Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13]>C(#N)C>[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O:13][C:12]([C:11]1[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[F:9])=[CH:1][C:2]1[N:3]([C:12](=[O:13])[C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[F:9])[C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1)=[O:13]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Cc1nc(C)c(C)[nH]1
Solvent: CC#N
Product: Cc1nc(C=C(OC(=O)c2ccccc2F)c2ccccc2F)n(C(=O)c2ccccc2F)c1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3.00 g (27.23 mmol) 2,4,5-trimethyl-1H-imidazol and 9.37 g (92.59 mmol) TEA are dissolved in 50 ml acetonitrile and cooled to 0° C. 14.25 g (89.87 mmol) 2-fluoro-benzoylchloride are added dropwise and the mixture is stirred 2 h at RT and let stand overnight. The solvent is removed under vacuum, the residue is dissolved in toluene and washed twice with water. The organic phase is filtered through Tonsil (K60) and concentrated under vacuum. The product is used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27]([O:29]CC)=O)[C:9]2=[O:32])=[CH:4][CH:3]=1.[CH3:33][NH2:34]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27]([NH:34][CH3:33])=[O:29])[C:9]2=[O:32])=[CH:6][CH:7]=1
Reactant: CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Solvent: CCO
Product: CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Yield: 29 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (22 mg, 0.0504 mmol) and methylamine (0.1 mL of a 8 M solution in ethanol) was prepared 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (6 mg, 29% yield) as a tan solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 9.87 (br s, 1 H), 8.52 (s, 1 H), 7.30-7.24 (m, 2 H), 7.20-7.16 (m, 2 H), 7.01-6.91 (m, 4 H), 6.71 (s, 1 H), 3.94 (s, 2 H), 2.96 (d, J=4.8 Hz, 3 H); MS m/z 422 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)[CH2:13][CH2:12]2)=[C:7]([CH3:27])[N:6]([CH2:28][C:29]2[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:30]=2[F:39])[C:5]1=[O:40].[C:47]([O:51][CH3:52])(=[O:50])[CH:48]=[CH2:49]>CO>[CH3:52][O:51][C:47](=[O:50])[CH2:48][CH2:49][NH:1][C@H:2]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)[CH2:15][CH2:16]2)=[C:7]([CH3:27])[N:6]([CH2:28][C:29]2[C:34]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:32]=[CH:31][C:30]=2[F:39])[C:5]1=[O:40]
Reactant: C=CC(=O)OC
Reactant: Cc1c(N2CCN(Cc3cccc([N+](=O)[O-])c3)CC2)c(=O)n(C[C@H](N)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Solvent: CO
Product: COC(=O)CCN[C@@H](Cn1c(=O)c(N2CCN(Cc3cccc([N+](=O)[O-])c3)CC2)c(C)n(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1
Yield: 75.5 %

Procedure:
In a closed tube, 3-((R)-2-amino-2-phenyl-ethyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-5-[4-(3-nitro-benzyl)-piperazin-1-yl]-1H-pyrimidine-2,4-dione (3-58) (20 mg, 0.031 mmol), methyl acrylate (9 μl, 0.093 mmol), and methanol (2 mL) were mixed at 70° C. for 4 hrs with stirring. The resulting solution was concentrated, and the residue was purified using silica gel chromatography (eluent: dichloromethane/methanol, 20/1) and dried in a vacuum to afford 17 mg of the compound as a colorless oil (yield 74%). 1H NMR (300 MHz, CDCl3) δ 2.17 (2H, m), 2.33 (3H, s), 2.38 (2H, t), 2.40-2.77 (6H, m), 3.58 (7H, m), 4.02-4.20 (3H, m), 5.39 (2H, d), 7.20-7.55 (9H, m), 7.77 (1H, d), 8.10 (1H, d), 8.17 (1H, s)
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][C:14](=[O:16])[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:13][C@H:14]([OH:16])[CH2:15]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: O=C1CC(c2nc(I)c3c(Cl)nccn23)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O[C@H]1C[C@@H](c2nc(I)c3c(Cl)nccn32)C1
Reaction time: 4.5 h

Procedure:
3-(8-Chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutanone (5.0 g, 14 mmol) was dissolved in a 1:1 mixture of MeOH (35.0 mL) and CH2Cl2 (35.0 mL). To the solution mixture sodium tetrahydroborate (560 mg, 14.0 mmol) was added slowly, gas evolution was observed. After 4.5 h at rt under nitrogen, the reaction was concentrated in vacuo. The crude mix was dissolved in EtOAc and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified using HPFC Jones 50 gram silica gel column eluting with 50% EtOAc in Hexane to 100% EtOAc, to yield the title compound as a light yellow solid; MS (ES+): m/z 349.81 (100) [MH+], 351.50 (30) [MH+++]; HPLC: tR=2.49 min (OpenLynx, polar—5 min); 1H NMR (CDCl3, 400 MHz) δ 2.41-2.54 (m, 2H) 2.78-3.05 (m, 1H) 3.12-3.32 (m, 1H) 4.08-4.75 (m, 1H) 5.30 (s, 1H) 7.31 (d, J=5.05 Hz, 1H) 7.57 (d, J=4.80 Hz, 1H)
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:8](I)=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:15][C:16]1[CH:17]=[CH:18][C:19]2=[C:20]([CH:36]=1)[O:21][CH2:22][C:23]1[CH:33]=[C:32]([CH:34]=[O:35])[CH:31]=[CH:30][C:24]=1/[C:25]/2=[C:26](/[CH3:29])\[C:27]#[N:28]>>[Br:1][C:2]1[C:3]2[N:4]([C:8]([CH:34]([OH:35])[C:32]3[CH:31]=[CH:30][C:24]4/[C:25](=[C:26](/[CH3:29])\[C:27]#[N:28])/[C:19]5[CH:18]=[CH:17][C:16]([F:15])=[CH:36][C:20]=5[O:21][CH2:22][C:23]=4[CH:33]=3)=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Reactant: Brc1cccn2c(I)c(C3CC3)nc12
Product: C/C(C#N)=C1/c2ccc(C(O)c3c(C4CC4)nc4c(Br)cccn34)cc2COc2cc(F)ccc21
Yield: 81.5 %

Procedure:
[step 3] Using 8-bromo-2-cyclopropyl-3-iodoimidazo[1,2-a]pyridine (2.2 g, 5.9 mmol) obtained in step 2 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (1.1 g, 3.7 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 14A, step 3, (E)-2-{8-[(8-bromo-2-cyclopropylimidazo[1,2-a]pyridin-3-yl)(hydroxy)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (1.6 g, 80%) was obtained.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[S:19]([NH:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)([C:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[C:27]([N:28]([CH3:30])[CH3:29])[C:26]=2[CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([NH:35][S:19]([C:22]5[C:34]6[C:26](=[C:27]([N:28]([CH3:30])[CH3:29])[CH:31]=[CH:32][CH:33]=6)[CH:25]=[CH:24][CH:23]=5)(=[O:21])=[O:20])[CH:37]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: CN(C)c1cccc2c(S(=O)(=O)Nc3cccc(B(O)O)c3)cccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CN(C)c1cccc2c(S(=O)(=O)Nc3cccc(-c4ccc5c(c4)CC[C@H]4N(C)C(=O)CC[C@]54C)c3)cccc12
Yield: 62.9 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (83 mg, 0.27 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 3-dansylaminophenylboronic acid (99 mg, 0.27 mmol), 0.3 mL of 2M sodium carbonate solution, 0.5 mL of toluene, and 0.1 mL of methanol, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with dichloromethane (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 94 mg (63%) of the title compound as a yellow solid. mp 130°-140° (decomp.) FDMS: m/e=553. α[D]589 =+3.01 (c=1.03 methanol).
Reaction SMILES: Cl.[O:2]1[C:6]2([CH2:11][CH2:10][CH:9]([CH:12]([NH2:15])[CH2:13][CH3:14])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1.[C:16](Cl)(=[O:19])[O:17][CH3:18]>ClCCl>[O:2]1[C:6]2([CH2:11][CH2:10][CH:9]([CH:12]([NH:15][C:16](=[O:19])[O:17][CH3:18])[CH2:13][CH3:14])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1
Reactant: COC(=O)Cl
Reactant: CCC(N)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: ClCCl
Product: CCC(NC(=O)OC)C1CCC2(CC1)OCCO2
Temperature: 0 °C

Procedure:
Into a 50 mL round-bottom flask was placed a solution of 1-1,4-dioxaspiro[4.5]decan-8-ylpropan-1-amine hydrochloride (as prepared in the previous step, 50 mg, 0.21 mmol, 1.00 equiv) in dichloromethane (10 mL) and TEA (42.8 mg, 0.42 mmol, 2.00 equiv). This was followed by the addition of methyl carbonochloridate (23.9 mg, 0.25 mmol, 1.20 equiv) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 2×20 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:17]=1.[C:18](Cl)(=[O:20])[CH3:19].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:16]=[CH:15][C:13]([NH:14][C:18](=[O:20])[CH3:19])=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:17]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccc(-c2nc3cc(Cl)ccc3o2)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1ccc(-c2nc3cc(Cl)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.7 %

Procedure:
To a solution of 4-(5-chlorobenzo[d]oxazol-2-yl)aniline (122.3 mg, 0.50 mmol) in pyridine (3 mL) at room temperature was added acetyl chloride (39 μL, 0.55 mmol). The resulting mixture was stirred at room temperature for 16 h. The solution was then poured into water, and the resulting precipitate collected by filtration. The solid was washed with diluted hydrochloric acid solution, followed by diluted sodium hydroxide solution, and then by water to afford 120 mg (84%) of the title compound (LCMS RT=6.38 min, MH+ 287.0)
Reaction SMILES: [F:1][C:2]([C:7]1[S:8][C:9]([NH:12]C(=O)C)=[N:10][N:11]=1)([F:6])[CH:3]([Cl:5])[Cl:4].[OH-].[Na+]>OS(O)(=O)=O>[F:1][C:2]([C:7]1[S:8][C:9]([NH2:12])=[N:10][N:11]=1)([F:6])[CH:3]([Cl:4])[Cl:5]
Reactant: CC(=O)Nc1nnc(C(F)(F)C(Cl)Cl)s1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1nnc(C(F)(F)C(Cl)Cl)s1
Yield: 98.5 %

Procedure:
1580 g of 2-(1',1'-difluoro-2',2'-dichloro-ethyl)-5-acetamido-1,3,4-thiadiazole were mixed with 5700 ml of concentrated H2SO4 and heated to 120°-130°C for 2 hours with ageitation. After cooling, the sulfuric acid containing solution was poured into icewater while stirring and neutralized with 30 % sodium hydroxide solution. The precipitate formed was separated and washed with water. After drying, 1320 g (98.5 %) of 2-(1',1'-difluoro-2',2'-dichloro-ethyl)-5-amino-1,3,4-thiadiazol having a melting point of 181°-182°C were obtained.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][N:7]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][C@H:5]([N:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:42])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[N:30][C:29]2=[O:43])[O:4]1.[C:44]1(=[O:50])[O:49][C:47](=[O:48])[CH2:46][CH2:45]1.CO>CN(C)C1C=CN=CC=1.ClCCl>[C:35]([NH:34][C:31]1[CH:32]=[CH:33][N:28]([C@H:5]2[CH2:6][N:7]([C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:8][C@@H:3]([CH2:2][O:1][C:44](=[O:50])[CH2:45][CH2:46][C:47]([OH:49])=[O:48])[O:4]2)[C:29](=[O:43])[N:30]=1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C1CCC(=O)O1
Reactant: O=C(Nc1ccn([C@H]2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@@H](CO)O2)c(=O)n1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: O=C(O)CCC(=O)OC[C@@H]1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H](n2ccc(NC(=O)c3ccccc3)nc2=O)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
Under argon atmosphere, 22.0 g of N-{1-[(2R,6S)-6-(hydroxymethyl)-4-tritylmorpholin-2-yl]-2-oxo-1,2-dihydropyrimidin-4-yl}benzamide and 7.04 g of 4-dimethylaminopyridine (4-DMAP) were suspended in 269 mL of dichloromethane, and 5.76 g of succinic anhydride was added to the suspension, followed by stirring at room temperature for 3 hours. To the reaction solution was added 40 mL of methanol, and the mixture was concentrated under reduced pressure. The residue was extracted using ethyl acetate and 0.5M aqueous potassium dihydrogenphosphate solution. The resulting organic layer was washed sequentially with 0.5M aqueous potassium dihydrogenphosphate solution, water and brine in the order mentioned. The resulting organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 25.9 g of the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH3:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21]#[N:22])=[CH:15][CH:14]=1.C[O-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[C:19]([C:16]3[CH:17]=[CH:18][C:13]([S:12][CH3:11])=[CH:14][CH:15]=3)=[CH:20][C:21]([NH2:22])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CSc1ccc(C=CC#N)cc1
Reactant: COc1cccc(NN)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(-n2nc(N)cc2-c2ccc(SC)cc2)c1
Temperature: 140 °C
Yield: 51.3 %

Procedure:
To a mixture of (3-methoxyphenyl)hydrazine (6 g) and 3-[4-(methylthio)phenyl]acrylonitrile (5.7 g) in methanol (100 ml) was added sodium methoxide (28 wt. % solution in methanol) (18 ml) at ambient temperature. The mixture was heated to dryness under nitrogen at 140° C. for 30 minutes. The resultant orange mass was partitioned between dichloromethane and ice water. The organic layer was dried over magnesium sulfate, and then filtered. This filtrate was evaporated in vacuo. The resultant mass was dissolved in ethyl acetate (150 ml) and refluxed for 1 hour in the presence of magnesium (IV) oxide (20 g). This mixture was cooled, and filtered. The filtrate was evaporated in vacuo. The resultant mass was purified by column chromatography on silica gel using dichloromethane as eluent to give {1-(3-methoxyphenyl)-5-[4-(methylthio)-phenyl]pyrazol-3-yl}amine (5.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[CH2:15]([N:17]([CH2:26][CH3:27])[C:18](=O)[CH2:19][C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)[CH3:16]>>[CH:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[S:6][C:5]=2[CH:13]=[CH:14][C:2]=1[N:1]=[C:18]([N:17]([CH2:15][CH3:16])[CH2:26][CH3:27])[CH2:19][C:20]1[S:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCN(CC)C(=O)Cc1cccs1
Reactant: Nc1ccc2sc3ccccc3c2c1
Product: CCN(CC)C(Cc1cccs1)=Nc1ccc2sc3ccccc3c2c1

Procedure:
The procedure of Example 28 was followed using 2-aminodibenzothiophene and N,N-diethyl-2-thiopheneacetamide giving the desired product as a solid, mp 114°-115° C. following purification on silica gel using methylene chloride.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:24][O:25][C:26]([C:28]1[O:29][C:30]([CH2:33]Br)=[CH:31][CH:32]=1)=[O:27]>>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[N:20]([CH2:33][C:30]4[O:29][C:28]([C:26]([O:25][CH3:24])=[O:27])=[CH:32][CH:31]=4)[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]cc(C2c3ccccc3C=Cc3ccccc32)c(=O)[nH]1
Reactant: COC(=O)c1ccc(CBr)o1
Product: COC(=O)c1ccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)o1

Procedure:
The subtitle compound was prepared from the product of example 1 step (iii) (1.1 g) and 5-bromomethyl-2-furancarboxylic acid methyl ester (0.96 g)(J. Chem. Soc. Perkin Trans. 1, 1981, 1125, Bull. Chem. Soc. Jpn. 1987, 60, 1807) according to the method of example 1 step (iv). Purification was by chromatography eluting with 50-80% ethyl acetate in isohexane. Yield 1.24 g.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([OH:19])/[CH:16]=[CH:17]/[CH3:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)N([O])C(C)(C)CCC1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:19])/[CH:16]=[CH:17]/[CH3:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C/C=C/C(O)c1cccc(OCc2ccccc2)c1
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: C/C=C/C(=O)c1cccc(OCc2ccccc2)c1

Procedure:
93.C was prepared from 93.B via oxidation with TEMPO and iodobenzene diacetate according to the analogous method described in Example 90.
Reaction SMILES: Br[CH2:2][CH2:3][S:4]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[CH3:15][C:16]1[N:20]=[CH:19][NH:18][N:17]=1>>[CH3:15][C:16]1[N:20]=[CH:19][N:18]([CH2:2][CH2:3][S:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[N:17]=1
Reactant: Cc1nc[nH]n1
Reactant: N#Cc1ccc(S(=O)(=O)CCBr)cc1
Product: Cc1ncn(CCS(=O)(=O)c2ccc(C#N)cc2)n1

Procedure:
To a stirred suspension of 10 g of thiosemicarbazide in 100 mL of pyridine was slowly added 7.8 ml of acetyl chloride at 0° C. The temperature was maintained throughout the addition (0-4° C.). The reaction mixture was allowed to warm to room temperature and stirred for 16 h. Evaporation gave 1-acetyl thiosemicarbazide. The crude 1-acetyl thiosemicarbazide was dissolved in 70 mL of MeOH and 12 g of sodium methoxide, and was refluxed for 10 h. The solvent was removed and the residue was dissolved in H2O, then acidified to pH 2 by the addition of 1N HCl. The resulting solid was filtered and washed with H2O to give 3-methyl-1,2,4-triazole-5-thiol. 1 g of 3-methyl-1,2,4-triazole-5-thiol was added to a solution of 61 mg of sodium nitrite in 3 ml of nitric acid and 6 mL of H2O at 0° C. The reaction-mixture was stirred for 1 h at 0° C., and basified with saturated sodium carbonate and concentrated. The residue was dissolved with MeOH and filtered. The filtrate was evaporated to give 3-methyl-1,2,4-triazole. 230 mg of 4-(2-bromoethylsulfonyl)benzonitrile was used in Procedure P with 3-methyl-1,2,4-triazole to yield 4-(2-(3-methyl-1H-1,2,4-triazole-1-yl)ethylsulfonyl)benzonitrile. 310 mg of 4-(2-(3-methyl-1H-1,2,4-triazole-1-yl)ethylsulfonyl)benzonitrile was reacted via Procedure T to give 4-(2-(3-methyl-1H-1,2,4-triazole-1-yl)ethylsulfonyl)benzoic acid.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1.O.[NH2:30][NH2:31].O>CN(C=O)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:31][N:30]=2)=[CH:22][CH:23]=1
Reactant: O=C(Cc1ccc(F)cc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cc3ccc(F)cc3)n[nH]c2c2cccnc2n1-c1ccccc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(4-fluorophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (3.2 g, 8.5 mmol, prepared in Synthetic Example 27) in DMF (50 ml) was added hydrazine monohydrate (80%, 1.2 ml, 30 mmol, 3.5 eq.), and the mixture was then stirred at 130° C. for 2 hours. The reaction mixture was admixed with water to precipitate crystals, allowed to stand until it was cooled, filtered off, washed with water, and dried to give 3-(4-fluorobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (3.1 g, 98%).
Reaction SMILES: N(OCCC(C)C)=O.[F:9][C:10]1[CH:11]=[C:12]([F:20])[C:13]2[S:17][C:16](N)=[N:15][C:14]=2[CH:19]=1.[ClH:21]>C(#N)C.[Cu](Cl)Cl>[Cl:21][C:16]1[S:17][C:13]2[C:12]([F:20])=[CH:11][C:10]([F:9])=[CH:19][C:14]=2[N:15]=1
Reactant: Nc1nc2cc(F)cc(F)c2s1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: Fc1cc(F)c2sc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution containing copper chloride (II) (0.89 g, 6.64 mmol) and tri(ethylene glycol)dimethyl ether (6 mL) in acetonitrile (60 mL) was added isoamyl nitrite (0.97 g, 8.30 mmol) and the reaction mixture was stirred at rt for 30 minutes. To this suspension was added dropwise a solution of 5,7-difluoro-1,3-benzothiazol-2-amine (1.03 g, 5.53 mmol) in tri(ethylene glycol)dimethyl ether (20 mL) and acetonitrile (30 mL). The reaction mixture was stirred at rt for 10 minutes and heated at 50° C. for 2.5 h. The reaction mixture was cooled to rt, and then poured cautiously into cold aqueous 6 M HCl (400 mL). The solution was extracted with EtOAc. The organic layer was washed with HCl (1.0 M), water and brine, filtered, and concentrated. The residue was purified by flash chromatography (Biotage Flash 40M) using 5% ethyl acetate in hexane to afford 2-chloro-5,7-difluoro-1,3-benzothiazole (0.55 g, 48%). 1H NMR (400 MHz, CD2Cl2) 7.02 (m, 1H), 7.52 (m, 1H).
Reaction SMILES: [OH:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16]([NH:19][CH:20]([CH2:23]O)[CH2:21][CH3:22])=[N:15][C:14](=[O:25])[N:13]([CH2:26][CH2:27][CH3:28])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2>O=S(Cl)Cl>[CH2:21]([CH:20]1[N:19]=[C:16]2[N:15]([C:14](=[O:25])[N:13]([CH2:26][CH2:27][CH3:28])[C:12]3[N:11]=[C:10]([C:5]45[CH2:4][CH2:3][C:2]([OH:1])([CH2:9][CH2:8]4)[CH2:7][CH2:6]5)[NH:18][C:17]=32)[CH2:23]1)[CH3:22]
Reactant: CCCn1c(=O)nc(NC(CC)CO)c2[nH]c(C34CCC(O)(CC3)CC4)nc21
Solvent: O=S(Cl)Cl
Product: CCCN1C(=O)N2CC(CC)N=C2c2[nH]c(C34CCC(O)(CC3)CC4)nc21
Temperature: 25 °C
Yield: 47.7 %

Procedure:
8-(4-Hydroxy-bicyclo[2.2.2]oct-1-yl)-6-(1-hydroxymethyl-propylamino)-3-propyl-3,7-dihydro-purin-2-one (110 mg) was dissolved in 3 mL of SOCl2 and stirred under reflux for 20 min. It was then cooled to rt and concentrated. The residue was quenched with saturated aq NaHCO3 and extracted with CHCl3. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by preparative HPLC afforded 50 mg of the titled compound as the TFA salt.