3nc4ccccc4[nH]3)C3CCCc4cccnc43)cc2)nc1

Procedure:
Using general procedure B: N-(1H-benzimidazol-2-ylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (0.1258 g, 0.316 mmol) and 5-n-butylpyridine-2-carboxaldehyde (0.0603 g, 0.294 mmol) were reacted with NaBH(OAc)3 (0.0942 g, 0.444 mmol) in CH2Cl2 (2.5 mL). Purification of the crude material by radial chromatography (2 mm TLC plate, 50:1:1 CH2Cl2: CH3OH: NH4OH) provided 0.0713 g (45%) of AMD9398 (free base).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[S:17]([OH:20])(=[O:19])=[O:18]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]([S:17]([OH:20])(=[O:19])=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(-c2ccccc2)c1
Reactant: O=S(=O)(O)Cl
Product: O=[N+]([O-])c1cccc(-c2ccccc2S(=O)(=O)O)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3′-Nitrobiphenyl (10 g) was added slowly to chlorosulfonic acid (20 mL) at room temperature and stirring was continued for 2 hours. The mixture was carefully dripped into ice water and extracted with DCM. The solvent was evaporated to give the title compound as a white powder.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[OH:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[OH-].[K+].Cl>CS(C)=O>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([N:16]2[CH:17]=[CH:18][C:13](=[O:12])[CH:14]=[CH:15]2)=[CH:8][C:6]=1[NH2:7])([O-:11])=[O:10]
Reactant: Oc1ccncc1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1cc(-n2ccc(=O)cc2)ccc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 3 h
Yield: 102.7 %

Procedure:
First, 8.628 g of 5-chloro-2-nitroaniline, 7.161 g of 4-hydroxypyridine, and 4.892 g of powdered potassium hydroxide were added to 60 ml of dry dimethylsulfoxide The mixture thus obtained was stirred at 130° C. for 3 hours in a nitrogen atmosphere. Then, 200 ml of ice water was added to the reaction mixture and neutralized with 4N hydrochloric acid. The resultant solution was stirred for 30 minutes, giving a precipitate. The precipitate was filtered and washed with water. The precipitate was subjected to silica gel column chromatography, and fractions eluted with 20% methanol in methylene chloride were collected. The collected fractions were combined and evaporated. The residue was recrystallized in methanol to give 11.868 g of yellowish orange crystals of 2-nitro-5-(4-oxo-4H-pyridin-1-yl)-aniline.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]([CH3:24])[CH2:15][CH2:16][N:17]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[C:1]([N:20]1[CH2:21][CH2:22][CH2:23][N:17]([CH2:16][CH2:15][N:14]([CH3:24])[CH3:13])[CH2:18][CH2:19]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CN(C)CCN1CCCNCC1
Product: CCCCCCC/C=C/C(=O)N1CCCN(CCN(C)C)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 1-(2-dimethylaminoethyl)-1,4-diazepane as starting raw materials, to produce an intended compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH3:17][Li]>O1CCCC1.CCOCC>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]([CH3:17])([OH:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Reactant: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(O)CCCc2nc3ccccc3c(N)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 100 ml of dry tetrahydrofuran was suspended 5.00 g of 9-amino-3,4-dihydroacridin-1(2H)-one at ice temperature and 78 ml (4 eq) of 1.2M CH3Li solution in ether was added thereto at such a rate as to avoid bubbling. The reaction mixture was stirred overnight as it warmed to ambient temperature. The next day 20 ml more of the CH3Li solution was added to drive the reaction to a completion. After 0.5 hour the reaction was quenched with excess water and 4.97 g of the precipitate was collected and air dried. The product was recrystallized from MeOH/toluene. The yield was 2.06 g (38%) of granules, melting point 250° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@@:4]1([CH3:18])[C@@H:9]2[O:10][C@@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][CH2:30][C:31]1[NH:32][CH:33]=[CH:34][N:35]=1>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@@:4]1([CH3:18])[C@H:9]([OH:10])[C@@H:8]([N:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][CH3:21])[CH2:30][C:31]2[NH:35][CH:34]=[CH:33][N:32]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: COc1ccccc1NCc1ncc[nH]1
Reactant: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Product: COc1ccccc1N(Cc1ncc[nH]1)[C@H]1c2cc([N+](=O)[O-])ccc2O[C@@](C)(C(OC)OC)[C@@H]1O
Yield: 67.3 %

Procedure:
The title compound (580 mg, 67%) was prepared using (2R,3R,4R)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (500 mg, 1.78 mmol) and 2-methoxyphenyl-1H-imidazol-2-ylmethylamine (231 mg, 1.78 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.CO[CH:10](OC)[N:11]([CH3:13])[CH3:12]>>[CH3:10][N:11]([CH3:13])[CH:12]=[N:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: COC(OC)N(C)C
Reactant: Nc1cnccn1
Product: CN(C)C=Nc1cnccn1

Procedure:
A solution of 2-aminopyrazine (16.45 g) in dimethylformamide dimethylacetal (22.4 g) was refluxed at 85° C. for 3 h, evaporated under reduced pressure, and used in the next step without further purification.
Reaction SMILES: COP([CH2:7][C:8]([C:10]1[CH:11]=[N:12][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]=1[CH3:15])=[O:9])(=O)OC.CC(C)([O-])C.[K+].[CH3:28][C@@:29]12[C:35]([CH3:37])([CH3:36])[C@@H:32]([CH2:33][CH2:34]1)[C:31](=O)[C:30]2=[O:39]>C(O)(C)(C)C>[CH3:28][C@@:29]12[C:35]([CH3:37])([CH3:36])[C@@H:32]([CH2:33][CH2:34]1)/[C:31](=[CH:7]\[C:8]([C:10]1[CH:11]=[N:12][N:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:14]=1[CH3:15])=[O:9])/[C:30]2=[O:39]
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Reactant: COP(=O)(CC(=O)c1cnn(-c2ccccc2)c1C)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1c(C(=O)/C=C2/C(=O)[C@@]3(C)CC[C@@H]2C3(C)C)cnn1-c1ccccc1
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
[2-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester (1.1 g) in tert-butanol (60 mL) at RT under an argon atmosphere was treated with potassium tert-butoxide (0.412 g) and the mixture was stirred for 30 minutes. Then (1S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione (0.499 g) was added at RT and the mixture was heated at reflux for 12 h under an argon atmosphere. The reaction mixture was partitioned between water and AcOEt, the layers were separated, the aqueous layer extracted twice with AcOEt. The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (heptane/AcOEt 100% to 80%) to give (1S,4R)-1,7,7-trimethyl-3-[2-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-eth-(E)-ylidene]-bicyclo[2.2.1]heptan-2-one (0.78 g) as a light yellow solid. MS (EI): 348.2 (M+).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:21])[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[C:12]([C:13]=1O)=[CH:11][CH:10]=[CH:9][N:8]=2)(=O)[CH3:2].Cl.Cl.[CH2:24]([NH:31][NH2:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C(O)(=O)C>[CH2:24]([N:31]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[N:8][C:7]=3[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:5](=[O:21])[C:4]=2[C:1]([CH3:2])=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NNCc1ccccc1
Reactant: CC(=O)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Cc1nn(Cc2ccccc2)c2c1c(=O)n(-c1ccccc1)c1ncccc21
Temperature: 25 °C
Yield: 61.5 %

Procedure:
Compound 102 obtained in Example 2, 3.0 g (10.7 millimoles), was suspended in 20 ml of glacial- acetic acid, and 3.1 g (16.1 millimoles) of benzylhydrazine dihydrochloride and 9.0 ml (64.2 millimoles) of triethylamine were added to the suspension. The mixture was heated under reflux for 10 hours. The reaction solution was cooled to room temperature, and the precipitate was collected by filtration and recrystallized from DMF-water to give 2.4 g (61.5%) of Compound 5.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.[Br:9][C:10]1[CH:15]=[CH:14][C:13](O)=[C:12]([CH2:17][CH3:18])[CH:11]=1>CN(C=O)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([O:4][CH3:1])=[C:12]([CH2:17][CH3:18])[CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: CCc1cc(Br)ccc1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCc1cc(Br)ccc1OC
Reaction time: 16 h
Yield: 67.5 %

Procedure:
Potassium carbonate (3.9 g, 28.3 mmol) and methyl iodide (0.59 mL, 9.43 mmol) were added to a solution of 4-Bromo-2-ethyl-phenol (1.9 g, 9.43 mmol, from step 1 of Example A(22)) dissolved in DMF (10 mL). The mixture was stirred for 16 h under N2 and then partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to a yellow oil. The oil was purifed by silica gel chromatography to give the title compound as a clear oil (1.37 g, 68%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[CH:5]=[C:4]([Br:13])[C:3]=1[OH:14].[Sn].O>CC(O)=O.Cl>[Br:13][C:4]1[C:3]([OH:14])=[CH:2][C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2
Reactant: Oc1ccc2cc(Br)c(O)c(Br)c2c1
Agent: Cl
Agent: [Sn]
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc2cc(Br)c(O)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 1,3-dibromonaphthalene-2,7-diol (48.76 g, 153.34 mmol) (Helv. Chim. Acta, 78, pp. 1037-1066, 1995) in AcOH/HCl is added tin (17.48 g, 147.21 mmol) in portions. The mixture is stirred vigorously at room temperature for 1 h. The reaction forms a paste and is stirred for an additional 4 h, at which point it becomes mobile again. Stirring is continued overnight. The mixture is poured into water (1 L) and extracted with EtOAc. The organic layer is dried over MgSO4, filtered and concentrated to afford a sticky beige solid. The solid is triturated with DCM and filtered to afford 3-bromonaphthalene-2,7-diol as a fluffy beige solid.
Reaction SMILES: [NH2-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].Cl[CH2:10][C:11]([NH:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])=[O:12].O>COC(C)(C)C>[CH3:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=1[NH:13][C:11](=[O:12])[CH2:10][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8]
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: O=C1CCCN1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: Cc1cccc(C)c1NC(=O)CN1CCCC1=O
Yield: 89.2 %

Procedure:
In 30 ml of t-butyl methyl ether was suspended 897 mg of sodium amide in a nitrogen stream, and 2.13 g of 2-pyrrolidinone was slowly added thereto dropwise, followed by refluxing for 2 hours. After allowing to cool, 1.97 g of 2-chloro-N-(2,6-dimethylphenyl)acetamide was added thereto, followed by refluxing for 2 hours. To the reaction mixture was added 50 ml of hot water of about 70° to 85° C., and the mixture was allowed to cool with stirring. The thus formed crystals in the aqueous layer were collected by filtration and dried under reduced pressure to obtain 2.19 g (89%) of the titled compound.
Reaction SMILES: C([O:4][C:5]([CH3:33])([CH2:7][CH2:8][CH2:9][N:10]1[CH2:19][C@@H:18]2[CH2:20][O:21][CH2:22][CH2:23][N:17]2[C:16]2[N:15]=[C:14]([C:24]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:25]=3[CH:26]=[CH:27][NH:28]4)[N:13]=[CH:12][C:11]1=2)[CH3:6])(=O)C.[OH-].[Na+]>CO>[NH:28]1[C:29]2[C:25](=[C:24]([C:14]3[N:13]=[CH:12][C:11]4[N:10]([CH2:9][CH2:8][CH2:7][C:5]([CH3:33])([OH:4])[CH3:6])[CH2:19][C@@H:18]5[CH2:20][O:21][CH2:22][CH2:23][N:17]5[C:16]=4[N:15]=3)[CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: CC(=O)OC(C)(C)CCCN1C[C@@H]2COCCN2c2nc(-c3cccc4[nH]ccc34)ncc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(O)CCCN1C[C@@H]2COCCN2c2nc(-c3cccc4[nH]ccc34)ncc21
Temperature: 50 °C
Reaction time: 4 h
Yield: 71.1 %

Procedure:
To a 25 mL pear flask was added (R)-5-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-2-methylpentan-2-yl acetate (PREPARATION x82, 48 mg, 0.107 mmol) in methanol (3 mL) to give a yellow solution. Aqueous NaOH (3N, 0.4 mL) was added and the mixture was stirred at 50° C. for 4 hours, before being cooled to room temperature. The reaction mixture was partitioned between saturated NaHCO3 and ethyl acetate, and the aqueous layer was extracted a second time with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated. After trituration with Et2O, the solid product was dried in vacuo to give the title compound as an off-white solid (31 mg, 71%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (s, 6H), 1.32-1.48 (m, 2 H), 1.53-1.73 (m, 2 H), 2.95-3.10 (m, 2 H), 3.11-3.25 (m, 2 H), 3.26-3.40 (m, 2H), 3.50-3.64 (m, 2 H), 3.93 (dd, J=10.99, 3.16 Hz, 1 H), 4.06 (dd, J=11.49, 3.16 Hz, 1 H), 4.19 (s, 1 H), 4.52 (d, J=11.62 Hz, 1 H), 7.11 (t, J=7.71 Hz, 1 H), 7.29-7.44 (m, 3 H), 7.77 (s, 1 H), 7.93 (dd, J=7.45, 0.88 Hz, 1 H), 11.11 (br s, 1 H); ESI-MS m/z [M+H]+ calc'd for C23H29N5O2, 408.24; found 408.3.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([N:17]2[C:21]([CH3:22])=[CH:20][N:19]=[CH:18]2)=[C:7]([CH:16]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].[CH2:25]=[O:26]>C1(C)C(C)=CC=CC=1>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([N:17]2[C:21]([CH3:22])=[CH:20][N:19]=[C:18]2[CH2:25][OH:26])=[C:7]([CH:16]=1)[C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: Cc1cncn1-c1ccc(C(F)(F)F)cc1C(=O)c1ccccc1
Reactant: C=O
Solvent: Cc1ccccc1C
Product: Cc1cnc(CO)n1-c1ccc(C(F)(F)F)cc1C(=O)c1ccccc1

Procedure:
In the manner given in Example 1, 5-(trifluoromethyl)-2-(5-methylimidazol-1-yl)benzophenone is heated in a bomb with paraformaldehyde in xylene to 140° C. to give 5-(trifluoromethyl)-2-[2-(hydroxymethyl)-5-methylimidazol-1-yl]benzophenone.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:14])[O:9][CH2:10][C:11](=O)[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C(COC)OC>[Cl:1][C:2]1[C:7]2[C:8](=[O:14])[O:9][CH2:10][C:11](=[S:24])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1COC(=O)c2c(Cl)cccc2N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: COCCOC
Product: O=C1OCC(=S)Nc2cccc(Cl)c21
Temperature: 25 °C
Reaction time: 24 h
Yield: 162.5 %

Procedure:
6-Chloro-4,1-benzoxazepin-2,5-dione (10.6 g, 50 mmole) in dimethoxyethane (250 ml) was treated with Lawesson's reagent (12.1 g, 30 mmole) and the mixture stirred at room temperature for 24 hours. The solution was filtered and evaporated. The residue in ethyl acetate was washed with sodium bicarbonate solution and dried (Na2SO4). The solution was diluted with hexane and filtered through silica. The filtrate was evaporated to give the product (11.1 g, 97%), m.p. 177°-180° C.