Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:10](=[N:16][OH:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:9])[CH3:8].I[CH:19]([CH3:21])[CH3:20].O>CC(C)=O.C(Cl)Cl>[C:7]([C:10](=[N:16][O:17][CH:19]([CH3:21])[CH3:20])[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:9])[CH3:8]
Reactant: CC(C)I
Reactant: CCOC(=O)C(=NO)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCOC(=O)C(=NOC(C)C)C(C)=O
Reaction time: 0.42 h

Procedure:
52 g of potassium carbonate were added to a mixture of 397.8 g of ethyl 2-acetyl-2-hydroxyiminoacetate in 200 ml of pure acetone cooled on an ice bath and then 25 ml of 2-iodopropane were added thereto over 25 minutes. The mixture was stirred for 2 hours and 800 ml of water and 500 ml of methylene chloride were added thereto. The mixture was stirred and decanted and the aqueous phase was extracted with methylene chloride. The mixture was dried and vacuum filtered and the filtrate was evaporated to obtain 41.5 g of ethyl 2-acetyl-2-(1-methylethoxyimino)-acetate.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:23]>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:22]([O:24][C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)=[O:23])=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N2CCOCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of 2.60 g (14.6 mmol) of 4-morpholinoaniline in 20 ml of methylene chloride were added 14.07 ml (105 mmol) of triethylamine and 3.53 g (17.5 mmol) of 4-nitrophenyl chloroformate under ice-cooling, followed by stirring at room temperature for 7 hours. After the solvent was evaporated, water was added to the residue, and the precipitated crystals were collected by filtration, washed water, and dried to give 4-morpholino-N-(4-nitrophenoxycarbonyl)aniline.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][CH2:21][CH:22]([CH3:42])[CH:23]([C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[F:41])[S:24]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)(=[O:26])=[O:25])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CC=CC=1.F.C(=O)(O)[O-].[Na+].CCCCCC>C(Cl)Cl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([S:24]([CH:23]([C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[F:41])[CH:22]([CH3:42])[CH2:21][CH2:20][CH2:19][OH:18])(=[O:26])=[O:25])=[CH:32][CH:31]=1
Reactant: CC(CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(CCCO)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.6 %

Procedure:
The 2-[5-(t-butyldiphenylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-2-methylpentyl]-1,4-difluorobenzene (Isomer 38-B) (450 mg, 0.717 mmol) obtained in Example 38 was dissolved in methylene chloride (10 ml). Under ice cooling, hydrogen fluoride-pyridine (0.41 ml) was added dropwise. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 14 hours. To the reaction mixture was added a saturated aqueous solution (20 ml) of sodium bicarbonate, followed by extraction with diethyl ether. The organic layer was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and brine and dried over anhydrous magnesium sulfate. After filtration, the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to yield a colorless oil. The resulting colorless oil was solidified with hexane, whereby the title compound (194 mg, 70%) was obtained as a white powder.
Reaction SMILES: C([Li])CCC.Br[C:7](Br)=[CH:8][C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CO.C(OCC)(=O)C>C1COCC1>[C:8]([C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])#[CH:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=C(Br)Br
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#C[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 88.3 %

Procedure:
Butyl lithium (48 mL, 0.08 mol) was added at -78° C. to a stirred solution of (R)-t-butyl 2-(2,2-dibromoethenyl)-1-pyrrolidinecarboxylate (14.2 g, 0.04 mol) in dry THF (300 mL). The color turned to dark yellow. After 15 min. methanol (10 mL) and ethyl acetate (10 mL) were added and the solution was allowed to warm to room temperature. The solvent was removed and the residue was partitioned between ethyl acetate and water. The ethyl acetate phase was concentrated and applied to a silica gel column. Elution with ethyl acetate:Skellysolve B (1:10) gave 6.9 g (88%) of product as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].Cl[CH2:11][C:12](Cl)=[O:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[OH:8][C:7]1[C:2]2[NH:1][C:12](=[O:13])[CH2:11][O:9][C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1c(O)cccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1COc2cccc(O)c2N1
Reaction time: 16 h
Yield: 65 %

Procedure:
To a solution of 2-aminobenzene-1,3-diol (2.00 g, 16.0 mmol) and TEA (1.94 g, 19.2 mmol) in anhydrous DMF (30 mL) was added 2-chloroacetyl chloride (1.81 g, 16.0 mmol). After 16 h, K2CO3 (2.65 g, 19.2 mmol) was added and the reaction mixture was stirred for another 16 h. The mixture was diluted with water and extracted with DCM. The combined organic extracts were washed with water, brine, the combined organic extracts dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography. (1.7 g, yield 65%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Ic1ccccc1
Reactant: c1ccc2[nH]ccc2c1
Product: c1ccc(-n2ccc3ccccc32)cc1

Procedure:
Following General Procedure A (90° C., 30 hours), 1H-indole (176 mg, 1.5 mmol) is coupled with iodo-benzene (112 μL, 1.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: hexanes) to provide 180 mg (93% isolated yield) of the desired product as a light green oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(O)(=O)C.[N+:13]([O-])([OH:15])=[O:14]>N([O-])=O.[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(F)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(F)ccc1O
Temperature: 15 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
In a 500-ml flask, place 44.8 g (0.4 m) of 4-fluorophenol (1a; X=F) and 132 ml of acetic acid and stir to a solution. Add 0.6 g of sodium nitrite and cool the solution to 15° C. Add 36.0 g (0.4 m) of 70% nitric acid in drop wise keeping the temperature at 22-27° C. over 10-15 min. Stir the resulting yellow slurry at room temperature for 3 hrs. Warm the mixture to 65° C. to make a clear solution and add 132 ml of warm (65° C.) water slowly. Stir the resulting slurry and cool to 15° C. Collect solid, wash with water thoroughly, and dry in air to give 53.4 g (85%) of 4-fluoro-2-nitrophenol (2a; X=F) as yellow granular solids.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=O.Cl.[NH2:12][OH:13].C([O-])(=O)C.[Na+]>CO.CCOCC>[OH:13][N:12]=[CH:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: N#Cc1ccc(C=NO)cc1
Temperature: 70 °C
Yield: 89 %

Procedure:
The compound was prepared according to Biasotti et al. Bioorg. Med. Chem. 2003, 11, 2247. A suspension of 4-formylbenzonitrile (500 mg, 3.81 mmol, 1.00 eq), hydroxylamine hydrochloride (290 mg, 4.19 mmol, 1.10 eq), and sodium acetate (1.56 g, 19.05 mmol, 5.00 eq) in MeOH (50 mL) was heated at 70° C. for 4 h before concentration to dryness. The residue was then slurried in Et2O, filtered, and concentrated to afford the desired intermediate (496 mg, 3.39 mmol, 89%).
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[C:22](O)=[O:23].N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:22]([C:13]3[CH:14]=[CH:15][C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:12]=3)=[O:23])[CH2:2]1)[CH2:8]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1ccc2ccccc2c1
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc2ccccc2c1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 2-naphthoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.94-2.03 (m, 3 H), 2.29-2.40 (m, 4H), 3.40 (s, 2H), 3.51 (s, 4H), 4.43 (s, 1H), 7.54-7.62 (m, 2H), 7.86-8.02 (m, 4H), 8.40 (d, J=1 Hz, 1H); MS (APCI/NH3) m/z 307 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)=O)[CH:7]=[CH:8][CH:9]=1.[N+:25](CS(C1C=CC(C)=CC=1)(=O)=O)#[C-:26].C(O[K])(C)(C)C.O>COCCOC>[F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:26]#[N:25])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)O[K]
Solvent: COCCOC
Solvent: O
Product: N#CC(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
At 0° C. to a solution of bis(3-(trifluoromethoxy)phenyl)methanone (3 g, 8.6 mmol), prepared as described in Procedure 11, in DME (60 mL) was added 1-(isocyanomethylsulfonyl)-4-methylbenzene (3.3 g, 17.1 mmol) and tBuOK (25.7 mL, 1.0 M solution in tBuOH, 25.7 mmol). The reaction mixture was allowed to warm to rt and stirred for 18 h. H2O (100 mL) was added to the reaction mixture and the aqueous layer was extracted with DCM (3×100 mL). The combined organic layers were washed with sat. NaCl (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by ISCO chromatography (150 g) using hexane/EtOAc (0-5% over 30 min, 5-20% over 20 min) to give 2,2-bis(3-(trifluoromethoxy)phenyl)acetonitrile as a yellow oil at a retention time of 46 min (1.4 g, 45% yield). HPLC: RT=4.13 min, Purity 100% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm). NMR: 400 MHz 1H (CDCl3) 7.45 ppm, 2H, t, J=8.13 Hz; 7.30 ppm, 2H, d, J=7.91 Hz; 7.23 ppm, 2H, d, J=9.23 Hz; 7.17 ppm, 2H, s; 5.17 ppm, 1H, s.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[N:23][N:22]([CH:25]([CH3:29])[C:26](=O)[CH3:27])[C:21]4=[O:30])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:31][C@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:33]>[Pd].CCCCO.CCCCO.CCCCO.CCCCO.[Ti].S1C=CC=C1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH:24]=[N:23][N:22]([CH:25]([CH3:29])[CH:26]([NH:33][CH:32]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH3:31])[CH3:27])[C:21]4=[O:30])=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Reactant: C[C@@H](N)c1ccccc1
Agent: [Pd]
Agent: [Ti]
Solvent: CCCCO
Solvent: c1ccsc1
Product: CC(NC(C)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O)c1ccccc1
Reaction time: 48 h

Procedure:
A mixture of (±)-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-(1-methyl-2-oxopropyl)-3H-1,2,4-triazol-3-one (0.05 mol) (prepared as described in EP-A-0,228,125 and (+)-(R)-α-methylbenzenemethanamine (0.1 mol) in TBF (500ml) was hydrogenated at 50° C. for 48 hours with Pd/C 10% (10 g) as a catalyst in the presence of titanium(IV) n-butoxide (28.4 g) and thiophene solution (10 ml). The catalyst was filtered off. Pd/C 10% (10 g) was added again. Hydrogenation was continued at 50° C. for 48 hours. After uptake of H2, the mixture was cooled, then the catalyst was filtered off and the filtrate was evaporated. The residue was stirred in CH2Cl2 (500 ml) and H2O (50ml) was added. The mixture was acidified with a concentrated HCl solution, alkalized with a concentrated NH4OH solution and filtered over dicalite. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was triturated in DIPE, filtered off and dried, yielding 23.5 g (91%) of [(R*,R*)(R)+(R*,S*)(R)]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-[2-[( 1 -phenylethyl)amino]-1 -methylpropyl]-3H-1,2,4-triazol-3-one (interm. 1).
Reaction SMILES: [CH:1](I)([CH3:3])[CH3:2].[F:5][C:6]([F:18])([F:17])[C:7]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][NH:9][N:8]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C.CN(C)C1C=CN=CC=1>[CH:1]([N:9]1[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([C:6]([F:5])([F:17])[F:18])=[N:8]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Reactant: CC(C)I
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn(C(C)C)nc1C(F)(F)F
Temperature: 60 °C
Reaction time: 3 h
Yield: 44.3 %

Procedure:
Isopropyl iodide (1.225 g, 7.21 mmol) was added to a solution of ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (500 mg, 2.402 mmol) and DIEA (652 mg, 5.04 mmol) in DMF (5 mL) and the reaction stirred at RT for 3 h and 60° C. for 3 h. The reaction was diluted with ethyl acetate (30 mL), washed with 5% citric acid (30 mL), saturated sodium bicarbonate (30 mL) and brine (30 mL), dried (Na2SO4) and concentrated in vacuo to give an oil. LC and LCMS showed starting material still present (˜40%). The oil was dissolved in DMF (4 mL), treated with DIEA (652 mg, 5.04 mmol), isopropyliodide (1.22 g, 7.21 mmol) and catalytic 4-dimethylaminopyridine (˜5 mg) and stirred at RT overnight. The reaction was diluted with ethyl acetate (30 mL), washed with 5% citric acid (30 mL) saturated sodium bicarbonate (30 mL) and brine (30 mL), dried Na2SO4), concentrated in vacuo and purified by column chromatography (ethyl acetate/hexane) to afford ethyl 1-isopropyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (266 mg, 44% yield). 1H NMR (300 MHz, DMSO-d6): δ 1.26 (s, 9 H), 1.43 (d, 6 H), 4.23 (q, 2 H), 4.64 (hp, 1 H), 8.62 (s, 1 H); MS (ESI) m/z: 251.0 (M+H+).
Reaction SMILES: CS(O[C@@H:6]1[C@@H:10]([CH2:11][O:12]S(C)(=O)=O)[O:9][C@@H:8]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:7]1)(=O)=O.[OH-].[Na+].Cl>O>[C@@H:8]1([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[O:9][C@@H:10]2[CH2:11][O:12][C@@H:6]2[CH2:7]1
Reactant: Cc1cn([C@H]2C[C@H](OS(C)(=O)=O)[C@@H](COS(C)(=O)=O)O2)c(=O)[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cn([C@H]2C[C@H]3OC[C@H]3O2)c(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
3',5'-Di-O-(methanesulfonyl)thymidine (248 g, 0.62M) was added in portions to a stirred solution of sodium hydroxide (74.7 g, 1.87M) in water (1.6 L). On addition 3 the reaction mixture became a yellow-orange solution. This stirred solution was then heated to reflux for 2 hr. Once the reaction mixture had cooled to room temperature, 6N hydrochloric acid (100 mL) was added. The reaction mixture was concentrated in vacuo by removing 1.3 L of water. The resulting slurry was cooled in an ice bath for 2 hr. The solid was then filtered and washed sparingly with ice water, and then vacuum dried to constant weight (103.7 g, 74%). The product 3, mp 188°-190° C. (lit. 190°-193° C.) was used without further purification. 1H NMR (360 MHz, d6 -DMSO) 11.35 (s, 1H, NH), 8.01 (s, 1H, H-6), 6.49 (q, 1H, H-1 '), 5.47 (m, 1H, H-3'), 4.88 and 4.67 (m, 2H, H-5'), 4.22 (d, 1H, H-4'), 2.47 (m, 2H, H-2') 1.77 (S, 3H, CH3). 13C NMR (75 MHz, d6 -DMSO) 163.64 (C2), 151.10 (C4), 136.57 (C6), 109.62 (C5), 88.29 (C4'), 86.85 (C1'), 79.83 (C3'), 75.14 (C5'), 37.17 (C2'), 12.33 (CH3). Analysis (C10H12N2O4) C, H, N.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[C:9](OCC)(=[O:14])[CH2:10][C:11]([CH3:13])=O>C(O)C>[CH3:13][C:11]1[NH:5][C:6]([NH2:8])=[N:7][C:9](=[O:14])[CH:10]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CCO
Product: Cc1cc(=O)nc(N)[nH]1
Reaction time: 8 h
Yield: 125.6 %

Procedure:
Dry ethanol (600 mL), 91.89 g of guanidine carbonate, and 146.1 g of ethyl acetoacetate were added to a 1 L flask. The reaction solution was gradually heated to reflux temperature and stirred overnight. Ethanol (300 mL) was evaporated, and the reaction mixture was heated under reflux for two hours. After the reaction mixture was cooled, 300 mL of hexane was added. The resulting precipitate was filtered, washed and dried. 119.3 g of 6-methyl-iso cytosine was obtained.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[N+:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2)([O-:12])=[O:11].[H-].[Na+]>CN(C=O)C.O>[N+:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:17]=[CH:16]2)([O-:12])=[O:11]
Reactant: ClCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(ccn2CCN2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
Dissolve 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (2.36 g, 13.9 mmol) and 5-nitro-1H-indole (1.50 g, 9.23 mmol) in DMF (25 mL) and carefully treat with sodium hydride (60% dispersion, 1.50 g, 37.5 mmol). Stir the mixture at room temperature overnight, then dilute with cold water (100 mL) and extract with EtOAc (3×50 mL). Was the combined organic portions with water (2×50 mL) and brine (50 mL). Dry, filter and concentrate under vacuum. Purify the crude material by flash chromatography, using 100% acetone as eluant, to give the title compound as a yellow oil (2.08 g, 87%). MS (ES+) 260.1 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 8.57 (d, 1H, J=2.2 Hz), 8.10 (dd, 1H, J=9.2, 2.2 Hz), 7.37 (d, 1H, J=9.2 Hz), 7.30 (d, 1H, J=3.1 Hz), 6.67 (d, 1H, J=3.1 Hz), 4.29 (t, 2H, J=7.3 Hz), 2.89 (t, 2H, J=7.0 Hz), 2.54 (m, 4H), 1.78 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([OH:11])[CH:5]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].CC(=O)CC>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:6]([O:11][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[CH:5]=1
Reactant: CCCCCCCCCCCCCCBr
Reactant: COC(=O)c1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1OCCCCCCCCCCCCCC
Temperature: 25 °C
Yield: 98.6 %

Procedure:
A mixture of 15.0 g of product from Example 102, 53.2 g of 1-bromotetradecane, 37 g of potassium carbonate, 1.04 g of potassium iodide and 350 ml of 2-butanone is heated at reflux for 28.5 hours. The reaction is cooled to room temperature, filtered and the filtrate concentrated in vacuo. The residue is recrystallized from methylene chloride/hexane to give 49.33 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-])=O)[CH:4]=1>CO.[Pd]>[NH2:10][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[OH:9]
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(O)c(N)c1

Procedure:
Commercially available 4-methoxy-2-nitrophenol (1 g, 5.9 mmol) was dissolved in 10 mL methanol, and 10% Pd/C was added to the mixture. The mixture was hydrogenated in a Parr™ shaker at 30 psi until consumption of hydrogen ceased. The mixture was filtered through Celite and concentrated under reduced pressure, to yield 2-amino-4-methoxyphenol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:17]([O-])=O)=[C:11]([CH:14]=[CH:15][CH:16]=1)[NH:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CO>[NH2:17][C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:16][CH:15]=[CH:14][C:11]=1[NH:12][CH3:13]
Reactant: CNc1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: NN
Solvent: O
Solvent: CO
Product: CNc1cccc(OCc2ccccc2)c1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.1 %

Procedure:
To a mixture of 3-benzyloxy-N-methyl-2-nitroaniline (453.3 mg), 80% methanol (6.8 ml), anhydrous ferric chloride (13.6 mg) and carbon (13.6 mg) was dropwise added hydrazine monohydrate (255.6 μl), and the mixture was stirred for 5 hours at ambient temperature. Insoluble material was filtered off, and the filtrate was concentrated in vacuo. To the residue were added ethyl acetate and saturated sodium bicarbonate solution, and the separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate-n-hexane) to give 2-amino-3-benzyloxy-N-methylaniline (348.9 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][N:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Si]([C:15]#[N:16])(C)(C)C.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>C(Cl)Cl>[S:17]([N:1]1[CH:6]([C:15]#[N:16])[CH:5]=[CH:4][CH:3]=[N:2]1)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: C[Si](C)(C)C#N
Reactant: c1ccnnc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2N=CC=CC2C#N)cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of pyridazine, 30-ia, (5 mL, 69.12 mmol), aluminum chloride (28 mg, 0.21 mmol) and TMSCN (16.75 mmol) in DCM (60 mL) was stirred under a nitrogen atmosphere at 0° C. for 20 min. A solution of TsCl (22.75 g, 119.7 mmol) in DCM (40 mL) was added dropwise. The reaction was warmed to room temperature, stirred for an additional 60 h, and concentrated in vacuo. The residue was washed with EtOH (150 mL) and the resulting solids were filtered to afford the title compound, 30-ib, (15 g, 83%). 1H NMR (300 MHz, CDCl3) δ7.93 (d, J=8.4 Hz, 2H), 7.38 (d, J=1.8 Hz, 2H), 6.23-6.21 (m, 2H), 5.79 (d, J=6.3 Hz, 1H), 2.44 (s, 3H). LC-MS: (M+H)+ 262.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:21]=[CH:22][C:23]4[C:27]([C:28]([O:30]C)=[O:29])=[C:26]([CH3:32])[S:25][C:24]=4[CH:33]=3)[CH:11]=2)=[O:9])[CH2:4]1.O[Li].O.Cl>C1COCC1.CO.O.O>[CH3:1][O:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:21]=[CH:22][C:23]4[C:27]([C:28]([OH:30])=[O:29])=[C:26]([CH3:32])[S:25][C:24]=4[CH:33]=3)[CH:11]=2)=[O:9])[CH2:4]1
Reactant: COC(=O)c1c(C)sc2cc(Oc3ccnc4cc(C(=O)N5CC[C@@H](OC)C5)sc34)ccc12
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CO[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)O)c(C)sc5c4)c3s2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.3 %

Procedure:
To a solution of methyl 6-[(2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)oxy]-2-methylbenzo[b]thiophene-3-carboxylate 11b (258 mg, 0.535 mmole) in a mixture of THF/MeOH/H2O (3:2:1, 6 ml) was added LiOH.H2O (224 mg, 5.35 mmole). The reaction was stirred 24 hours at ambient temperature. The mixture was diluted with H2O (10 ml) and acidified to pH 1 with 1 M HCl. The precipitate was collected by vacuum filtration, rinsed with MeOH, and dried at 50° C. under vacuum to afford 116 mg (45%) of a pale brown solid. 1H NMR (DMSO-d6) δ 8.58 (1H, d, J=5.4 Hz), 8.44 (1H, d, J=8.9 Hz), 8.07 (1H, s), 8.00 (1H, d, J=24 Hz), 7.39 (1H, dd, J=2.4, 8.9 Hz), 6.78 (1H, d, J=5.4 Hz), 4.10–3.81 (3H, m), 3.69–3.54 (4H, m), 3.27, 3.24 (3H, s), 2.81 (3H, s).