Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[C:16]3[C:22]([C:23](=O)[C:24]#[C:25][CH2:26][CH2:27][CH2:28][N:29]4[C:37](=[O:38])[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[C:30]4=[O:39])=[CH:21][NH:20][C:17]3=[N:18][CH:19]=2)[CH:11]=[N:10]1.C(=O)(O)O.[NH2:45][C:46]([NH2:48])=[NH:47]>COCCO>[NH2:48][C:46]1[N:47]=[C:25]([CH2:26][CH2:27][CH2:28][N:29]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]2=[O:39])[CH:24]=[C:23]([C:22]2[C:16]3[C:17](=[N:18][CH:19]=[C:14]([C:12]4[CH:11]=[N:10][N:9]([CH3:8])[CH:13]=4)[CH:15]=3)[NH:20][CH:21]=2)[N:45]=1
Reactant: Cn1cc(-c2cnc3[nH]cc(C(=O)C#CCCCN4C(=O)c5ccccc5C4=O)c3c2)cn1
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: COCCO
Solvent: CCN(CC)CC
Product: Cn1cc(-c2cnc3[nH]cc(-c4cc(CCCN5C(=O)c6ccccc6C5=O)nc(N)n4)c3c2)cn1

Procedure:
8.5 0.92 ml (6.7 mmol) of triethylamine is added to a solution of 116 mg (0.265 mmol) of 2-{6-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-6-oxohex-4-ynyl}isoindole-1,3-dione and 70 mg (0.39 mmol) of guanidine carbonate in 4 ml of ethylene glycol monomethyl ether, and the mixture is heated at the boil for 6 hours. After cooling, the mixture is evaporated, and the residue is purified by preparative HPLC, giving 2-(3-{2-amino-6-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-pyrimidin-4-yl}propyl)isoindole-1,3-dione as brown solid; ESI 479, EMD 1183586.
Reaction SMILES: C(O[B:5]1[O:9][C:8]([CH3:11])([CH3:10])[C:7]([CH3:13])([CH3:12])[O:6]1)(C)C.C([Li])CCC.[F:19][C:20]1[CH:21]=[C:22]([CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:26][C:24]1[CH:23]=[C:22]([CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:21]=[C:20]([F:19])[C:25]=1[B:5]1[O:6][C:7]([CH3:12])([CH3:13])[C:8]([CH3:10])([CH3:11])[O:9]1
Reactant: Fc1cc(F)cc(C2CCOCC2)c1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Product: CC1(C)OB(c2c(F)cc(C3CCOCC3)cc2F)OC1(C)C
Yield: 100 %

Procedure:
Method 3 was followed using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.2 equiv.), butyllithium (1.1 equiv.) and 4-(3,5-difluorophenyl)tetrahydro-2H-pyran (1.0 equiv.) to give 2-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in 100% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 1.16-1.19 (m, 12H), 1.65-1.74 (m, 4H), 2.60-2.75 (m, 1H), 3.37-3.51 (m, 2H), 4.01 (dt, J=11.54, 3.42 Hz, 2H), 6.67 (d, J=8.22 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10]3[C:12]4[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=4[S:14][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]=[C:4]([C:19]([O:21]C)=[O:20])[CH:3]=1>CN(C)C=O.Cl>[OH:1][C:2]1[C:11]2[C:10]3[C:12]4[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=4[S:14][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]=[C:4]([C:19]([OH:21])=[O:20])[CH:3]=1
Reactant: COC(=O)c1cc(O)c2c(ccc3sc4ccccc4c32)n1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(O)c1cc(O)c2c(ccc3sc4ccccc4c32)n1

Procedure:
A mixture of 2.0 g. (0.0065 mole) of methyl 1-hydroxy[1]benzothieno[3,2-f]quinoline-3-carboxylate (about 90 percent pure) in N,N-dimethyl formamide is heated to its reflux temperature, and several drops of 10 percent aqueous hydrochloric acid are added every fifteen minutes for 2 hours. The resulting yellow solid is separated by filtration to provide 1-hydroxy[1]benzothieno[3,2-f]quinoline-3-carboxylic acid, m.p. >285° C. (dec.). Analysis: Calculated for C16H9NO3S: %C, 65.1; %H, 3.1; %N, 4.7; Found: %C, 64.9; %H, 2.9; %N, 4.8. Purity is greater than 98 percent according to nuclear magnetic resonance spectral analysis.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([N:65]1[CH2:70][CH2:69][CH:68]([NH2:71])[CH2:67][CH2:66]1)(OC(C)(C)C)=O>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:71][CH:68]5[CH2:69][CH2:70][NH:65][CH2:66][CH2:67]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-N—Boc 4-amino piperidine. Further, after washing with water (10 ml), t-butoxycarbonyl (Boc) protection group was removed using 40% TFA in dichloromethane (6 ml). The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11-1.27 (m, 1H) 1.30-1.51 (m, 4H) 1.52-1.69 (m, 3H) 1.69-1.90 (m, 6H) 2.41-2.59 (m, 2H) 2.97 (d, J=12.38 Hz, 2H) 3.31 (s, 3H) 3.73-3.89 (m, 1H) 3.94 (s, 3H) 4.06 (t, J=13.52 Hz, 2H) 4.38-4.52 (m, 1H) 7.48 (dd, J=8.34, 1.77 Hz, 1H) 7.51 (d, J=1.77 Hz, 1H) 7.90 (s, 1H) 8.14 (d, J=7.83 Hz, 1H) 8.21 (s, 1H) 8.26 (d, J=8.34 Hz, 1H). [M+H] calc'd for C27H35F2N7O3 544. found 544.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[CH3:14][S:15]SC>O1CCCC1.O>[Cl:1][C:2]1[C:3]([F:8])=[C:4]([S:15][CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccccc1Cl
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CSc1cccc(Cl)c1F
Temperature: 25 °C

Procedure:
A solution of 10 g (grams) (76 mmol (millimoles)) of 1-chloro-2-fluorobenzene in 75 mL (milliliters) of dry tetrahydrofuran (THF) was cooled with a dry ice/acetone bath and 34 mL (84 mmol) of 2.5M butyllithium was added dropwise under a nitrogen blanket over 45 min with stirring and cooling. The resulting solution was stirred for 2 hours at -78° C. A solution of 8.1 mL (91 mmol) of dimethyl disulfide in 10 mL of dry THF was added with stirring over a 30-min period keeping the temperature below -65° C. The mixture was allowed to warm to ambient temperature for 1 hour. It was then diluted with 75 mL of water. The resulting mixture was extracted with diethyl ether and the ether extract was dried over sodium sulfate and concentrated by evaporation under reduced pressure to obtain a yellow oil. This oil was purified by flash chromatography on 230-400 mesh silica gel eluting with a hexane/ethyl acetate mixture to obtain 9.0 g (69 percent of theory) of the title compound as a light yellow oil.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:56])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][OH:53])[CH:46]([O:54][CH3:55])[CH2:45]2)[CH:7]([CH3:57])[CH:6]([O:58][Si:59]([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:61])[CH3:60])[CH2:5][C:4]1=[O:66])[CH3:2].C(N(CC)CC)C.[CH3:74][S:75](Cl)(=[O:77])=[O:76]>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:56])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][O:53][S:75]([CH3:74])(=[O:77])=[O:76])[CH:46]([O:54][CH3:55])[CH2:45]2)[CH:7]([CH3:57])[CH:6]([O:58][Si:59]([C:62]([CH3:63])([CH3:64])[CH3:65])([CH3:61])[CH3:60])[CH2:5][C:4]1=[O:66])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCO)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCOS(C)(=O)=O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2"'-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (80.8 mg) in methylene chloride (1.0 mL) was added triethylamine (23 μL) followed by methanesulfonyl chloride (7.2 μL) and the mixture stirred at room temperature. After 10 minutes, the reaction was quenched by the addition of saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic portion dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (2:1)+1% methanol) gave the title compound (74 mg).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([O:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:16][CH:17]=2)[N:12]=1.O>C(OCC)(=O)C>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][O:21][C:15]1[N:14]=[C:13]2[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:1](=[O:9])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:12]2)=[CH:17][CH:16]=1
Reactant: CN(C)CCOc1ccc2ccc(N)nc2n1
Reactant: O=C(O)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)CCOc1ccc2ccc(NC(=O)c3ccccc3)nc2n1
Temperature: 4 °C
Yield: 29.7 %

Procedure:
The procedure is similar to that described in Example 1, but starting with benzoic acid (5.5 g), N,N'-carbonyldiimidazole (8.1 g) and 2-amino-7-(2-dimethylaminoethoxy)-1,8-naphthyridine (11.6 g), heating for 5 hours under reflux. The reaction mixture is poured into water (1500 cc) and extracted with ethyl acetate (2×1000 cc). After concentration of the organic phases to dryness under reduced pressure (4 kPa), the oily residue obtained (9.2 g) is dissolved in boiling ethyl acetate (25 cc). Then, after 2 hours' cooling at 4° C., the crystallized solid is separated by filtration, washed with ethyl acetate (3 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-[7-(2-Dimethylaminoethoxy)-1,8-naphthyridin-2-yl]benzamide (4.5 g), m.p. 109° C., is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10](O)[C@H:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:30])CC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([F:30])[C@H:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H]1C(=O)OCc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H]1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
The title compound was prepared in a similar manner as described by L. Demange et al., Tetrahedron Letters 2001, 42, 651-653: To a solution of (2S,3R)-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (360 mg, 1.12 mmol) in CH2Cl2 (30 mL), cooled to −78° C., was added dropwise DAST (0.740 mL, 5.60 mmol). The reaction mixture was stirred at −78° C. for 5 h, and then was allowed to warm to RT and stirred overnight. After cooling to 0° C., the reaction was quenched with MeOH, followed by addition of aqueous NaHCO3 solution. Volatiles were removed under reduced pressure and the residue was taken up in EtOAc. The organics were washed with aqueous NaHCO3 (3×), water and brine, dried (Phase separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc/c-hexane 1:9) to give the title compound (99% purity by HPLC/215 nm). TLC Rf (EtOAc/c-hexane 1:4)=0.2; MS (LC/MS): 346 [M+Na]+, 268 [MH−tBu]+, 224 [MH−Boc]+; tR (HPLC conditions b): 5.01 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[CH2:10][OH:11].ClCCl>O1CCCC1.[O-2].[O-2].[Mn+4]>[NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[CH:10]=[O:11]
Reactant: Cc1cc(Br)c(N)c(CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(Br)c(N)c(C=O)c1
Temperature: 40 °C
Reaction time: 16 h
Yield: 78.9 %

Procedure:
The (2-amino-3-bromo-5-methylphenyl)methanol (7.80 g, 36.1 mmol) was dissolved in tetrahydrofuran (20 mL). Dichloromethane (50 mL) was added along with activated carbon (16.3 g). Manganese dioxide (9.4 g, 108 mmol) was added and the solution stirred at 40° C. for 16 h. The solution was cooled to room temperature and vacuum filtered through a celite. The solvent was removed at reduced pressure and the 2-amino-3-bromo-5-methylbenzaldehyde (6.10 g, 28.5 mmol) obtained by recrystallization from diethyl ether/hexanes (1:10, 100 mL) (78% yield): Melting point 99.6-101.2° C. 1H NMR (300 MHz, CDCL3) 9.77 (s, 1H), 7.46 (s, 1H), 7.26 (s, 1H), 6.48 (bs, 2H), 2.76 (s, 3H). HRMS m/z 213.9902; calcd for M+H 213.9962.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:19][CH:20]3[CH2:38][CH:37]4[N:22]([C:23](=[O:43])[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40]([OH:42])=O)([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:21]3)=[CH:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10]2)=[CH:5][CH:4]=1.COC1C=C2C(C(OC3CC4N(C(=O)OCCCCC=CC5C(C([NH:84][S:85]([CH:88]6[CH2:90][CH2:89]6)(=[O:87])=[O:86])=O)(NC4=O)C5)C3)=CC(C3C=CC=CC=3)=N2)=CC=1>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:19][CH:20]3[CH2:38][CH:37]4[N:22]([C:23](=[O:43])[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40]([NH:84][S:85]([CH:88]6[CH2:90][CH2:89]6)(=[O:87])=[O:86])=[O:42])([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:21]3)=[CH:8][C:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCOC(=O)N4C3)cc(-c3ccccc3)nc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCOC(=O)N4C3)cc(-c3ccccc3)nc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCOC(=O)N4C3)cc(-c3ccccc3)nc2c1

Procedure:
The title compound 25 was synthesized from compound 24 following the same procedure described for the synthesis of N-[17-(7-methoxy-2-phenylquinolin-4-yloxy)-2,14-dioxo-3,15-diaza-13-oxatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl]-(cyclopropyl)sulfonamide (23): m/z=689 (M+H)+.
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[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[I:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1>>[I:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(I)cc4)cc23)CC1
Yield: 59.4 %

Procedure:
Beginning with 10.0 mg (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 32.0 mg (0.131 mMol) 4-iodobenzoic acid, 12.0 mg (60%) of the title compound were recovered.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:10])=[N:4][C:5]([F:9])=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[P:17](=[S:23])(Cl)([O:20][CH3:21])[O:18][CH3:19]>C(#N)C>[P:17](=[S:23])([O:10][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[C:5]([F:9])[N:4]=1)([O:20][CH3:21])[O:18][CH3:19]
Reactant: Oc1nc(F)c(Cl)cc1Cl
Reactant: COP(=S)(Cl)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COP(=S)(OC)Oc1nc(F)c(Cl)cc1Cl
Temperature: 50 °C
Yield: 42.6 %

Procedure:
A mixture was prepared by admixing, with stirring, 20 grams (g) (0.11 mole (m)) of 3,5-dichloro-6-fluoro-2-pyridinol, 16 g (0.116 m) of potassium carbonate, 0.2 g of mercuric chloride and 250 milliliters (ml) of acetonitrile. To this mixture, with stirring, was added dropwise 16 g (0.1 m) of O,O-dimethyl phosphorochloridothioate. After the addition was complete, the mixture was stirred for an additional 0.5 hour and then heated to about 50° C., with stirring, for 2 hours. The reaction mixture was cooled to room temperature and filtered to remove insolubles. The solvent was removed by evaporation under reduced pressure. The residue was dissolved in 100 ml of benzene and washed with water. The organic layer was dried and filtered. The benzene was removed by evaporation. The residue (20 g of an oil) was crystallized from 30 ml of hexane to give 13 grams of O,O-dimethyl O-(3,5-dichloro-6-fluoro-2-pyridinyl) phosphorothioate. The product, a solid, melted at room temperature and had a refractive index of nd25 =1.5370. Upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 27.40, 2.28 and 4.27 percent, respectively, as compared with the theoretical contents of 27.46, 2.31 and 4.58 percent, respectively, as calculated for the above compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[N+:15]([C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1)([O-:17])=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-Boc-4-piperidinol (10 g, 50 mmol), 4-nitrophenol (7.0 g, 50 mmol) and triphenylphosphine (15.7 g, 60 mmol) were dissolved in dry tetrahydrofuran (150 mL), and cooled on the ice bath. Diisopropyl azodicarboxylate (11.8 mL, 60 mmol) was added slowly, and stirred for 2 days at room temperature. The solvent was distilled off under reduced pressure, diethyl ether was added, and the solid precipitate was filtered off. The filtrate was concentrated and the product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1). Trifluoroacetic acid was added to the obtained residue and stirred at room temperature for 1 hour. After distillation under reduced pressure, 1N sodium hydroxide aqueous solution was added, and the mixture extracted with ethyl acetate. After drying with anhydrous sodium sulfate, the product was concentrated and dried to obtain the target substance (6.75 g, 61%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:7][CH2:8][CH3:9].[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:22][N:21]=1)([O-])=O>N1C=CC=CC=1.O>[CH2:7]([N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:22][N:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:8][CH3:9]
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1ccncc1
Reactant: CCCN(CCCCN)c1ccccn1
Solvent: c1ccncc1
Solvent: O
Product: CCCN(CCCCNc1ncc(Cc2ccncc2)c(=O)[nH]1)c1ccccn1

Procedure:
2-[N-(4-aminobutyl)-N-propylamino]pyridine (0.9 g) and 2-nitroamino-5-pyrid-4-ylmethylpyrimid-4-one (0.72 g) were heated together under reflux in pyridine (2.5 ml) for 21 hr. After stripping the residue was taken up in water, basified, and extracted with ether. The aqueous was acidified (pH 6.5), extracted with dichloromethane and stripped to give an oil which was crystallized from ethanol/water to give 2-[4-(N-propyl-N-pyrid-2-ylamino)butylamino]-5-pyrid-4-ylmethylpyrimid-4-one 1.2 H2O; 0.45 g (38%) m.p. 58°-60° C.
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[C:11]3[C:12](=[O:26])[N:13]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:14]4[N:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]=3[NH:9][N:8]=2)=[CH:4][CH:3]=1.[C:29](N1C=CN=C1)(=[O:31])[CH3:30]>CN(C=O)C.C(=O)([O-])O.[Na+]>[C:29]([O:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[C:11]3[C:12](=[O:26])[N:13]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:14]4[N:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]=3[NH:9][N:8]=2)=[CH:4][CH:3]=1)(=[O:31])[CH3:30]
Reactant: O=c1c2c(Cc3ccc(O)cc3)n[nH]c2c2cccnc2n1-c1ccccc1
Reactant: CC(=O)n1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of 3-(4-hydroxybenzyl)-5-phenyl-1H-pyrazolo [4,3-c][1,8]naphthyridin-4 (5H)-one (192 mg, 0.52 mmol, prepared in Example 41) in DMF (2 ml) was added a solution of 1-acetylimidazole (114 mg, 1.04 mmol, 2 eq.) in DMF (2 ml) while ice-cooling, and the mixture was stirred overnight at room temperature, and then diluted with aqueous sodium hydrogen carbonate. Precipitates were filtered off, and the mixture was dried and purified by flash column chromatography to afford 3-(4-acetoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (128 mg, 60%).
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([C:16]([OH:18])=O)=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[F:52][C:53]([F:65])([F:64])[O:54][C:55]1[CH:56]=[C:57]([CH:61]([NH2:63])[CH3:62])[CH:58]=[CH:59][CH:60]=1.CCN(CC)CC>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:52][C:53]([F:64])([F:65])[O:54][C:55]1[CH:56]=[C:57]([CH:61]([NH:63][C:16]([C:9]2[S:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:11][C:10]=2[C:12]([F:13])([F:14])[F:15])=[O:18])[CH3:62])[CH:58]=[CH:59][CH:60]=1
Reactant: O=C(O)c1sc(-c2ccccc2)nc1C(F)(F)F
Reactant: CC(N)c1cccc(OC(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(NC(=O)c1sc(-c2ccccc2)nc1C(F)(F)F)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.3 %

Procedure:
To a solution of 2-phenyl-4-trifluoromethyl-thiazole-5-carboxylic acid (35 mg, 0.128 mmol) in DMF (1 mL) was added PyBOP (73 mg, 0.141 mmol) and DMAP (16 mg, 0.128 mmol). A solution of 1-(3-trifluoromethoxyphenyl)-ethylamine (27 mg, 0.128 mmol) in DMF (0.5 mL) was then added, followed by Et3N (36 μL, 0.256 mmol). This mixture was stirred at 25° C. for 18 h. The reaction mixture was applied directly to a preparatory HPLC column for purification (C18, 10-100% methanol/water/0.1% trifluoroacetic acid) which gave the amide as a white solid (24.9 mg, 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])N.S(=O)(=O)(O)[OH:11]>>[Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=S(=O)(O)O
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: Oc1ccc(Cl)c(Cl)c1

Procedure:
3,4-Dichloroaniline was treated with 60% of aqueous sulfuric acid solution which was recovered from Example 5 by a method similar to that described in Example 5. After diazotization, inorganic crystals formed in the diazotization was removed by filtration and the filtrate thus obtained as hydrolyzed and treated by a method similar to those described in Example 5. 32.4 Grams of 3,4-dichlorophenol (118° - 122° C/10 mmHg) was obtained. The yield was found to be 80.5%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6][CH2:5]2.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[CH:7][CH2:6][CH2:5]2
Reactant: C1COCCN1
Reactant: O=C1CCCc2cc(Br)ccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)CCC=C2N1CCOCC1
Temperature: 0 °C
Reaction time: 20 h
Yield: 93.5 %

Procedure:
To 6-bromo-3,4-dihydronaphthalen-1(2H)-one (0.475 g, 2.110 mmol) in toluene (5 mL) was added morpholine (0.735 mL, 8.44 mmol) at room temperature. The reaction mixture was cooled to 0° C. and titanium tetrachloride (1.0 M in toluene) (1.161 mL, 1.161 mmol) was added over a period of 3 min. The brown heterogeneous reaction mixture was allowed to come to room temperature and stirred for 20 h. The reaction mixture was diluted with 5 mL of anhydrous toluene and filtered over a thin pad of CELITE®. The filter pad was washed with addition anhydrous toluene (2×10 mL). The pale yellow filtrate was concentrated under reduced pressure to yield 4-(6-bromo-3,4-dihydronaphthalen-1-yl)morpholine (0.580 g, 1.972 mmol, 93% yield) as an oil.