Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[C:8](=[N:15][OH:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:25](Cl)(=[O:28])[CH2:26][CH3:27]>>[C:25]([O:16][N:15]=[C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:7]1[CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]([OH:20])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1)(=[O:28])[CH2:26][CH3:27]
Reactant: CCC(=O)Cl
Reactant: CC(C)(C)c1cc(C(=NO)c2ccccc2)cc(C(C)(C)C)c1O
Product: CCC(=O)ON=C(c1ccccc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
3,5-di-t-butyl-4-hydroxybenzophenone oxime and propionyl chloride were treated in the same way as in Example 3 to obtain 3,5-di-t-butyl-4-hydroxybenzophenone O-propionyloxime.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH:14][CH2:15][C:16]([OH:18])=[O:17])[CH:5]=[CH:4][C:3]1=2.S(Cl)(Cl)=O.[CH3:24]O>>[CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([NH:14][CH2:15][C:16]([O:18][CH3:24])=[O:17])[CH:5]=[CH:4][C:3]1=2
Reactant: CO
Reactant: CC1(C)CCC(C)(C)c2cc(NCC(=O)O)ccc21
Solvent: O=S(Cl)Cl
Product: COC(=O)CNc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
8 g (22 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylglycine and 100 ml of methanol were introduced into a round-bottomed flask and 9 ml (0.12 mol) of thionyl chloride were added dropwise. The mixture was stirred at room temperature for 12 hours, the reaction medium evaporated, and the residue taken up in sodium bicarbonate solution and ethyl ether. The organic phase was decanted off, dried over magnesium sulfate and evaporated. 6 g (100%) of the expected ester were recovered.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:21]([OH:23])=[O:22])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:5]=1.[ClH:31]>O1CCOCC1>[NH2:1][C@H:2]([C:21]([OH:23])=[O:22])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:5]=1.[ClH:31]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cn(NCc2ccccc2)c2ccccc12)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1cn(NCc2ccccc2)c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dissolve Boc-Trp(NHBn) (1.97 g, 5 mmol) in a solution of 4N hydrochloric acid in dioxane (10 mL). Stir at room temperature for 30 minutes and evaporate the solvent in vacuo to give Trp(NHBn)·hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:9]=O)=[N:5][CH:6]=[CH:7][N:8]=1.Cl.[O:12]1[C:16]2[C:17]([CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[CH:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.O1CCCC1>[O:12]1[C:16]2[C:17]([CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([CH2:9][C:4]4[C:3]([O:2][CH3:1])=[N:8][CH:7]=[CH:6][N:5]=4)[CH2:25][CH2:24]3)=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[CH:13]1
Reactant: c1cc(CCC2CCNCC2)c2occc2c1
Reactant: COc1nccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1nccnc1CN1CCC(CCc2cccc3ccoc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
After adding 124 mg of 3-methoxypyrazine-2-carboxaldehyde and 200 mg of 4-[2-(benzofuran-7-yl)ethyl]piperidine hydrochloride to 3 ml of tetrahydrofuran, 238 mg of sodium triacetoxyborohydride was added and the mixture was stirred overnight at room temperature. Aqueous sodium carbonate solution was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (218 mg, 82% yield).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][S:16]([C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1)(=[O:18])=[O:17])[CH3:3]
Reactant: CCOC(=O)CN
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)CNS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.3 %

Procedure:
To a solution of 4.00 g (0.029 mol) of glycine ethyl ester hydrochloride in 40 mL of chloroform and 7.0 mL of pyridine was added 5.58 g (0.029 mol) of 4-fluorobenzenesulfonyl chloride and the reaction was stirred at room temperature for 15 h. The reaction mixture was then washed with water and 5% HCl solution and the organics were dried over MgSO4, filtered and concentrated in vacuo. The resulting white solid was washed with ether/hexanes (1:1) and dried in vacuo to provide 4.72 g (63%) of the sulfonamide as a white solid. Electrospray Mass Spec 261.8 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH2:14]([C:21]1[C:22]([NH2:33])=[N:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([C:21]1[NH:26][C:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:24][N:23]2[C:10](=[O:12])[C:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)=[N:33][C:22]=12)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ncc(-c2ccccc2)nc1Cc1ccccc1
Reactant: O=C(O)C(=O)Cc1ccc(O)cc1
Product: O=c1c(Cc2ccc(O)cc2)nc2c(Cc3ccccc3)[nH]c(-c3ccccc3)cn1-2

Procedure:
Synthesized using method A with 3-(4-hydroxyphenyl)-2-oxopropanoic acid and 3-benzyl-5-phenylpyrazin-2-amine as starting materials. Exact mass calculated for C26H22N3O2+ m/z+408.17, found m/z+408.
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.[H-].[Na+].CN(C)C=O.Br[CH:38]1[CH2:43][CH2:42][CH2:41][CH:40]=[CH:39]1>C(OCC)(=O)C>[CH:43]1([N:6]2[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]3[N:3]=[C:2]([CH3:1])[N:29]=[C:5]23)[CH2:42][CH2:41][CH2:40][CH:39]=[CH:38]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Reactant: BrC1C=CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2C=CCCC2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17 %

Procedure:
A mixture of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (5 g), sodium hydride (0.62 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 10 min, 3-bromocyclohexene (1.8 mL) was added, and the mixture was stirred at the same temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1 g, 17%).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH:5]([F:10])[CH2:4]1.[CH:18]1[CH:19]=[CH:20][C:21]2[NH:26][CH:25]=[C:24]([CH2:27][CH2:28]O)[C:22]=2[CH:23]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.[OH-].[Na+]>ClCCl>[F:10][CH:5]1[C:6]2([C:25]3[NH:26][C:21]4[C:22]([C:24]=3[CH2:27][CH2:28][O:9]2)=[CH:23][CH:18]=[CH:19][CH:20]=4)[CH2:7][CH2:8][C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([N:2]([CH3:17])[CH3:1])[CH2:4]1
Reactant: OCCc1c[nH]c2ccccc12
Reactant: CN(C)C1(c2ccccc2)CCC(=O)C(F)C1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN(C)C1(c2ccccc2)CCC2(OCCc3c2[nH]c2ccccc32)C(F)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(±)-4-dimethylamino-2-fluoro-4-phenylcyclohexanone (1.61 g, 6.83 mmol, mixture of both diastereoisomers, mainly polar diastereoisomer) together with tryptophol (1.10 g, 6.83 mmol) was dissolved in absolute dichloromethane (75 ml) at 0° C. (inside temperature). Trimethylsilyl triflate (1.67 g, 7.51 mmol, 1.36 ml, 1.225 g/ml) was then added quickly in drops to absolute dichloromethane (10 ml). The reaction mixture immediately changed colour from yellow to red-brown. The reaction mixture was stirred for 5 h at room temperature and became cloudy during this. 5N sodium hydroxide solution (100 ml) was added to the reaction mixture and stirred for 10 min. After phase separation the aqueous phase was extracted with dichloromethane (4×50 ml). The combined organic phases were dried over sodium sulphate, filtered and then completely freed of volatile constituents in a vacuum. An attempt was made to separate the residue by chromatography [silica gel (150 g), chloroform/ethanol 50:1 (500 ml), 19:1 (500 ml), 9:1 (1000 ml), 1:1 (500 ml), methanol (1000 ml)]. 467 mg (1.23 mmol, 18%, mp 259-263° C.) of a more non-polar diastereomer, 506 mg (1.34 mmol, 20%, mp 217-222° C.) of a diastereomer of average polarity and 168 mg (0.44 mmol, 6%, mp 245-247° C.) of a more polar diastereoisomer were isolated. The individual fractions were recrystallised from methanol.
Reaction SMILES: C[O:2][C:3]1[CH:26]=[CH:25][C:6]([O:7][CH:8]([P:17](=[O:24])([O:21]CC)[O:18]CC)[P:9](=[O:16])([O:13]CC)[O:10]CC)=[CH:5][CH:4]=1>Cl>[OH:2][C:3]1[CH:26]=[CH:25][C:6]([O:7][CH:8]([P:17](=[O:18])([OH:21])[OH:24])[P:9](=[O:10])([OH:16])[OH:13])=[CH:5][CH:4]=1
Reactant: CCOP(=O)(OCC)C(Oc1ccc(OC)cc1)P(=O)(OCC)OCC
Agent: Cl
Product: O=P(O)(O)C(Oc1ccc(O)cc1)P(=O)(O)O

Procedure:
Tetraethyl (4-methoxyphenoxymethylene)-bisphosphonate (2 g) and concentrated hydrochloric acid (20 ml) were refluxed overnight. Evaporation to dryness in vacuo gave the title compound as an oil which crystallized.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][C:17]#[CH:18])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:38][O:39][CH:40]([O:43][CH3:44])[CH2:41][NH2:42].CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:38][O:39][CH:40]([O:43][CH3:44])[CH2:41][NH:42][C:13](=[O:15])[C@H:12]([NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])[CH2:16][C:17]#[CH:18]
Reactant: C#CC[C@@H](NS(=O)(=O)c1ccc(C)cc1)C(=O)O
Reactant: COC(CN)OC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CC[C@@H](NS(=O)(=O)c1ccc(C)cc1)C(=O)NCC(OC)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (R)-2-(4-methylbenzenesulfonamido)pent-4-ynoic acid (11.0 g, 41.2 mmol), HOBt (6.67 g, 49.4 mmol), iPr2NEt (6.40 g, 49.4 mmol), (2,2-dimethoxyethyl)amine (8.70 g, 82.33 mmol), and EDCI (9.5 g, 49 mmol) in DMF (100 mL) was stirred for 24 h at RT. The reaction mixture was concentrated, taken up in H2O, and extracted with EtOAc (3×). The organic extracts were dried over MgSO4 and concentrated to give the title compound. 1H NMR (400 MHz, CDCl3): δ 2.15 (s, 1H), 2.43 (m, 1H), 2.51 (s, 3H), 2.88 (m, 1H), 2.94 (s, 3H), 2.96 (s, 3H), 3.37 (m, 3H), 3.85 (m, 1H), 4.33 (m, 1H), 6.78 (s, 1H), 7.33 (d, 8.0 Hz, 2H), 7.76 (d, 8.0 Hz, 2H), 8.01 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1>CN(C=O)C.C(Cl)Cl>[CH2:22]([O:21][C:19]([N:16]1[CH2:15][CH2:14][CH:13]([NH:12][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[N+:8]([O-:10])=[O:9])[CH2:18][CH2:17]1)=[O:20])[CH3:23]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: CCOC(=O)N1CCC(N)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)N1CCC(Nc2cc(Cl)ccc2[N+](=O)[O-])CC1
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a solution of 2.03 g (11.6 mmol) of 4-chloro-2-fluoro-nitrobenzene in DMF (12.0 mL) at rt was added 2.00 g (11.6 mmol) of ethyl 4-amino-1-piperidinecarboxylate. A yellow precipitate formed within 30 min and the reaction was further diluted with DMF (12.0 mL) and CH2Cl2 (5.0 mL) and was shaken at 300 RPM overnight. The solvent was removed under reduced pressure and the resulting solid was dried under vacuum. The crude product was purified by flash chromatography (silica, 0-5% MeOH/CH2Cl2) to afford 2.83 g (81%) of the title compound. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.4. MS (electrospray): m/z calculated for C14H18ClN3O4 [M++Na] 350.09, observed 350.0. 1H NMR (400 MHz, CDCl3): 8.13 (apparent d, J=9.1 Hz, 2H), 6.84 (d, J=2.0 Hz, 1H), 6.62 (dd, J=9.4, 2.3 Hz, 1H), 4.15 (q, J=14.9, 7.3 Hz, 2H), 4.08 (br d, J=12.4 Hz, 2H), 3.70-3.58 (m, 1H), 3.17-3.05 (m, 2H), 2.07 (br dd, J=13.1, 3.1 Hz, 2H), 1.63-1.50 (m, 2H), 1.28 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:23])[CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:23])[CH:20]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(Br)c3O2)cc1
Reactant: OB(O)c1ccccc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4ccccc4)c3O2)cc1
Yield: 81.6 %

Procedure:
Treatment of (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.00 g, 4.98 mmol) with phenyl boronic acid (0.912 g, 7.48 mmol), dichlorobis(tri-o-tolylphosphine)palladium(II) (0.196 g, 0.249 mmol), and potassium carbonate (1.72 g, 12.46 mmol) generally according to the procedure described for Intermediate 37 gave 1.62 g (82%) of (±)-(5-fluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a yellow oil. Rf=0.54 (silica, ethyl acetate:hexanes 1:4); Anal. calcd. for C22H19FO4S-0.2 C4H8O2: C, 65.82; H, 4.99. Found: C, 65.77; H, 4.99.
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[SH:13].F[C:15]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=1[CH:17]=[O:18]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH:17]([C:16]1[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:15]=1[S:13][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]=1)=[O:18]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Reactant: Sc1ccc2ccccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=Cc1cc([N+](=O)[O-])ccc1Sc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 2.5 mol/L sodium hydroxide aqueous solution (2.1 mL, 5.2 mmol) and tetrabutylammonium bromide (0.020 g, 0.061 mmol) were added to 2-naphthalenethiol (0.20 g, 1.2 mmol), followed by stirring at 25° C. for 15 minutes. A toluene (2.1 mL) solution of 2-fluoro-5-nitrobenzaldehyde (0.21 g, 1.2 mmol) was added to the reaction liquid, followed by stirring at 110° C. for 3.5 hours. The conventional post-reaction treatment was performed to give 2-[(2-formyl-4-nitrophenyl)thio]naphthalene. 2-[(2-Formyl-4-nitrophenyl)thio]naphthalene (0.30 g, 0.98 mmol) was dissolved in toluene (15 mL), and 2,4-thiazolidinedione (0.46 g, 3.9 mmol), piperidine (0.039 mL, 0.39 mmol), acetic acid (0.022 mL, 0.039 mmol) and molecular sieves 4A (1.5 g) were added thereto, followed by stirring at 110° C. for 2.5 hours. After the conventional post-reaction treatment, the product was triturated with ethanol to give Compound 171 (0.13 g, yield 33%).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][O:10]C(OC)=O)[O:7][C@@H:6]([N:15]2[CH:23]=[C:21]([CH3:22])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:5]1)=[N+:2]=[N-:3].C(=O)(O)[O-].[Na+]>CO>[N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:15]2[CH:23]=[C:21]([CH3:22])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: COC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Yield: 83.3 %

Procedure:
A mixture of 3'-azido-3'-deoxy-5'-O-(methoxycarbonyl)thymidine (2.50 g, 7.68 mmoles) from Example A14 and sodium bicarbonate (0.50 g) was heated 2.5 h at reflux in methanol (75 mL). The solvent was removed by rotary evaporation and the residual semi-solid was triturated with cold 5% aq. sodium bicarbonate (50 mL). The resulting solid was collected by filtration and dried in a vacuum oven at 55° C. for 17 h affording 1.71 g (83.4%) of 3'-azido-3'-deoxythymidine: mp 119°-121° C.; 1H NMR (DMSO-d6) δ1.79 (d, J=1.04 Hz, 3H C-5 CH3), 2.10-2.56 (m, 2H, C-2'H), 3.31-3.92 (m, 3H, C-3' and C-5'H), 4.40 (m, 1H, C-4'H), 5.19 (t, J=5.22 Hz, 1H, OH), 6.11 (t, J=6.46 Hz, 1H, C-1'H), 7.68 (q, J=1.04, 1H, C-6H) and 10.65 (broad, 1H, NH); TLC Rf =0.35, silica gel, CHCl3 :CH3OH/90:10.
Reaction SMILES: [N:1]1([C:6]2[N:7]=[CH:8][C:9]3[CH2:14][CH:13]([C:15]([O:17]C)=[O:16])[CH2:12][C:10]=3[N:11]=2)[CH:5]=[N:4][N:3]=[N:2]1.N1(C2N=C3CCC(C(O)=O)C3=CC=2)C=NN=N1>>[N:1]1([C:6]2[N:7]=[CH:8][C:9]3[CH2:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12][C:10]=3[N:11]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: COC(=O)C1Cc2cnc(-n3cnnn3)nc2C1
Agent: O=C(O)C1CCc2nc(-n3cnnn3)ccc21
Product: O=C(O)C1Cc2cnc(-n3cnnn3)nc2C1

Procedure:
The title compound was prepared from methyl 2-(1H-tetrazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxylate in an analogous fashion to that described in Step F of the synthesis of 2-(1H-tetrazol-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxylic acid.
Reaction SMILES: [N:1]1[C:2](=[O:12])[CH:3]=[CH:4][CH:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12.[H-].[Na+].Cl[CH2:16][C:17]#[N:18].Cl>CN(C=O)C.CCOC(C)=O>[C:17]([CH2:16][N:1]1[C:2](=[O:12])[CH2:3][CH2:4][C:5]2[CH:6]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:7]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)#[N:18]
Reactant: O=c1cccc2ccccc2n1
Reactant: N#CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCN1C(=O)CCc2ccccc2C1c1ccccc1
Reaction time: 1 h
Yield: 190.5 %

Procedure:
To a solution of 1.80 g of the benzazepinone of Example 1 (7.6 mmol) in 15 mL of DMF was added 13 mg of KI (0.76 mmol, 0.01 eq.) and 200 mg of NaH (8.4 mmol, 1.1 eq.). After 1 hr at 25°, 0.58 mL of ClCH2CN (9.2 mmol, 1.2 eq.) was added, causing a dark red solution to form. After 24 hr an additional 200 mg of NaH (8.4 mmol, 1.1 eq.) and 0.58 mL of ClCH2CN (9.2 mmol, 1.2 eq.) were added. After a further 8 hr, 150 mL 0.5N of HCl was added, followed by 150 mL of EtOAc. The EtOAc layer was then washed with saturated NaCl (2×150 mL), dried (Na2SO4), and the solvents evaporated to yield 2.0 g of crude 2-cyanomethyl-1-phenyl-1,2,4,5-tetrahydro-2 (3H)benzazepin-3-one as a red oil. This oil was immediately dissolved in 60 mL of glacial HOAc, 0.5% of 10% Pd/C was added, and the resulting mixture was hydrogenated for 4 hr at 50 psi. An additional 0.5 g of 10% Pd/C was added and the mixture hydrogenated a further 4 hr at 50 psi. The reaction mixture was filtered through celite, the filtrate evaporated, and the residue partitioned between 2N NaOH and EtOAc. The organic phase was washed with saturated NaCl, dried (Na2SO4), and evaporated to yield 0.40 g of crude 2-(2-aminoethyl compound as a yellow oil. This oil was immediately dissolved in 60 mL of PhCH3, 50 mg of p-TSA was added, and the resulting mixture refluxed for 24hr with a Dean-Stark water separator. The reaction mixture was cooled to 25° , the volatiles were removed in vacuo, and the residue partitioned between saturated NaHCO3 and EtOAc. The EtOAc layer was washed with saturated NaCl, dried (Na2SO4), and evaporated to yield 383 mg of 10-phenyl-1,2,4,5-tetrahydro-10H-imidazo[1,2-b]benzazepine free base (19%) as a viscous yellow oil. Conversion to the hydrochloride salt (EtOH/ethanolic HCl) produced as white amorphous solid, mp ~150° (dec.).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[C:32]2[N:31]=[C:30]3[N:33]([C:37]4[C:38]([CH3:46])=[N:39][C:40]([O:44][CH3:45])=[N:41][C:42]=4[CH3:43])[CH2:34][CH2:35][CH2:36][N:29]3[C:28]=2[C:27]([CH2:47][OH:48])=[CH:26][CH:25]=1>CS(C)=O.C(#N)C.C(=O)([O-])O.[Na+]>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([CH:47]=[O:48])=[C:28]2[C:32]=1[N:31]=[C:30]1[N:33]([C:37]3[C:38]([CH3:46])=[N:39][C:40]([O:44][CH3:45])=[N:41][C:42]=3[CH3:43])[CH2:34][CH2:35][CH2:36][N:29]21
Reactant: COc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(CO)c23)c(C)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC#N
Product: COc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(C)n1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 79.2 %

Procedure:
Dess-Martin reagent (10.1 g, 23.8 mmol) was added to a stirred solution of [9-chloro-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]methanol (8.08 g, 21.6 mmol) in dimethyl sulfoxide (5.0 mL) and acetonitrile (100 mL) at 0 ° C., and the mixture was stirred at 0 ° C. for 50 min. Additional Dess-Matrin reagent (4.00 g, 9.43 mmol) was added to the stirred mixture, and the mixture was stirred at 0 ° C. for 60 min. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, filtrated and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a yellow solid (6.35 g, 17.1 mmol, 79%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:12])[C:7]=1[C:8]([O:10]C)=O.Cl[C:14]1[S:15][CH:16]=[CH:17][N:18]=1>CO>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[C:8](=[O:10])[N:18]1[CH:17]=[CH:16][S:15][C:14]1=[N:12]2
Reactant: COC(=O)c1c(N)cccc1F
Reactant: Clc1nccs1
Solvent: CO
Product: O=c1c2c(F)cccc2nc2sccn12
Reaction time: 2 h

Procedure:
25.4 parts of methyl 6-fluoroanthranilate and 18 parts of 2-chlorothiazole were heated to 150° C., and the methanol formed was distilled off over a bridge. The reaction was complete after 2 hours. The solid residue was neutralized, and recrystallized from isopropanol. 30 parts of 6-fluoro-5H-thiazolo[2,3-b]quinazolin-5-one of melting point 205°-207° C. were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH:19](I)([CH3:21])[CH3:20].Cl>CC(C)=O>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:19]([CH3:21])[CH3:20])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: CC(C)I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OC(C)C)cc1O
Reaction time: 48 h

Procedure:
A 1.50 g portion of methyl 2,4-dihydroxybenzoate was dissolved in 30 ml of acetone, and 3.10 g of potassium carbonate and 1.7 ml of isopropyl iodide were added, followed by 48 hours of heating under reflux. After completion of the reaction, the reaction solution was poured into 1N hydrochloric acid aqueous solution, extracted with chloroform and dried over anhydrous sodium sulfate and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1-2:1) to give 1.60 g of methyl 2-hydroxy-4-isopropoxybenzoate.