Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Sn:5](Cl)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[CH3:30][O:31][C:32]([CH:34]=[CH:35][C:36]1[N:37]=[CH:38][N:39]2[CH:43]=[CH:42][S:41][C:40]=12)=[O:33].O>C1COCC1>[CH3:30][O:31][C:32]([CH:34]=[CH:35][C:36]1[N:37]=[CH:38][N:39]2[CH:43]=[C:42]([Sn:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH2:3][CH3:4])[S:41][C:40]=12)=[O:33]
Reactant: COC(=O)C=Cc1ncn2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C=CC(=O)OC)c2s1
Reaction time: 0.25 h

Procedure:
Tri-n-butylstannyl chloride (250 μl) and 2.1 ml of a 1.0 N lithiumbis(trimethylsilyl)amide/THF solution were added in that order to a solution of 7-(2-methoxycarbonylvinyl)imidazo[5,1-b]thiazole (a mixture of geometrical isomers) in dry THF in an argon atmosphere at −78° C. The mixture was stirred at the same temperature for 15 min. Water was added thereto. The mixture was extracted with ethyl acetate, followed by washing with saturated brine. The extract was dried over anhydrous magnesium sulfate and then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to give 408 mg of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:28]=[CH:27][C:17]([O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[CH:16][CH:15]=2)[N:13]=1>C(Cl)Cl>[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:27][CH:28]=2)[N:13]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(-c2csc(N)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(-c2ccc(OCC(=O)O)cc2)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 143.4 %

Procedure:
Trifluoroacetic acid (50 mL) was added to a solution of the product of example 2 (3.81 g, 12.4 mmol) in CH2Cl2 (50 mL). The resulting mixture was stirred at room temperature (20-22°) for 4 h, then concentrated under reduced pressure (coevaporated with CH2Cl2 and then Et2O). The residue was triturated with Et2O, then filtered and dried to afford 4.45 g (quantitative yield) of the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J=8.8 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 6.96 (s, 1H), 4.72 (s, 2H). The product was used without further purification for the following reaction (example 4).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:10]([CH:11]=[O:12])[C:9]=2[OH:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:17].[K+]>C(O)C.O.[N+]([O-])([O-])=O.[Ag+]>[C:1]1([CH2:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:10]([C:11]([OH:17])=[O:12])[C:9]=2[OH:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [OH-]
Reactant: O=Cc1cccc(Cc2ccccc2)c1O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccc(Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 34.3 %

Procedure:
According to the general method of Sharma et al., 2000, Synth. Commun., 30:397-405, a stirred solution of the 3-(phenylmethyl)salicylaldehyde (1.27 g, 6 mmol) in ethanol (16 ml) was treated dropwise with a solution of silver nitrate (2.0 g, 12 mmol) in water (16 ml). A solution of potassium hydroxide (2.69 g, 48 mmol) was then added dropwise over 40 minutes. The solution was allowed to stir at RT for 6 h. The mixture was filtered through a pad of celite, and the filter pad washed with water (2×10 ml). The filtrate was washed with diethyl ether (2×15 ml) and then acidified with 1N HCl. The milky suspension was extracted with diethyl ether (2×30 ml), and the combined extracts were dried (Na2SO4) and the solvent removed to yield 3-(phenylmethyl)salicylic acid as a tan solid (0.47 g, 34%). 1H-NMR (CDCl3, 400 MHz): δ 4.02 (s, 2H), 6.84 (t, 1H, J=8 Hz), 7.19-7.32 (m, 6H), 7.79 (d, 1H, J=8 Hz), 10.74 (s, 1H).
Reaction SMILES: [BH4-].[Li+].Cl[Si](C)(C)C.[CH:8]1([C:11]2[C:16](/[CH:17]=[CH:18]/[N+:19]([O-])=O)=[CH:15][CH:14]=[C:13]([C:22]([F:25])([F:24])[F:23])[N:12]=2)[CH2:10][CH2:9]1>C1COCC1>[CH:8]1([C:11]2[C:16]([CH2:17][CH2:18][NH2:19])=[CH:15][CH:14]=[C:13]([C:22]([F:25])([F:23])[F:24])[N:12]=2)[CH2:10][CH2:9]1
Reactant: O=[N+]([O-])/C=C/c1ccc(C(F)(F)F)nc1C1CC1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1ccc(C(F)(F)F)nc1C1CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.4 %

Procedure:
To a stirred solution of lithium borohydride (232 μL, 0.465 mmol) in THF was added chlorotrimethylsilane (118 μL, 0.930 mmol) dropwise. After stirring for 15 minutes, argon was bubbled through the reaction mixture for 2 minutes to eliminate any trimethylsilane in the reaction mixture. (E)-2-cyclopropyl-3-(2-nitrovinyl)-6-(trifluoromethyl)pyridine (30 mg, 0.116 mmol) was added (in 1 mL of THF). The reaction was heated to reflux for 2 hours, cooled to 0° C. and carefully quenched with methanol (1 mL). The reaction mixture was concentrated, diluted with dichloromethane and 20% aqueous KOH. The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated to yield 2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)ethanamine (26 mg, 0.113 mmol, 97.2% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]#[N:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].Cl.[OH-].[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]#[N:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC=C1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [Mg]
Agent: [Na+]
Solvent: CO
Product: N#CCC1CCN(Cc2ccccc2)CC1
Reaction time: 4 h

Procedure:
To a solution of benzylpiperidin-4-ylideneacetonitrile (compound of Example 26; 1 g, 4.7 mmol) in methanol (50 mL), magnesium turnings (4.58 g, 188.3 mmol) was added at 0° C. The reaction mixture was stirred at 5° C. to 10° C. for 4 h. The magnesium salts were dissolved by addition of concentrated hydrochloric acid, and the mixture was basified with 10N sodium hydroxide solution. The precipitate was filtered and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water (2×15 mL) followed by brine (10 mL). The organic phase obtained was dried over anhydrous sodium sulphate and evaporated to afford the title compound.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1.Br[CH2:18][CH2:19][C:20](C)=[CH2:21]>>[CH2:14]([O:13][C:11](=[O:12])[CH:10]([S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:16])=[CH:6][CH:5]=1)(=[O:9])=[O:8])[CH2:18][CH:19]=[CH:20][CH3:21])[CH3:15]
Reactant: CCOC(=O)CS(=O)(=O)c1ccc(C)cc1
Reactant: C=C(C)CCBr
Product: CC=CCC(C(=O)OCC)S(=O)(=O)c1ccc(C)cc1

Procedure:
5-Methyl-2-(3-methyl-but-2-enyl)-2-(toluene-4-sulfonyl-hex-4-enoic acid ethyl ester was prepared according to general method as outlined in example 9. Starting from ethyl α-(p-tolylsulfonyl)acetate (2.9 g, 10.9 mmol and 4-bromo2-methyl butene (3.42 g, 23 mmol). Yield 4.6 g; tan oil; MS 379.2 (M+H)+.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([O:21][CH3:22])=[N:6][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[CH:13][CH:12]=2)=[N:8][CH:9]=1.[OH:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH:28]=[CH:27]2.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[F:19][CH:18]([F:20])[O:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:7]2[N:6]=[C:5]([O:21][CH3:22])[C:4]([CH2:3][O:23][C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[NH:30][C:29](=[O:34])[CH:28]=[CH:27]4)=[CH:9][N:8]=2)=[CH:12][CH:13]=1
Reactant: COc1nc(Nc2ccc(OC(F)F)cc2)ncc1CCl
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(Nc2ccc(OC(F)F)cc2)ncc1COc1ccc2[nH]c(=O)ccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.8 %

Procedure:
A solution of 5-(chloromethyl)-N-(4-(difluoromethoxy)phenyl)-4-methoxypyrimidin-2-amine hydrochloride (0.14 g, 0.398 mmol) in DMF (1.5 mL) was added to a mixture of 6-hydroxyquinolin-2(1H)-one (0.08 g, 0.496 mmol) and Cs2CO3 (0.518 g, 1.590 mmol) in DMF (6.5 mL). The reaction mixture was stirred at room temperature for 18 h, then diluted with water and filtered. The filter cake was stirred in methanol/DCM (1:1) for 18 h, filtered, and dried to give 6-((2-((4-(difluoromethoxy)phenyl)amino)-4-methoxypyrimidin-5-yl)methoxy)quinolin-2(1H)-one as a beige solid (0.082 g, 45%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.67 (s, 1H), 9.76 (s, 1H), 8.35 (s, 1H), 7.96-7.70 (m, 3H), 7.36-6.93 (m, 6H), 6.51 (d, J=9.5 Hz, 1H), 4.94 (s, 2H), 3.99 (s, 3H). LCMS: R.T.=0.82; [M+H]+=441.1.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH2:52][OH:53])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-:55].[Na+].[Br-].[K+].Cl[O-].[Na+].Cl>O1CCCC1>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:45][CH:46]=4)[CH:34]=3)[O:32][C@@:10]1([C:52]([OH:55])=[O:53])[CH2:11][O:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-(trifluoromethoxy) phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 150 (0.45 g, 0.60 mmol, obtained from the synthetic method described in step 13 of example 15) in tetrahydrofuran (8 mL) were added sodium bicarbonate (0.56 g, 6.62 mmol), potassium bromide (14.3 mg, 0.12 mmol) and 2,2,6,6-tetramethylpiperidinooxy (9.38 mg, 0.06 mmol) in turn at 0° C., and then sodium hypochlorite (19 mL, available chlorine ≧5.5%) was added dropwise over a period of 10 min. The mixture was warmed up to room temperature and stirred for 1 hour, and then acidified with aqueous HCl (1 N) till pH becomes 4. The resulting mixture was extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with saturated aqueous sodium chloride (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 16a (0.50 g, 100%) as yellow oil. This material was not further purified.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[C:14]([O:47][CH3:48])=[CH:15][C:16]2[CH2:22][CH2:21][CH2:20][C:19]([C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]4[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[C:34]([O:42][CH3:43])[CH:33]=4)[CH2:27][CH:26]3[CH2:44]O)=[O:24])=[CH:18][C:17]=2[CH:46]=1.[CH2:49]([N:51](CC)[CH2:52][CH3:53])[CH3:50]>C(Cl)Cl>[CH2:49]([N:51]([CH2:44][CH:26]1[CH2:27][N:28]([CH2:31][C:32]2[CH:33]=[C:34]([O:42][CH3:43])[C:35]([O:40][CH3:41])=[C:36]([O:38][CH3:39])[CH:37]=2)[CH2:29][CH2:30][N:25]1[C:23]([C:19]1[CH2:20][CH2:21][CH2:22][C:16]2[CH:15]=[C:14]([O:47][CH3:48])[C:13]([O:12][CH3:11])=[CH:46][C:17]=2[CH:18]=1)=[O:24])[CH2:52][CH3:53])[CH3:50]
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)N1CCN(Cc3cc(OC)c(OC)c(OC)c3)CC1CO)=C2
Reactant: CCN(CC)CC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCN(CC)CC1CN(Cc2cc(OC)c(OC)c(OC)c2)CCN1C(=O)C1=Cc2cc(OC)c(OC)cc2CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.8 %

Procedure:
To a solution of oxalyl chloride (360 mg) in methylene chloride (5 ml) is added dropwise at -78° C. a (340 mg) solution of dimethyl sulfoxide (340 mg) in methylene chloride (2 ml), and the mixture is stirred for 10 minutes. To the resulting reaction mixture is added dropwise a solution of 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -4-(3,4,5-trimethoxybenzyl)piperazine-2-methanol (750 mg) in methylene chloride (2 ml), then the mixture is stirred for 15 minutes. To the reaction mixture is added triethylamine (1 g), then the reaction temperature is raised up to room temperature. The reaction mixture is poured into ice-water, followed by extraction with methylene chloride. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is dissolved in methanol (10 ml). To the solution is added diethylamine hydrochloride (1.4 g), and the mixture is stirred for 3 hours at 50° C. To the reaction mixture is added, after cooling, sodium cyanoborohydride (90 mg), followed by stirring for one hour at room temperature. The reaction mixture is poured into ice-water, followed by extraction with methylene chloride. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is purified by means of a silica gel column chromatography (eluent:ethyl acetate-methanol=9:1) to give 2-diethylaminomethyl-1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -4-(3,4,5-trimethoxybenzyl)piperazine (230 mg). This product is converted to its hydrochloride, followed by recrystallization from ethanol to give colorless crystals, m.p. 157-160° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([Cl:10])=[N:8][CH:7]=[CH:6][N:5]=1.[OH:11][C@@H:12]1[CH2:17][CH2:16][C@H:15]([C:18](O)=[O:19])[CH2:14][CH2:13]1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:10][C:9]1[C:4]([CH2:3][NH:2][C:18]([C@H:15]2[CH2:16][CH2:17][C@@H:12]([OH:11])[CH2:13][CH2:14]2)=[O:19])=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: O=C(O)[C@H]1CC[C@@H](O)CC1
Reactant: NCc1nccnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1nccnc1Cl)[C@H]1CC[C@@H](O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 2-aminomethyl-3-chloropyrazine hydrochloride (content 76%, 69.4 mmol, 16.43 g), cis-4-hydroxycyclohexanecarboxylic acid (69.4 mmol, 10 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (104 mmol, 19.95 g), 4-dimethylaminopyridine (6.94 mmol, 0.847 g) in dichloromethane (200 ml) was added N,N-diisopropylethylamine (173 mmol, 30.3 ml, 22.41 g) until pH became eight and the reaction mixture was stirred at room temperature for 18 hours. Then it was concentrated in vacuo, ethyl acetate and water were added and the organic layer separated. The water layer was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; dichloromethane with gradient of 0% to 7% methanol). All fractions that contained product were combined and concentrated in vacuo. The residue was dissolved in dichloromethane (400 ml) and washed with 2 M sodium hydroxide (aq) (three times 100 ml), washed with brine, dried (MgSO4) and concentrated in vacuo to give (cis)-N-((3-chloropyrazin-2-yl)methyl)-4-hydroxycyclohexanecarboxamide (15.47 g)
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>C(N)C1C=CC=CC=1>[CH2:5]([NH:4][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1cc(-c2ccc(Cl)nn2)ccc1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: NCc1ccccc1
Product: COc1cc(-c2ccc(NCc3ccccc3)nn2)ccc1OC(F)F
Yield: 158 %

Procedure:
5 g (17 mmol) of 3-chloro-6-(4-difluoromethoxy-3-methoxyphenyl)pyridazine are heated in 30 ml of benzylamine at 180° C. for 1 hour. The mixture is stirred into 500 ml of saturated potassium carbonate solution, and the resulting precipitate is filtered off with suction, washed thoroughly with water, dried and recrystallized from ethyl acetate. 4.8 g (77.4%) of 3-benzylamino-6-(4-difluoromethoxy-3-methoxyphenyl)pyridazine of m.p. 136° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[N:15]([CH2:24][C:25](O)=[O:26])[N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:28]2[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.C[N:38](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N>CN(C=O)C.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[N:15]([CH2:24][C:25]([NH2:38])=[O:26])[N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:28]2[CH:33]=[CH:32][C:31]([CH:34]([CH3:35])[CH3:36])=[CH:30][CH:29]=2)=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)c1ccc(-c2nc3c(-c4ccccc4)nn(CC(=O)O)c3c(=O)n2-c2ccc(Cl)cc2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)c1ccc(-c2nc3c(-c4ccccc4)nn(CC(N)=O)c3c(=O)n2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the crude [6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-7-oxo-3-phenyl-6,7-dihydro-pyrazolo[4,3-d]pyrimidin-1-yl]-acetic acid prepared from previous step, HATU (41.1 mg, 0.108 mmol) and iPr2NEt (37.6 μL, 0.216 mmol) in DMF (0.5 mL) is stirred at room temperature for 1 hour before transferred dropwise into 7 N ammonia in methanol solution (1.0 mL) at 0° C. The resultant reaction mixture is stirred at room temperature for 1 hour before removal of the solvent under reduced pressure. The residue is purified by preparative LC/MS to provide the title compound; HPLC-MS calculated for C28H24ClN5O2 (M+H+) 498.2. Found 498.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH:7]=1.[Cl:28][C:29]1[C:30]([C:36]#[N:37])=[N:31][CH:32]=[C:33](Cl)[N:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:33]3[CH:32]=[N:31][C:30]([C:36]#[N:37])=[C:29]([Cl:28])[N:34]=3)=[CH:16][CH:17]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: N#Cc1ncc(Cl)nc1Cl
Reactant: CC1(C)OB(c2ccc(NS(=O)(=O)c3cc(Cl)ccc3F)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ncc(-c2ccc(NS(=O)(=O)c3cc(Cl)ccc3F)cc2)nc1Cl
Temperature: 100 °C

Procedure:
5-Chloro-2-fluoro-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzenesulfonamide (709 mg) was added to a reaction vessel containing a magnetic stirring bar together with 3,5-dichloro-pyrazine-2-carbonitrile (300 mg), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (Pd(dppf)2Cl2) (100 mg) and cesium carbonate (1.69 g), followed by 6 ml dioxane and 1 ml water, and the mixture heated to 100° C. under stirring. After 3 h the reaction mixture was cooled to RT and quenched with a saturated aqueous sodium bicarbonate solution (40 ml) and extracted with EtOAc (3×80 ml). The combined aqueous phases were dried over sodium sulfate, filtered and evaporated to afford the crude product as a brown oil. Purification by flash chromatography on silica gel using a mixture of EtOAc and heptane as the eluent afforded 5-chloro-N-[4-(6-chloro-5-cyano-pyrazin-2-yl)-phenyl]-2-fluoro-benzenesulfonamide as a brown foam after evaporation of the solvents under reduced pressure. Yield: 160 mg (22%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CC(C)=O>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[CH3:23]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(C(C)=O)cc1
Reaction time: 18 h

Procedure:
To an ambient slurry of p-hydroxyacetophenone (20 g, 147 mmol) and K2CO3 (30.4 g, 220 mmol) in acetone (150 mL) was added ethyl bromoacetate (17.2 mL, 154 mmol). The slurry was stirred for 18 h and was quenched by the addition of H2O (150 mL) and Et2O (75 mL). The layers were separated, and the aqueous was extracted with additional Et2O (3×75 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give an oil that was used without further purification. MS (ESI) m/e 223 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.22 (t, J=7.12 Hz, 3H), 2.52 (s, 3H), 4.18 (q, J=7.12 Hz, 2H), 4.90 (s, 2H), 7.04 (m, 2H), 7.92 (m, 2H).
Reaction SMILES: C([Li])(CC)C.Br[C:7]1[CH:8]=[C:9]([CH:17]=[C:18]([Br:20])[CH:19]=1)[O:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.CN(C)[CH:23]=[O:24].C(O)(=O)C>CCCCCC.CCOCC>[Br:20][C:18]1[CH:19]=[C:7]([CH:8]=[C:9]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:17]=1)[CH:23]=[O:24]
Reactant: CN(C)C=O
Reactant: Brc1cc(Br)cc(Oc2cccnc2)c1
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=Cc1cc(Br)cc(Oc2cccnc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.7 %

Procedure:
A 1.3M solution of s-butyllithium in hexane (9.2 ml) was added dropwise to a stirred solution of 3-(3,5-dibromophenoxy)pyridine (Preparation 6; 3.29 g) in dry ether (100 ml) at -78° C., and the resulting mixture was stirred at this temperature for 15 minutes. N,N-dimethylformamide (2.2 g) was then added dropwise and this mixture stirred at the same temperature for 1 hour. Glacial acetic acid (1.6 ml) was next added and the reaction solution was allowed to warm to room temperature, washed sequentially with saturated aqueous sodium bicarbonate solution and water, then dried (MgSO4). Evaporation under vacuum of the solvent gave an oil which was chromatographed on silica gel. Elution with dichloromethane first gave impurity which was followed by pure product. The product fractions were combined and evaporated under vacuum to give the title compound as an oil (1.80 g); δ (CDCl3): 7.36-7.43(4H,m), 7.76(1H,s), 8.45-8.50(2H,m), 9.90(1H,s). Found: C,51.76; H,2.89; N,5.04. C12H8BrNO2 requires C,51.82; H,2.90; N,5.04%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:16])[CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([O-:3])=[O:2].Br[CH2:18][CH2:19][O:20][CH2:21][CH2:22]Br.C([O-])([O-])=O.[K+].[K+].CCOCC.CCCCCC>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([N:16]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:7]=[CH:8][C:9]=1[N:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)([O-:3])=[O:2]
Reactant: BrCCOCCBr
Reactant: Nc1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=[N+]([O-])c1cc(N2CCOCC2)ccc1N1CCCCC1
Yield: 70.3 %

Procedure:
The title compound was prepared following the procedure of Example 10, step (b) using 152 mg (0.687 mmol) of 3-nitro-4-piperidin-1-yl-phenylamine (as prepared in Example 10, step (a)), 78.6 mg (0.625 mmol) of 2-bromoethyl ether and 433 mg (3.13 mmol) of anh K2CO3 except the mixture was heated to reflux in 2 mL of toluene for 20 h. Chromatography on a 10-g silica SPE column with 40% Et2O-hexane afforded 128 mg (70%) of the title compound as a dark orange resin: Mass spectrum (ESI, m/z): Calcd. for C15H21N3O2, 292.2 (M+H), found 292.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[CH3:12][N:13]=[C:14]=[O:15]>C(#N)C>[CH3:12][NH:13][C:14]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:15]
Reactant: CN=C=O
Reactant: NCCSCc1ccccn1
Solvent: CC#N
Product: CNC(=O)NCCSCc1ccccn1

Procedure:
A mixture of 2-[(2-aminoethyl)thiomethyl]pyridine (7.0 g.) and methyl isocyanate (2.7 g.) in acetonitrile was heated for 18 hours in a pressure vessel at 100°. After cooling, the solid obtained was collected and recrystallised from acetonitrile/ether to give N-methyl-N'-[2-(2-pyridylmethylthio)ethyl]urea m.p. 63°-66°.