Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC[O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]([CH2:32][CH:33]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[C:14]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[NH:27][C:26](=[O:31])[CH:25]=[CH:24]3)=[O:15])[CH2:7][CH2:6]1.Cl.[OH-].[K+]>CO>[OH:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]([CH2:32][CH:33]2[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]2)[C:14]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[NH:27][C:26](=[O:31])[CH:25]=[CH:24]3)=[O:15])[CH2:7][CH2:6]1
Reactant: COCOC1CCN(CCN(CC2CCCCCCC2)C(=O)CCCCOc2ccc3[nH]c(=O)ccc3c2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(CCCCOc1ccc2[nH]c(=O)ccc2c1)N(CCN1CCC(O)CC1)CC1CCCCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
In 30 ml of methanol is dissolved 12.10 g of 6-{4-[N-(4-methoxymethoxy-1-piperidinyl)ethyl-N-cyclooctylmethylaminocarbonyl]butoxy}carbostyril. Thereto is added 240 ml of 5% hydrochloric acid. The mixture is stirred for 8 hours at room temperature. To the mixture is added with a 10% aqueous potassium hydroxide solution under ice cooling to make the mixture alkaline. The resulting mixture is extracted with methylene chloride. The extract is washed with water and dried with anhydrous magnesium sulfate. The solvent is removed by evaporation. The residue is purified by means of a silica gel column chromatography (eluant; chloroform:methanol=8:1) and recyrstallized from ethanol to obtain 6.50 g of 6-{4-[N-(4-hydroxy-1-piperidinyl)ethyl-N-cyclooctylmethylaminocarbonyl]butoxy}carbostyril.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([CH:15]=1)[O:7][CH:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1.C(OC([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][C@@H:26]1[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O)(C)(C)C>>[CH2:31]([C@@H:26]1[NH:25][CH2:30][CH2:29][N:28]([C:2]2[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([O:7][CH:8]3[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]3)[CH:15]=2)[CH2:27]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COc1ccc(Br)cc1OC1CCN(C)CC1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1Cc1ccccc1
Product: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCN(C)CC1

Procedure:
The title compound was prepared by the method outlined for Example 1 using 4-(5-bromo-2-methoxy-phenoxy)-1-methyl-piperidine as the aryl halide and 2(S)-benzyl-piperazine-1-carboxylic acid tert-butyl ester as the amine component. The title compound was isolated as an orange oil. 1H NMR (MeOH-d4) 7.33-7.29 (m, 2H), 7.25-7.22 (m, 3H), 6.85 (d, J=8.8, 1H), 6.55 (d, J=2.8, 1H), 6.50 (dd, J=8.8, 2.8, 1H), 4.24 (m, 1H), 3.74 (s, 3H), 3.35-3.27 (m, 2H), 3.05-3.00 (m, 2H), 2.91-2.85 (m, 1H), 2.74-2.65 (m, 5H), 2.36 (m, 3H), 2.28 (s, 3H), 1.90 (m, 2H), 1.78 (m, 2H). LC/MS (Method B) 0.97 min, [M+1]+ 396.
Reaction SMILES: Cl.[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:4])[CH3:3].[F:32][C:33]([F:39])([F:38])[S:34](Cl)(=[O:36])=[O:35]>>[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:27][CH2:28][N:29]([S:34]([C:33]([F:39])([F:38])[F:32])(=[O:36])=[O:35])[CH2:30][CH2:31]1)=[O:25])([CH3:3])[CH3:4]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3C(C)C)CC1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)C(F)(F)F)CC2)n3C(C)C)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-isopropyl-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and trifluoromethanesulfonyl chloride. Light-yellow solid. MS (m/z): 545.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH2:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[C:24]([O:27][CH3:28])[CH:23]=[CH:22][CH:21]=3)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:29](OC(=O)C)(=[O:31])[CH3:30]>CCOCC>[C:29]([C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:11]([CH2:16][C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[C:24]([O:27][CH3:28])[CH:23]=[CH:22][CH:21]=2)[C:12]([O:14][CH3:15])=[O:13])(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C(Cc1cnc2cccc(OC)c2c1)c1ccc(OC)c(OC)c1
Solvent: CCOCC
Product: COC(=O)C(Cc1cnc2cccc(OC)c2c1)c1cc(OC)c(OC)cc1C(C)=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 59 %

Procedure:
To a solution of methyl 2-(3,4-dimethoxyphenyl)-3-(5-methoxyquinolin-3-yl)propanoate CCH 34144-5 (46 mg, 121 μmol) in acetic anhydride (2.0 mL, 21.2 mmol) at 0° C. in a 50 mL round-bottomed flask equipped with a magnetic stirrer was added HClO4 (ca. 70% solution in water, 0.1 mL, 1.2 mmol). The reaction mixture was then allowed to warm up to RT, stirred for 45 min and diluted with Et2O (40 mL). The solid was filtered and washed several times with Et2O giving a brown residue. The residue was then suspended in CH2Cl2 (40 mL) before neutralisation with saturated aqueous NaHCO3 solution. The organic phase was isolated, washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 0:100) gave methyl 2-(2-acetyl-4,5-dimethoxyphenyl)-3-(5-methoxyquinolin-3-yl)propanoate CCH 34154 as a yellow solid (30 mg, 59% yield).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].O[CH2:13][CH:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(O)C>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)[O:21][CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][O:4]1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: OCC(O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCO
Product: Clc1ccc(C2(CBr)OCC(c3ccccc3)O2)cc1

Procedure:
A mixture of 11.6 parts of 2-bromo-4'-chloroacetophenone, 8.4 parts of α-(hydroxymethyl)benzylalcohol, 0.1 parts of p-toluene sulfonic acid, 210 parts of benzene and 40 parts of ethanol is stirred and refluxed for 24 hours. The reaction mixture is evaporated and the residue is triturated in methanol. The product is filtered off and crystallized from methanol, yielding 2-(bromomethyl)-2-(p-chlorophenyl)-4-phenyl-1,3-dioxolane; mp. 60° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.CC(C)([O-])C.[K+].[Br:16][C:17]1[CH:18]=[C:19](F)[C:20]([C:23]#[N:24])=[N:21][CH:22]=1.Cl>C1COCC1>[Br:16][C:17]1[CH:18]=[C:19]([NH:1][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=2)[C:20]([C:23]#[N:24])=[N:21][CH:22]=1
Reactant: N#Cc1ncc(Br)cc1F
Reactant: Cc1cc(C)nc(N)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(C)nc(Nc2cc(Br)cnc2C#N)c1
Reaction time: 0.17 h

Procedure:
This example describes the conversion of (A6) to (A7) as illustrated in Scheme 1. To a solution of 2-amino-4,6-dimethylpyridine (30.4 g, 249 mmol) in THF (200 mL) at 0° C. was added potassium tert-butoxide (1.0 M in THF, 249 mL, 250 mmol) at such a rate to keep the internal temperature less then 10° C. After the addition was complete, the reaction mixture was stirred for 10 min, and then ˜60% of the reaction mixture was transferred via cannula to a cooled solution of 5-bromo-2-cyano-3-fluoropyridine (Manchester Organics, Ltd.; CAS: 886373-28-0, Runcorn, UK) (25.0 g, 124 mmol) in THF (200 mL). The reaction mixture was analyzed by LC which indicated near-complete consumption of the 5-bromo-2-cyano-3-fluoropyridine. The reaction mixture was diluted with water (400 mL) followed by hydrochloric acid (1.0 M in water, 50 mL, 50 mmol), and the resulting mixture was filtered. The collected solids were washed with water (2×50 mL). After 2 hours, the filtrate was filtered. The two collections of solids were combined, diluted with 4:1 hexanes/ethyl acetate (400 mL), and stirred. After 30 minutes, the mixture was filtered to afford 5-bromo-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carbonitrile. MS ESI calc'd. for C13H12BrN4 [M+H]+ 303 and 305. found 303 and 305. 1H NMR (600 MHz, CD3OD) δ 8.89 (d, J=2.4 Hz, 1H), 8.24 (d, J=1.8 Hz, 1H), 6.71 (s, 1H), 6.68 (s, 1H), 2.37 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[CH:19][N:18]=1.C(N(CC)CC)C>O1CCCC1>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:17]3[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[CH:19][N:18]=3)[CH:3]=2)[NH:7][CH:6]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CN(C)CCc1c[nH]c2ccc(N)cc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)CCc1c[nH]c2ccc(Nc3ncc([N+](=O)[O-])cc3[N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 7 %

Procedure:
5-Amino-3-(2-dimethylaminoethyl)indole and 2-chloro-3,5-dinitropyridine were used. Triethylamine was used as base, tetrahydrofuran was used as solvent, and the reaction was stirred at room temperature for 1 hour. Direct filtration of the reaction mixture afforded a red solid which was recrystallized in ethanol to afford the title compound (7%) as a red solid: mp, 194.0°-195.0° C.; 13C NMR (DMSO-d6) δ152.2, 150.7, 134.7, 134.1, 131.2, 128.2, 127.1, 126.7, 123.9, 119.1, 114.8, 112.7, 111.4, 59.7, 44.9, 22.8; HRMS calculated for C17H18N6O4 370.1391, found 370.1358. Anal. calcd. for C17H18N6O4.1/2H2O: C, 53.82; H, 5.04; N, 22.15. Found: C, 53.55; H, 4.58; N, 21.98.
Reaction SMILES: [CH3:1][C:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][C@@:5]1([CH3:37])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26]C(=O)OC(C)(C)C)=[CH:25][C:19]=3[S:18](=[O:35])(=[O:34])[N:17]=2)[C:6]1=[O:36].[ClH:40]>O1CCOCC1>[ClH:40].[NH2:26][C:24]1[CH:23]=[CH:22][C:20]2[NH:21][C:16]([C:7]3[C:6](=[O:36])[C@:5]([CH2:4][CH2:3][C:2]([CH3:1])([CH3:38])[CH3:39])([CH3:37])[C:14]4[C:9]([C:8]=3[OH:15])=[CH:10][CH:11]=[CH:12][CH:13]=4)=[N:17][S:18](=[O:35])(=[O:34])[C:19]=2[CH:25]=1
Reactant: CC(C)(C)CC[C@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)CC[C@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Yield: 93 %

Procedure:
A solution of Example 48F (1.91 g, 3.45 mmol) in 4 M hydrochloric acid in 1,4-dioxane (30 mL) was stirred at 25° C. for 1 hour. The solution was concentrated in vacuo and the residue was triturated in diethyl ether to give 1.58 g (93%) of a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 0.38 (td, J=12.87, 3.68 Hz, 1H) 0.78 (m, 10H) 1.59 (s, 3H) 2.08 (m, 1H) 2.23 (td, J=12.78, 4.60 Hz, 1H) 7.07 (m, 2H) 7.53 (m, 2H) 7.77 (m, 2H) 8.16 (d, J=7.72 Hz, 1H) 13.58 (s, 1H); MS (ESI+) m/z 454 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:19][NH:20][C:21]([C:23]1[S:24][CH:25]=[CH:26][C:27]=1[NH:28][C:29]1[C:34]([Cl:35])=[CH:33][N:32]=[C:31](Cl)[N:30]=1)=[O:22]>>[CH:1]([O:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][C:16]([NH:18][C:31]3[N:30]=[C:29]([NH:28][C:27]4[CH:26]=[CH:25][S:24][C:23]=4[C:21](=[O:22])[NH:20][CH3:19])[C:34]([Cl:35])=[CH:33][N:32]=3)=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCCOc2cc(N)ccc21
Reactant: CNC(=O)c1sccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1sccc1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OC(C)C)ncc1Cl

Procedure:
The title compound was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid isopropyl ester and 3-(2,5-dichloro-pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methylamide in an analogous manner to Example 1410. Product isolated as an orange foam (152 mg, 87%). LCMS (m/e) 517 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 11.65 (s, 1H), 9.57 (s, 1H), 8.56-8.44 (m, 1H), 8.27 (s, 1H), 8.25 (d, 1H, J=4.3 Hz), 7.76 (d, 1H, J=5.4 Hz), 7.52 (s, 1H), 7.33-7.20 (m, 1H), 7.20-7.07 (m, 1H), 4.91-4.74 (m, 1H), 4.13-3.96 (m, 2H), 3.73-3.50 (m, 2H), 2.78 (d, 3H, J=4.3 Hz), 2.00-1.85 (m, 2H), 1.35-1.00 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11](S(C)(=O)=O)=[N:10][C:9]=2[CH2:17][O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:10][C:9]=2[CH2:17][O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: CS(=O)(=O)c1nc(COCC(F)(F)F)c(-c2ccc(F)cc2)o1
Solvent: C1COCCO1
Product: Fc1ccc(-c2oc(N3CCNCC3)nc2COCC(F)(F)F)cc1
Reaction time: 16 h
Yield: 85.1 %

Procedure:
A solution of 5-(4-Fluoro-phenyl)-2-methanesulfonyl-4-(2,2,2-trifluoro-ethoxymethyl)-oxazole (0.30 g; 0.85 mmol) in dry dioxane (6 ml) is treated with piperazine (0.37 g; 4.25 mmol) and heated in a pressure tube at 170 C. for 16 hours. The reaction mixture is partitioned between ethyl acetate (50 ml) and water (20 ml). The aqueous phase is washed with ethyl acetate (20 ml). The combined organic phases are washed with saturated brine (10 ml), dried over sodium sulfate and concentrated to dryness. Purification by radial chromatography on silica gel using a methanol-ethyl acetate gradient (5%-20%) afforded the product as a light yellow solid (0.26 g; 86%). HNMR (CDCl3): 7.55 (m, 2H), 7.14 (t, 2H, J=8.8 Hz), 4.65 (s, 2H), 4.03 (qt, 2H, J=9.0 Hz), 3.57 (t, 4H, J=4.9 Hz), 3.01 (t, 4H, J=4.9 Hz). Mass spectrum: m/e calculated (MH+)=360; observed (MH+)=360.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[F:21][C:4]1[CH:3]=[C:2]([C:27]2[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Product: COc1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 4-Methoxybenzene boronic acid. MS (M+H) 383.2
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=1)[C:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20]2)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31]([O:35][C:36](=[O:39])[CH2:37]Br)([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=1)[C:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([O:27][CH2:37][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:39])[CH:21]=[CH:20]2)=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)NCCOc1cccc(C(=O)c2ccc3cc(O)ccc3c2)c1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc2cc(C(=O)c3cccc(OCCNC(=O)OC(C)(C)C)c3)ccc2c1
Yield: 81.8 %

Procedure:
2-Hydroxynaphthalene 330e (0.60 g, 1.5 mmol) was alkylated with t-butylbromoacetate (0.24 mL, 1.5 mmol) in the presence of K2 CO3 (0.20 g, 1.5 mmol) in DMF (7 mL) in the usual way to yield a colorless solid (0.64 g) after silica gel chromatography. IR(KBr): cm-1 3340, 1746, 1684. 1H NMR(300 MHz, CDCl3): 8.21 (s, 1H), 7.94-7.10 (m, 9H), 5.0 (br, 1H), 4.68 (s, 2H), 4.09 (t, 2H, J=7 Hz), 3.56-3.52 m, 2H), 1.52 (s, 9H), 1.44 (2, 9H). MS(NH3): 539 (base, M+NH4), 522 (25%, M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.Cl[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:21](=[O:22])[O:23][CH:24]([CH3:26])[CH3:25])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Reactant: CC(C)OC(=O)Cl
Solvent: c1ccncc1
Product: Cc1ccc(F)cc1-c1ccc2cc(NC(=O)OC(C)C)ncc2c1
Yield: 74 %

Procedure:
A solution 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (52.0 mg, 206 mop in pyridine (1.0 mL) was treated dropwise with a solution isopropyl chloroformate (210μl, 1.0M, 210 μmol) at ambient temperature for 30 mins, and the mixture concentrated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate and extracted twice with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford a residue that was purified by reverse phase HPLC (gradient of acetonitrile in water with 0.1% formic acid) to yield the title compound as a white powder (51.6 mg, 74%). 1H NMR (400 MHz, DMSO) δ 10.16 (s, 1H), 9.13 (s, 1H), 8.23 (s, 1H), 8.02 (s, 1H), 7.94 (d, J=8.6 Hz, 1H), 7.71 (dd, J=8.5, 1.6 Hz, 1H), 7.37 (dd, J=7, 6 Hz, 1H), 7.22-7.13 (m, 2H), 4.96 (septet, J=6.2 Hz, 1H), 2.25 (s, 3H), 1.29 (d, J=6.3 Hz, 6H). LCMS (Method E): RT=6.067 min, M+H+=339.1.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:29][N:30]([CH3:33])[CH:31]=[S:32]>C1COCC1>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH:25]([OH:26])[C:31]([N:30]([CH3:33])[CH3:29])=[S:32])=[CH:27][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CN(C)C=S
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CN(C)C(=S)C(O)c1ccc(OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 45.5 %

Procedure:
To a solution of distilled diisopropylamine (22.9 mL, 175 mmol) in 400 mL of anhydrous THF at −78° C. was added 1.6 M n-butyllithium in hexanes (100 mL, 160 mmol) over a period of 45 min. The mixture was stirred at −78° C. for 1.5 h. To the solution was cannulated over a period of 1 h a solution of 4-benzyloxybenzaldehyde (30.9 g, 146 mmol) and N,N-dimethylthioformamide (13.7 mL, 160 mmol) in 100 mL of distilled THF. The reaction mixture was stirred at −78° C. for 16 h. The reaction was then quenched with 500 mL of saturated NH4Cl solution. The mixture was extracted with EtOAc (3×1 L), and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was then recrystallyzed from EtOAc/hexanes to afford 20.0 g (66.5 mmol, 46%) of an off-white solid.
Reaction SMILES: C([O:8][C:9]1[N:10]([C:19]2[N:20]=[C:21]([NH2:27])[NH:22][C:23](=[O:26])[C:24]=2[N:25]=1)[C@@H:11]1[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[CH2:12]1)C1C=CC=CC=1>CO.O.[Pd]>[OH:8][C:9]1[N:10]([C:19]2[N:20]=[C:21]([NH2:27])[NH:22][C:23](=[O:26])[C:24]=2[N:25]=1)[C@@H:11]1[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[CH2:12]1
Reactant: Nc1nc2c(nc(OCc3ccccc3)n2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: Nc1nc2c(nc(O)n2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1

Procedure:
The final stage of the synthesis is accomplished according to the published procedure of Lin et al. (J. Med. Chem. 28:1194-1198, 1985). A solution of 8-(benzyloxy)-2'-deoxyguanosine (0.20 g, 0.54 mmol) in a mixture of methanol (8 mL) and water (8 mL) is hydrogenated over 10% palladium on carbon (0.3 g) at 50 psi and room temperature for 18 hours. The catalyst is removed from filtration and the solvent evaporated to dryness to yield 8-hydroxydeoxyguanosine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([S:15][CH3:16])=[N:13][CH:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1.[OH-:25].[NH4+]>C(O)(=O)C.OO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([S:15]([CH3:16])=[O:25])=[N:13][CH:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1
Reactant: CSc1ncc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reactant: [OH-]
Agent: OO
Agent: [NH4+]
Solvent: CC(=O)O
Product: CS(=O)c1ncc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reaction time: 8 h

Procedure:
A solution of 450 mg (1.25 mmol) of the end product of Example 25 in 10 ml of acetic acid and 1 ml of 30% hydrogen peroxide was allowed to stand at room temperature overnight. The solution was treated with ice and ammonium hydroxide; the resulting solid was collected, washed with water, dissolved in methylene chloride, treated with anhydrous sodium sulfate and charcoal, filtered and evaporated in vacuo to a white foam, mp 95°-110°: Ir (KBr) 1610, 1480 and 1047 cm-1 ; nmr (CDCl3) 2.95 (s, 3H), 4.15 (d, J=13Hz, 1H), 5.25 (d, J=13Hz, 1H), 6.95-8.40 (m, aromatic, 8H); uv λ max 219 nm (ε=37500), infl. 243 (20000); sh. 265 (13700), infl. 305 (1200); mass spectrum m/e 373 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11].[NH2:30][CH2:31][CH2:32][OH:33].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:30][CH2:31][CH2:32][OH:33])=[O:26])=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11]
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)O)c(F)c2)c2ccccc2Cl)ccc1=O
Reactant: NCCO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1cc(C(=O)CC(c2ccc(C(=O)NCCO)c(F)c2)c2ccccc2Cl)ccc1=O

Procedure:
In analogy to example 207, step 2, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluorobenzoic acid was coupled with 2-aminoethanol using BOP reagent in tetrahydrofuran to give the title compound as a colorless foam, MS (ESI+): m/z=457.2 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:19][CH3:20])=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])=O.CN.[C:23]([BH3-])#[N:24].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>C(O)(=O)C.CO>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[CH3:20][O:19][C:4]1[C:3]([CH2:1][NH:24][CH3:23])=[CH:18][CH:17]=[CH:16][C:5]=1[O:6][C:7]1[N:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10]
Reactant: COc1c(C=O)cccc1Oc1nc(C)ccc1C#N
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1cccc(Oc2nc(C)ccc2C#N)c1OC
Yield: 41 %

Procedure:
2-(3-Formyl-2-methoxy-phenoxy)-6-methyl-nicotinonitrile (0.30 g, 1.1 mmol), methylamine (2M in methanol, 3.0 mL, 6.0 mmol) and sodium cyanoborohydride (90 mg, 1.4 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (50 mL) for 20 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.13 g, 1.1 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 2-(2-methoxy-3-methylaminomethyl-phenoxy)-6-methyl-nicotinonitrile fumarate (180 mg, 40%) as an off-white solid.