Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][CH2:30][CH2:31][CH2:32]Br>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:32][CH2:31][CH2:30][O:29][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][O:23]2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: BrCCCOC1CCCCO1
Reactant: CC(C)c1ccc(NC(=O)C2CCCc3ccccc32)cc1
Product: CC(C)c1ccc(N(CCCOC2CCCCO2)C(=O)C2CCCc3ccccc32)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 6 using N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.75 g) and 3-(tetrahydropyran-2-yloxy)propyl bromide (0.52 mL) as starting materials, N-(4-isopropylphenyl)-N-[3-(tetrahydropyran-2-yloxy)propyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.9 g) was obtained.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[OH:10][C:11]1[C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>C(O)(=O)C.O>[N+:6]([C:17]1[CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]([OH:10])=[C:19]([CH:18]=1)[C:20]([OH:22])=[O:21])([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccc(C(=O)O)c1O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc([N+](=O)[O-])cc(C(=O)O)c1O
Reaction time: 0.17 h

Procedure:
A mixture of 40 ml of sulfuric acid and 33 ml of nitric acid is stirred for 10 minutes and then 10 ml of acetic acid is added. To this is added a suspension of 10 g of 2-hydroxyisophthalic acid (Org. Syn., Vol. 5, p. 617) in 20 ml of acetic acid slowly with cooling in a water bath. A 10 ml portion of acetic acid is added. The reaction mixture is dissolved in water and extracted with ether. The ether is washed with saturated saline, dried over sodium sulfate and evaporated giving 5-nitro-2-hydroxyisophthalic acid as an orange oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[I-].[Na+].[OH:19][C:20]1[CH:29]=[CH:28][C:27]2[N:26]=[C:25]([NH2:30])[C:24]3[N:31]=[C:32]([CH2:37][O:38][CH3:39])[N:33]([CH2:34][CH2:35][CH3:36])[C:23]=3[C:22]=2[CH:21]=1>CC(C)=O.ClCCl>[CH3:39][O:38][CH2:37][C:32]1[N:33]([CH2:34][CH2:35][CH3:36])[C:23]2[C:22]3[CH:21]=[C:20]([O:19][CH2:9][CH2:10][N:11]4[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]4)[CH:29]=[CH:28][C:27]=3[N:26]=[C:25]([NH2:30])[C:24]=2[N:31]=1
Reactant: CCCn1c(COC)nc2c(N)nc3ccc(O)cc3c21
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCCn1c(COC)nc2c(N)nc3ccc(OCCN4CCCCC4)cc3c21
Temperature: 25 °C
Yield: 25.2 %

Procedure:
Potassium carbonate (1.48 g, 10.75 mmol), N-(2-chloroethyl)-piperidine hydrochloride (483 mg, 2.62 mmol), sodium iodide (100 mg, 0.66 mmol), and 8-hydroxy-2-methoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (500 mg, 1.75 mmol) were combined in acetone as a slurry and heated at reflux overnight. The reaction mixture was cooled to ambient temperature and filtered. The filter cake was washed with acetone and the combined filtrate was concentrated under reduced pressure to afford a solid. The solid material was dissolved in dichloromethane and purified by chromatography on a HORIZON HPFC system (eluting with a gradient of CMA:chloroform from 0:100 to 40:60). The resulting material was concentrated under reduced pressure and crystallized from acetonitrile to afford 175 mg of 2-methoxymethyl-8-(2-piperidin-1-ylethoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as tan crystals, mp 160-162° C. Anal. calcd for C22H31N5O2.0.33 CH3CN.0.33H2O: C, 65.18; H, 7.90; N, 17.82. Found: C, 65.18; H, 8.05; N, 18.10.
Reaction SMILES: [C:1]([O:4]C(=O)C)(=[O:3])[CH3:2].[OH:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12]>N1C=CC=CC=1>[C:1]([OH:4])(=[O:3])[CH3:2].[OH:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)NCO
Solvent: c1ccncc1
Product: CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic anhydride (25 g) and pyridine (10 drops) is added to N-(hydroxymethyl)acetamide (9 g, 0.1 mol). The reaction mixture is stirred overnight at room temperature, concentrated in vacuo and chased with xylene to give the title product as an oil (11.9 g, 0.9 mol) which is identified by 1HNMR spectral analysis.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]([NH:11][C:12](=[O:14])[CH3:13])=[CH2:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1>CO.[Pd]>[F:1][C:2]1[C:3]([CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C=C(NC(C)=O)c1ncc(F)cc1F
Agent: [Pd]
Solvent: CO
Product: CC(=O)NC(C)c1ncc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.5 %

Procedure:
To N-(1-(3,5-difluoropyridin-2-yl)vinyl)acetamide (Method 24; 2.2 g, 11.1 mmol) in MeOH (5 ml) under N2 was added 10% Pd/C (0.0537 g, 0.0505 mmol). The solution was charged with 1 atmosphere of H2. The reaction was stirred at room temperature for 1 hour. The catalyst was removed by filtration and the filtrate was dried to give the title compound as a white solid (0.10 g, 99%). 1H NMR (400 MHz) 8.47 (d, J=2.4 Hz, 1H), 8.34 (d, J=7.2 Hz, 1H), 7.89 (m, 1H), 5.21 (m, 1H), 1.81 (s, 3H), 1.34 (d, J=6.8 Hz, 3H). MS: Calcd.: 200. Found: [M+H]+ 201.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>CC#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc(Br)cc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN1CCN(CCCOc2ccc(Br)cc2)CC1
Temperature: 75 °C
Reaction time: 5 h
Yield: 87.6 %

Procedure:
To a mixture of 1-bromo-4-(3-bromopropoxy)benzene (300 mg, 1.02 mmol) and 1-methylpiperazine (100 mg, 1.02 mmol) in CH3CN (6 mL) was added Cs2CO3 (365 mg, 1.10 mmol). The mixture was stirred at 75° C. for 5 hours. The mixture was poured into ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered, and concentrated to give the title compound (280 mg, 75% yield) as a yellow oil.
Reaction SMILES: [Cl:1][CH:2]([CH2:15][CH3:16])[C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[O:11][C:7]=2[CH:6]=1)=[O:4].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:17]([N:9]1[C:8]2[CH:13]=[CH:14][C:5]([C:3](=[O:4])[CH:2]([Cl:1])[CH2:15][CH3:16])=[CH:6][C:7]=2[O:11][C:10]1=[O:12])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCC(Cl)C(=O)c1ccc2[nH]c(=O)oc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(Cl)C(=O)c1ccc2c(c1)oc(=O)n2Cc1ccccc1

Procedure:
62.50 g (260.79 mmol) 6-(2-chloro-butyryl)-3H-benzoxazol-2-one, 31 mL (261.00 mmol) benzylbromide, 160.00 g (1157.74 mmol) potassium carbonate and 3000 mL acetone are stirred for 24 h at RT. The reaction mixture is concentrated by rotary evaporation i. V. and the residue is separated on silica gel (eluant cyclohexane/EA). The suitable fractions are concentrated by rotary evaporation i. V. and the residue is crystallised with EtOH.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH:12]([CH2:16][NH:17][C:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([CH2:29][CH2:30][CH2:31][NH:32][C:33]2[N:34]([C:38]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:35]=[CH:36][N:37]=2)[N:24]=[CH:23]3)=[O:19])[C:13]([O-:15])=[O:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+]>O1CCCC1.O>[C:1]1([CH2:7][O:8][C:9]([NH:11][CH:12]([CH2:16][NH:17][C:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([CH2:29][CH2:30][CH2:31][NH:32][C:33]2[N:34]([C:38]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH:35]=[CH:36][N:37]=2)[N:24]=[CH:23]3)=[O:19])[C:13]([OH:15])=[O:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NC(CNC(=O)c1ccc2c(cnn2CCCNc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1)C(=O)[O-])OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC(CNC(=O)c1ccc2c(cnn2CCCNc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1)C(=O)O)OCc1ccccc1
Reaction time: 18 h
Yield: 52.8 %

Procedure:
Methyl 2-((phenylmethoxy)carbonylamino-3-((1-(3-((1-(triphenylmethyl)imidazol-2-yl)amino)propyl)(1H-indazol-5-yl))carbonylamino)propanoate (1.55 g, 2.03 mmol) was dissolved in tetrahydrofuran (20 mL). Lithium hydroxide monohydrate (1.71 g, 40.6 mmol) was dissolved in water and added to the reaction. The reaction was stirred overnight under N2 for 18 h. The tetrahydrofuran was removed under high vacuum. The pH of the remaining aqueous layer was adjusted to 5 with 1N HCl. The aqueous layer was extracted with methylene chloride. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated to an oil under high vacuum. The oil was recrystallized from hexane:ethyl acetate to give 800.9 mgs (53%) of product. ESMS: Calcd. for C44H41N7O5, 747.32. Found, 748.3 [M+H]+1 Analytical HPLC, Method A, Rt=15.66 min, Purity=94%.
Reaction SMILES: [PH2:1](=[O:3])[OH:2].[CH2:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH2:21]([P:1]([OH:2])[OH:3])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4]
Reactant: C=CCCCCCCCCCCCCCCCC
Reactant: O=[PH2]O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCP(O)O
Yield: 98.6 %

Procedure:
Example 7 is repeated with 66 g (0.5 mol) of phosphinic acid, 140.0 g (0.5 mol) of octadecene, 23 mg of tris(dibenzylideneacetone)dipalladium and 32 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene in 500 g of tetrahydrofuran followed by working up to obtain 157 g (85% of theory) of octadecylphosphonous acid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH:5]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:11]1([CH:5]2[CH:6]=[C:7]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:8][CH2:9][N:4]2[C:1](=[O:3])[CH3:2])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)N1CCC(=O)CC1c1ccccc1
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)N1CCC(N2CCCC2)=CC1c1ccccc1

Procedure:
To a mixture of 1-acetyl-2-phenylpiperidin-4-one (3.364 mmol, 1.0 eq.) and pyrrolidine (3.7 mmol, 1.1 eq.) in toluene (16 ml) was added PTSA (0.336 mmol, 0.1 eq.) and the reaction mixture was heated to reflux for 5 h using a Dean-Stark apparatus. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=3)[C:10]([C:11](=O)[C:12]#[CH:13])=[C:6]2[CH:5]=[CH:4][CH:3]=1.Cl.[CH:23]1([NH:28][C:29]([NH2:31])=[NH:30])[CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+].CCOCC>CN(C)C=O.O>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=3)[C:10]([C:11]3[CH:12]=[CH:13][N:31]=[C:29]([NH:28][CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[N:30]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(=O)c1c(-c2cccc(C)c2)nn2c(Cl)cccc12
Reactant: N=C(N)NC1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: Cc1cccc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 25 °C
Yield: 45.5 %

Procedure:
To a solution of 1-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (4.04 g, 13.0 mmol) in N,N-dimethylformamide (100 mL) was added cyclopentyl guanidine hydrochloride (6.36 g, 39 mmol), followed by solid potassium carbonate (5.39 g, 39 mmol). The resultant solution was heated to reflux for 6 hours. Upon cooling to room temperature, ether was added followed by water. The organics were washed with brine, and the aqueous extracted with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (3:10 ethyl acetate:hexanes) to give 4-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (2.39 g, 43%) as a yellow foam. 1H NMR (CDCl3) δ 8.47 (d, 1H), 7.99 (d, 1H), 7.48 (s, 1H), 7.39 (d, 1H), 7.33–7.24 (m, 3H), 7.05 (d, 1H), 6.33 (d, 1H), 5.38 (broad s, 1H), 4.36 (m, 1H), 2.40 (s, 3H), 2.10 (m, 2H), 1.78 (m, 2H), 1.67 (m, 2H), 1.58 (m, 2H); MS m/z 404 (M+1).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[NH:27][C:26](=[O:28])[O:25][C:24]([CH2:31][CH3:32])([CH2:29][CH3:30])[C:23]=4[CH:33]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:34]O>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([S:13]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[NH:27][C:26](=[O:28])[O:25][C:24]([CH2:29][CH3:30])([CH2:31][CH3:32])[C:23]=4[CH:33]=3)=[O:34])=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC1(CC)OC(=O)Nc2ccc(OCCCCSc3ccc(C4CCCCC4)cc3)cc21
Reactant: OO
Product: CCC1(CC)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(C4CCCCC4)cc3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-cyclohexyl-phenylmercapto)-butoxy]-4,4-diethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([NH:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:28]#[N:29])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[C:28]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:9]=1[NH:8][C:4]1[CH:3]=[C:2]([NH:1][S:38]([CH3:37])(=[O:40])=[O:39])[CH:7]=[CH:6][CH:5]=1)=[CH:17][C:16]([NH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[N:15][CH:14]=2)#[N:29]
Reactant: N#Cc1cnc2cnc(NCCN3CCOCC3)cc2c1Nc1cccc(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(Nc2c(C#N)cnc3cnc(NCCN4CCOCC4)cc23)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 33.6 %

Procedure:
4-(3-aminophenylamino)-6-(2-morpholinoethylamino)-1,7-naphthyridine-3-carbonitrile (111 mg, 0.29 mmol, 1 eq) was suspended in methylene chloride (10 mL). Triethylamine (44 uL, 0.32 mmol, 1.1 eq) was added and the mixture was cooled to 0° C. Methylsulfonyl chloride (24 uL, 0.31 mmol, 1.1 eq) was added and the mixture was stirred at room temperature for 12 hr. Another 44 uL triethylamine (1.1 eq) and 48 uL methylsulfonyl chloride (2.2 eq) were added and reaction mixture was stirred for 12 hr. Work-up and preparative HPLC yielded 45.5 mg product (34% yield): 1H NMR (400 MHz, DMSO-D6) δ ppm 2.39-2.47 (m, 4 H) 2.56 (t, J=6.82 Hz, 2 H) 2.99-3.03 (m, 3 H) 3.27-3.42 (m, 2 H) 3.55-3.61 (m, 4 H) 6.63 (t, J=6.06 Hz, 1 H) 7.00-7.04 (m, 1 H) 7.04 (s, 1 H) 7.08 (d, J=8.59 Hz, 1 H) 7.12-7.16 (m, 1 H) 7.36 (t, J=8.34 Hz, 1 H) 8.26 (s, 1 H) 8.84 (s, 1 H) 9.69 (s, 2 H).
Reaction SMILES: [ClH:1].O1CCOCC1.[CH2:8]([O:10][C:11]([C@@H:13]([NH:22][C@H:23]1[CH2:29][CH2:28][C@H:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][N:25]([CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])[C:24]1=[O:44])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])[CH3:9]>>[ClH:1].[CH2:8]([O:10][C:11]([C@@H:13]([NH:22][C@H:23]1[CH2:29][CH2:28][C@H:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][N:25]([CH2:36][C:37]([OH:39])=[O:38])[C:24]1=[O:44])[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CC[C@H](c2ccccc2)CN(CC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CC[C@H](c2ccccc2)CN(CC(=O)O)C1=O
Reaction time: 16 h

Procedure:
4 ml of a 4N hydrogen chloride/dioxane solution in which was dissolved 0.95 g of t-butyl α-{3(S)-[1(S)-ethoxycarbonyl-3-phenylpropylamino]-2-oxo-6(R)-phenylperhydroazepin-1-yl}acetate (Isomer A-2) [prepared as described in Example 1(l)] were allowed to stand for 16 hours; at the end of this time, the solvent was distilled off, and the syrupy residue was mixed with a small amount of ethyl acetate and diisopropyl ether and then filtered, to give 0.80 g of the title compound as a crystalline powder, melting at 200°-202° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][OH:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[SH:8].[Cl:13][C:14]1[N:15]=[N:16][C:17](Cl)=[CH:18][C:19]=1[CH:20]([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][OH:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[S:8][C:17]1[N:16]=[N:15][C:14]([Cl:13])=[C:19]([CH:20]([CH3:22])[CH3:21])[CH:18]=1
Reactant: CC(C)c1cc(Cl)nnc1Cl
Reactant: OCCc1cc(Cl)c(S)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1cc(Sc2c(Cl)cc(CCO)cc2Cl)nnc1Cl
Temperature: 90 °C
Yield: 52.4 %

Procedure:
A solution of 2-(3,5-dichloro-4-mercapto-phenyl)-ethanol (73) (620 mg, 2.78 mmol) in dimethyl sulfoxide (25 mL) was treated with 3,6-dichloro-4-isopropyl-pyridazine (7) (530 mg, 2.78 mmol) and potassium carbonate (1.54 g, 11.12). The resulting mixture was heated to 90° C. for 18 h. At this time, the reaction was cooled to 25° C., poured into a solution of water (200 mL) and a 1N aqueous hydrochloric acid solution (25 mL). The mixture was extracted with ethyl acetate (2×200 mL). The organics were then washed with water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried with magnesium sulfate, filtered, and concentrated under vacuum. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70:30 petroleum ether/ethyl acetate) afforded 2-[3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-ylsulfanyl)-phenyl]-ethanol (74) (550 mg, 52%) as a pale yellow oil; EI(+)-HRMS m/e calcd for C15H15Cl3N2OS (M+H)+ 377.0044, found 377.0043. Exact Mass=375.9971; Molecular weight=377.72
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:39][CH2:38][C:18]2([N:22]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:21][N:20]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:19]2=[O:37])[CH2:17][CH2:16]1)=O)(C)(C)C>C(OCC)C>[CH2:30]([N:20]1[C:19](=[O:37])[C:18]2([CH2:38][CH2:39][NH:15][CH2:16][CH2:17]2)[N:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:21]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1ccccc1)CN2c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: O=C1N(Cc2ccccc2)CN(c2ccc(F)cc2)C12CCNCC2
Reaction time: 1 h

Procedure:
Cool trifluoroacetic acid (20 mL) using an ice bath and add 8-tert-butoxycarbonyl-3-benzyl-1-(4-fluoro-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]decane (10 mmol). After 1 h, dilute with diethyl ether (150 mL), filter to obtain a residue. Purify to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH2:12][OH:13])=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:21])[N:3]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[NH2:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:21])[N:3]=1
Reactant: COC(=O)c1c(C)nc(N)c(CO)c1-c1ccc(C)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)c1c(C)nc(N)c(C=O)c1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.6 %

Procedure:
A suspension of methyl 6-amino-5-(hydroxymethyl)-2-methyl-4-(p-tolyl)nicotinate (3.14 g, 10.97 mmol) in dichloromethane (DCM) (100 ml) was treated with PCC (2.84 g, 13.16 mmol) and stirred at rt for 1 day. The mixture was filtered through Celite™, washed with DCM, and concentrated. Purification with column chromatography (0-100% EtOAc/Hexane) afforded methyl 6-amino-5-formyl-2-methyl-4-(p-tolyl)nicotinate (2.45 g, 8.62 mmol, 79% yield) as yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.60 (s, 1 H), 7.26-7.21 (m, 2 H), 7.19-7.13 (m, 2 H), 3.48 (s, 3 H), 2.49 (s, 3 H), 2.41 (s, 3 H); LCMS (m/z) ES+=285 (M+1).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:21])[C:6]1[CH:11]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[N:9]=[C:8]([NH:16][CH:17]2[CH2:20][CH2:19][CH2:18]2)[CH:7]=1.Cl>CO>[CH:17]1([NH:16][C:8]2[CH:7]=[C:6]([CH:11]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[N:9]=2)[C:5]([OH:21])=[O:4])[CH2:18][CH2:19][CH2:20]1
Reactant: COC(=O)c1cc(NC2CCC2)nc(S(C)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)c1cc(C(=O)O)cc(NC2CCC2)n1
Reaction time: 3 h
Yield: 82.7 %

Procedure:
Add 2 N NaOH (1.26 mL) to 2-cyclobutylamino-6-methanesulfonyl-isonicotinic acid methyl ester (0.24 g 0.85 mmol) in methanol (5 mL). Stir 3 h, acidify to about pH=3 with 1 N HCl, extract into ethyl acetate, wash organic layer with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound (0.19 g, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[N:17]=[CH:16][N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@H:18]2[C@H:25]3[C@H:21]([O:22]C(C)(C)[O:24]3)[C@@H:20]([CH2:28][OH:29])[O:19]2)=[O:7])=[CH:4][CH:3]=1.Cl[S:33]([NH2:36])(=[O:35])=[O:34]>>[S:33](=[O:35])(=[O:34])([O:29][CH2:28][C@@H:20]1[C@@H:21]([OH:22])[C@@H:25]([OH:24])[C@H:18]([N:13]2[CH:12]=[N:11][C:10]3[C:14]2=[N:15][CH:16]=[N:17][C:9]=3[NH:8][C:6](=[O:7])[C:5]2[CH:30]=[CH:31][C:2]([Br:1])=[CH:3][CH:4]=2)[O:19]1)[NH2:36]
Reactant: NS(=O)(=O)Cl
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1cnc2c(NC(=O)c3ccc(Br)cc3)ncnc21
Product: NS(=O)(=O)OC[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccc(Br)cc4)ncnc32)[C@H](O)[C@@H]1O
Yield: 69 %

Procedure:
Using essentially the same procedure as example 39, step c, 4-bromo-N-{9-[(3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-9H-purin-6-yl}benzamide (0.305 g, 0.622 mmol) was reacted with chlorosulfonamide, and the product was purified by flash chromatography (50 to 100% EtOAc/hexanes) to afford the title compound (0.243 g, 69%).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([I:9])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:8][C:7]1[C:2]([Br:1])=[N:3][C:4]([I:9])=[CH:5][CH:6]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(I)nc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Brc1nc(I)ccc1OCc1ccccc1

Procedure:
2-Bromo-6-iodopyridin-3-ol was reacted with potassium carbonate and benzyl bromide to obtain 3-(benzyloxy)-2-bromo-6-iodopyridine, which was then reacted in a similar manner to Reference Example 11, Example 22 and Example 4, successively. Further, the resulting product was subjected to catalytic reduction using palladium/carbon to obtain an objective compound.