Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:27])[CH2:16][N:17]3[C:21]([CH3:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[N:18]3)[CH2:11][CH2:10]2)[S:7][CH:8]=1.[C:28]1([C:34]#[CH:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl[O-].[Na+]>O1CCCC1>[CH3:22][C:21]1[N:17]([CH2:16][C:15]([N:12]2[CH2:13][CH2:14][CH:9]([C:6]3[S:7][CH:8]=[C:4]([C:3]4[CH:35]=[C:34]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:1][N:2]=4)[N:5]=3)[CH2:10][CH2:11]2)=[O:27])[N:18]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:20]=1
Reactant: C#Cc1ccccc1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C=NO)cs2)CC1
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(-c3cc(-c4ccccc4)on3)cs2)CC1

Procedure:
4-[4-[(Hydroxyimino)methyl]-2-thiazolyl]-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine (i.e. the product of Example 2, Step C) (0.2 g, 0.5 mmol) was suspended in tetrahydrofuran (20 mL), and phenylacetylene (1.1 mL, 1 mmol) was added, followed by a slow dropwise addition of Clorox® bleach solution (6.15 wt. % sodium hypochlorite, 10 mL) over 1 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×0 mL). The combined organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure to give an oil, which was purified by flash column chromatography on silica gel using 10% methanol in ethyl acetate as eluant to give 70 mg of the title product, a compound of present invention, as a clear yellow oil.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N:17]([CH3:19])[CH3:18])[CH:15]=2)[C:10]([CH3:20])=[CH:9][C:8]1=[O:21].FC(F)(F)C(O)=O>>[CH3:18][N:17]([CH3:19])[C:14]1[CH:15]=[C:16]2[C:11]([C:10]([CH3:20])=[CH:9][C:8](=[O:21])[N:7]2[CH2:6][CH:2]=[O:1])=[CH:12][CH:13]=1
Reactant: Cc1cc(=O)n(CC2OCCO2)c2cc(N(C)C)ccc12
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(=O)n(CC=O)c2cc(N(C)C)ccc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 59 %

Procedure:
To 0.32 g of 1-(1,3-dioxolan-2-ylmethyl)-7-dimethylamino-4-methylquinolin-2(1H)-one, 3 mL of 90% aqueous trifluoroacetic acid solution was added, and stirred at room temperature for four days, the solvent was removed under reduced pressure, ethyl acetate and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 0.16 g of (7-dimethylamino-4-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde as a yellow foam.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([C@@H:34]4[CH2:38][CH2:37][CH2:36][NH:35]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2].[CH3:39][C:40]([CH3:42])=O>>[C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([C@@H:34]4[CH2:38][CH2:37][CH2:36][N:35]4[CH:40]([CH3:42])[CH3:39])=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(C)=O
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@@H]4CCCN4)ncn3)cccc2s1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@@H]4CCCN4C(C)C)ncn3)cccc2s1

Procedure:
(2S)-N-(2-(6-(2-Acetamidobenzo[d]thiazol-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)-phenyl)pyrrolidine-2-carboxamide [Example 69(b)] was reacted with acetone under the conditions of Example 3(d) to give the title compound as a white solid. MS (ESI, pos. ion.) m/z: 585 (M+1).
Reaction SMILES: [C:1]([S:20](F)(=[O:22])=[O:21])([C:4]([C:7]([C:10]([C:13]([C:16]([F:19])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[O-]S([O-])=O.[Na+:28].[Na+].O>O1CCOCC1>[C:1]([S:20]([O:22][Na:28])=[O:21])([C:4]([C:7]([C:10]([C:13]([C:16]([F:19])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: [Na+]
Agent: O=S([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=S(O[Na])C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
Fluorochemical sulfinates can be prepared by deiodosulfination of the corresponding iodides following the general procedure of Hu et al. in J. Org. Chem., Vol. 56, No. 8, 1991, page 2803. The fluorochemical sulfinates C4F9SO2Na and C6F13SO2Na were prepared by reduction of the corresponding sulfonyl fluorides C4F9SO2F and C6F13SO2F with Na2SO3 in a one to one mixture of water and dioxane. See also, U.S. Pat. No. 5,285,002, supra. The purity of these fluorochemical sulfinates, as determined by 19F NMR analysis, was about 90%.
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](OCC)(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].N1CCCCC1>C(O)C>[O:23]=[C:16]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][C:9]2[C:8](=[N:15][CH:14]=[CH:13][CH:12]=2)[N:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccnc1Nc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2cccnc2n(-c2ccccc2)c1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
6.28 g (31.7 mmol) of 2-(phenylamino)nicotinaldehyde was dissolved in ethanol (150 mL), and 7.62 g (47.6 mmol) of diethyl malonate and 1.35 g (15.9 mmol) of piperidine were added thereto. The resulting mixture was stirred overnight at 100° C. The reaction mixture was cooled, and a solid precipitated thereby was separated by filtration. The solid was washed sequentially with ethanol and diisopropyl ether. Thus, 7.42 g of the title compound was obtained as a pale yellow solid (yield: 800).
Reaction SMILES: [S:1]([C:5]1[CH:13]=[CH:12][C:8]([N+]([O-])=O)=[CH:7][CH:6]=1)(O)(=O)=O.[O:14]=[C:15]([N:18]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:19]1([CH2:25][O:26][CH3:27])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH2:16][CH3:17].COC(C)(C)C.C(N(CC)CC)C>O>[CH3:17][CH2:16][C:15]([N:18]([C:19]1([CH2:25][O:26][CH3:27])[CH2:20][CH2:21][N:22]([CH2:7][CH2:6][C:5]2[S:1][CH:8]=[CH:12][CH:13]=2)[CH2:23][CH2:24]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:14]
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCNCC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Solvent: O
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(CCc2cccs2)CC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 831.5 %

Procedure:
To a jacketed glass reactor with stirring, nitrogen blanket, internal temperature recorder, and reflux capabilities was charged 4-[(1-oxopropyl)phenylamino]-4-methoxymethyl piperidine nosylate (100.0 g, 21 mmol), 2-(2-thiophenylethyl) 4-nitro-benzene sulfonate (71.9 g, 23 mmol), tert-butyl methyl ether (MTBE, 222 g, 300 mL), and triethylamine (TEA, 436 g, 4.3 mol). The reaction mixture was warmed to 60±5° C. As the reaction progressed, a slurry was formed. After 5 hours, the system was cooled and charged with MTBE (296 g, 400 mL). This diluted system was washed sequentially with water (400 mL), 5% aqueous sodium bicarbonate (400 mL), water (400 mL), and water (400 mL). The solvent was removed by distillation and replaced with iso-propanol (394 g, 500 mL). The system was warmed to give a clear solution at 45° C. Water (800 g, 800 mL) was added to give a turbid system at 45° C. The hazy slurry was cooled slowly to ambient temperature, then further cooled to 5° C., and held at that temperature for approximately 15 hours. The resultant slurry was filtered and washed with 40% aqueous iso-propanol to provide white crystals. The solids were dried to constant weight under vacuum at 55° C. This process provided 67.5 g (84 mol %) of sufentanil as a white solid, purity over 99% by HPLC.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[N:5]=[C:4]([NH:15][C@H:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH3:17])[CH:3]=1.[C:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])[NH2:26].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C@@H:16]([NH:15][C:4]2[CH:3]=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([C:25]([NH2:26])=[O:27])=[CH:29][CH:30]=3)[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[N:13][CH:12]=[CH:11][N:10]=3)[N:5]=2)[CH3:17])=[CH:19][CH:20]=1
Reactant: C[C@H](Nc1cc(Cl)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](Nc1cc(-c2ccc(C(N)=O)cc2)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 17 h
Yield: 20.9 %

Procedure:
150 mg of (S)-4-chloro-N2-[1-(4-fluorophenyl)ethyl]-N6-(pyrazin-2-yl)pyridine-2,6-diamine (Reference Example 2), 108 mg of 4-carbamoylphenylboronic acid, 567 mg of cesium carbonate, 21 mg of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and 13 mg of tris(dibenzylideneacetone)dipalladium were added in turn to a degassed mixed solution of 3 ml of 1,4-dioxane and 0.6 ml of water, and the mixture was stirred at 100° C. for 17 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 39 mg of (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}benzamide. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain 31 mg of the objective compound as orange powder.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:18]#[CH:19])[CH:7]=[C:8]3[C:13]=2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]3([CH3:17])[CH3:16])[CH2:3][CH2:2]1.[CH3:20][O:21][C:22](=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[CH3:20][O:21][C:22](=[O:31])[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:19]#[C:18][C:6]2[CH:7]=[C:8]3[C:13](=[C:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=2)[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]3([CH3:17])[CH3:16])=[CH:28][CH:29]=1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1cc(C2CC2)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following general procedure F and using 8-cyclopropyl-6-ethynyl-2,2,4,4-tetramethylchroman (Intermediate 34, 0.096 g, 0.38 mmol), methyl-4-iodo phenyl acetate (Reagent B, 0.094 g, 0.34 mmol), triethyl amine (3 mL), tetrahydrofuiran (3 mL), copper(I)iodide (0.025 g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.11 mmol) the title compound was obtained (0.137 g, 90%). 1H NMR (300 MHz, CDCl3): δ 7.47 (d, 2H, J=7.9 Hz), 7.29 (d, 1H, J=1.8 Hz), 7.24 (d, 2H, J=7.9 Hz), 6.82 (d, 1H, J=2.1 Hz), 3.70 (s, 3H), 3.63 (s, 2H), 2.22-2.13 (m, 1H), 1.85 (s, 2H), 1.38 (s, 6H), 1.36 (s, 6H), 0.94-0.86 (m, 2H), 0.68-0.63 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH2:11])[CH:10]=1)[NH:7][C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:5]2.Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:10]=1)[NH:7][C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:5]2
Reactant: Brc1ccccn1
Reactant: Nc1cc(Cl)cc2cc(-c3ccccc3)[nH]c12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Clc1cc(Nc2ccccn2)c2[nH]c(-c3ccccc3)cc2c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 9.5 %

Procedure:
7-Amino-5-chloro-2-phenyl-1H-indole (200 mg, 0.82 mmol) prepared in Example 3 was dissolved in toluene (30 mL). 2-Bromopyridine (182 mg, 1.15 mmol), Pd2(dba)3, Xantphos (42 mg, 0.07 mmol) and Na2CO3 were added thereto. The mixture was degassed, and stirred for 12 h at 100° C. After completion of the reaction, the reaction mixture was filtered through a cellite. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (eluent: EtOAc/n-Hex=1/3) to give the title compound (25 mg, Yield 13%).
Reaction SMILES: CO[AlH-](OC)OC.[Li+].C(B(C(CC)C)C(CC)C)(CC)C.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[C:36]([CH:40]1[CH2:45][CH2:44][C:43](=[O:46])[CH2:42][CH2:41]1)([CH3:39])([CH3:38])[CH3:37]>O1CCCC1>[C:36]([C@@H:40]1[CH2:41][CH2:42][C@H:43]([OH:46])[CH2:44][CH2:45]1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)C1CCC(=O)CC1
Agent: CCC(C)B(C(C)CC)C(C)CC
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: CO[AlH-](OC)OC
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To 5 ml. of 1.0M lithium trimethoxyaluminohydride in tetrahydrofuran, under nitrogen, there is added 1.25 ml. of tri-sec-butylborane. After 30 minutes, the flask, which now contains a solution of lithium tri-sec-butylborohydride, is cooled to -78° C. and 1.25 ml. of a 2.0M solution of 4-tert-butylcyclohexanone is introduced. The reaction mixture is stirred for 3 hours before it is hydrolyzed at 25° C. and then oxidized to give 96.5% of cis-4-tert-butylcyclohexanol and 3.5% of the trans-compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH:12][C:13]1[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:15]([OH:17])=O)=O.[CH2:22]([N:24]([CH2:28][CH3:29])[CH2:25][CH2:26][NH2:27])[CH3:23]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]1[N:27]([CH2:26][CH2:25][N:24]([CH2:28][CH3:29])[CH2:22][CH3:23])[C:15](=[O:17])[C:14]2[C:13](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]=1
Reactant: COc1ccccc1CC(=O)Nc1ccccc1C(=O)O
Reactant: CCN(CC)CCN
Solvent: CCO
Product: CCN(CC)CCn1c(Cc2ccccc2OC)nc2ccccc2c1=O
Yield: 34 %

Procedure:
A solution of 3.0 g (10 mmol) of methyl ester of N-(2-methoxyphenyl-acetyl)-anthranilic acid and 5.1 g (50 mmol) of 2-diethylaminoethylamine in ethanol (20 ml) was heated at 180° C. for 7 hours in a seald tube. After cooling, the thus obtained reaction mixture was purified by silica gel column chromatography (eluent; chloroform : ethanol=98:2) to obtain 1.24 g (yield 34 %) of 2-(2-methoxyphenylmethyl)-3-(2-diethylaminoethyl)-4(3H)-quinazolinone as an oily substance. 1.2 g of the oily substance were dissolved in ethanol (5 ml) and a 7% HCl-ethanol solution (1.5 ml) were added thereto. The resulting solution was allowed to cool overnight. The resulting colorless precipitates were collected by filtration to obtain 1.0 g of the captioned hydrochloride which is the desired compound.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.Br[CH2:12][CH2:13][CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:12]([O:10][C:3]1[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=1)=[CH:13][CH2:14][CH3:15]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC=COc1ccc([N+](=O)[O-])cc1
Reaction time: 48 h

Procedure:
A 500 ml flask equipped with a mechanical stirrer, condenser, thermometer, and heating mantle was charged with p-nitrophenol (30.0 g, 216 mmol), 4-bromo-1-butene (29.1 g, 216 mmol), potassium carbonate (32.8 g, 237 mmol) and DMF (300 ml). The reaction mixture was heated to reflux and stirred for 48 hours. It was then cooled and solvent removed under reduced pressure. The residue was dissolved in 250 ml of methylene chloride and washed repeatedly with water to remove traces of DMF. The methylene chloride layer was dried (MgSO4), filtered, and solvent removed under reduced pressure. The product was used without further purification for the next step. Yield=7.0 g (17%).
Reaction SMILES: [CH:1]1[N:5]([C@@H:6]2[O:10][C@@H:9]3[CH2:11][O:12][P:13]([OH:16])([O:15][C@H:8]3[C@H:7]2[OH:17])=[O:14])[C:4]2[NH:18][C:19]([NH2:23])=[N:20][C:21](=[O:22])[C:3]=2[N:2]=1>Cl>[CH2:11]1[O:12][P:13]([OH:16])(=[O:14])[O:15][CH:8]2[CH:7]([OH:17])[CH:6]([N:5]3[C:4]4[NH:18][C:19]([NH2:23])=[N:20][C:21](=[O:22])[C:3]=4[N:2]=[CH:1]3)[O:10][CH:9]12
Reactant: Nc1nc(=O)c2ncn([C@@H]3O[C@@H]4COP(=O)(O)O[C@H]4[C@H]3O)c2[nH]1
Agent: Cl
Product: Nc1nc(=O)c2ncn(C3OC4COP(=O)(O)OC4C3O)c2[nH]1

Procedure:
For cGMP determination 400 μL of HCl solution remaining after strips were removed and weighed were transferred into gama flow tubes and cyclic GMP was determined by radioimmunoassay.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>CCCCCCC>[C:1]([O:10][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)O
Solvent: CCCCCCC
Product: CCCCCCCC(=O)OC(=O)CCCCCCC
Temperature: 200 °C
Reaction time: 3 h

Procedure:
A glass reactor of 500 ml. capacity and equipped with a mechanical stirrer, temperature control means and a Dean-Stark type condenser was employed. To the reactor were charged 43.5 g. (300 millimols) of octanoic acid and 0.74 g. (3 m mols) of Co(OAc)2.4H2O. About 7 ml. of heptane was also added to the reactor and the Dean-Stark tube was filled with heptane. The reaction mixture was stirred vigorously and heated to 200° C. and nitrogen was bubbled through the reaction mixture at the rate of 50 cc/minute. The reaction was allowed to proceed for 3 hours under these conditions during which about 1 ml of H2O was collected in the Dean-Stark tube. Infrared analysis of the reaction mixture at the end of the 3 hour reaction period showed bands characteristic of the anhydride at 1825 and 1760 cm-1. GLC analysis of the reaction mixture showed that about 12% of the octanoic acid was converted to its anhydride to give 18 m mols of octanoic acid anhydride.
Reaction SMILES: [C:1](=[O:10])([O:5][CH2:6][CH2:7][O:8][CH3:9])[O:2][CH2:3]I.[Na].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[CH2:20][NH:21][C:22]([C:24]1[C:25](=[O:40])[C:26]([OH:39])=[C:27]2[C:32](=[O:33])[N:31]3[C@@H:34]([CH3:37])[CH2:35][O:36][C@@H:30]3[CH2:29][N:28]2[CH:38]=1)=[O:23].C(=O)([O-])[O-].[K+].[K+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:1](=[O:10])([O:5][CH2:6][CH2:7][O:8][CH3:9])[O:2][CH2:3][O:39][C:26]1[C:25](=[O:40])[C:24]([C:22]([NH:21][CH2:20][C:14]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=2[F:12])=[O:23])=[CH:38][N:28]2[C:27]=1[C:32](=[O:33])[N:31]1[C@@H:34]([CH3:37])[CH2:35][O:36][C@@H:30]1[CH2:29]2
Reactant: C[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(O)c3C(=O)N12
Reactant: COCCOC(=O)OCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Product: COCCOC(=O)OCOc1c2n(cc(C(=O)NCc3ccc(F)cc3F)c1=O)C[C@H]1OC[C@H](C)N1C2=O

Procedure:
The title compound was prepared from iodomethyl 2-(methyloxy)ethyl carbonate (122 mg, 0.468 mmol), 1b (50 mg, 0.117 mmol), potassium carbonate (48 mg, 0.351 mmol), and tetrabutylammonium hydrogen sulfate (40 mg, 0.117 mmol), using a similar process to that described in example 1. 1H NMR (CDCl3) δ 10.20 (m, 1H), 8.42 (s, 1H), 7.34 (m, 1H), 6.80 (m, 2H), 5.94 (d, J=6.8 Hz, 1H), 5.87 (d, J=6.4 Hz, 1H), 5.30 (dd, J=10, 4 Hz, 1H), 4.59 (m, 2H), 4.43-4.29 (m, 5H), 3.92 (m, 3H), 3.70-3.61 (m, 3H), 3.36 (s, 3H), 1.40 (d, J=6 Hz, 3H). ES+ MS: 538 (M+1).
Reaction SMILES: Cl.[CH:2]1([C@H:8]2[CH2:13][NH:12][CH2:11][C@@H:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[NH:31][N:30]=[C:29]([CH:32]3[CH2:34][CH2:33]3)[CH:28]=2)[CH:23]=[C:22]([CH3:35])[N:21]=1.ClC1N=C(NC2NN=CC=2)C=C(C)N=1>>[CH:2]1([C@H:8]2[CH2:13][N:12]([C:20]3[N:25]=[C:24]([NH:26][C:27]4[NH:31][N:30]=[C:29]([CH:32]5[CH2:34][CH2:33]5)[CH:28]=4)[CH:23]=[C:22]([CH3:35])[N:21]=3)[CH2:11][C@@H:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)C[C@@H]1CNC[C@H](C2CCCCC2)C1
Reactant: Cc1cc(Nc2cc(C3CC3)n[nH]2)nc(Cl)n1
Agent: Cc1cc(Nc2ccn[nH]2)nc(Cl)n1
Agent: Cl
Product: COC(=O)C[C@H]1C[C@@H](C2CCCCC2)CN(c2nc(C)cc(Nc3cc(C4CC4)n[nH]3)n2)C1

Procedure:
The title compound was prepared by the similar manner described in Example 1 using methyl (cis-5-cyclohexylpiperidine-3-yl)acetate hydrochloride instead of (S)-3-(tert-butoxycarbonylamino)piperidine, and 2-chloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)-6-methylpyrimidin-4-amine prepared in Referential Example 2 instead of 2-chloro-6-methyl-N-(1H-pyrazol-5-yl)pyrimidin-4-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26](O)(C)C)=[C:20]([O:30][CH3:31])[CH:19]=4)N=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1([O:48]C(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.NC1C=CC=CC=1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.ClCCCl.O.C(Cl)Cl.CCOCC>[C:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([NH:13][C:14]([C:15]2[S:16][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:9][C:10]=2[NH2:11])=[O:17])=[CH:19][C:20]=1[O:30][CH3:31])(=[O:48])[CH3:26]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(-n2nnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(C)(C)O
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: Nc1ccccc1
Solvent: ClCCCl
Product: COc1cc(NC(=O)c2sc(-c3ccc(Cl)cc3)cc2N)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 2.3 h
Yield: 69 %

Procedure:
To a solution of 3-amino-5-(4-chlorophenyl)thiophene-2-carboxylic acid prepared in Example 1, Part A (104 mg, 0.41 mmol) in NMP (1.8 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (195 mg, 0.51 mmol) and N,N-diisopropylethylamine (0.22 mL, 1.26 mmol). After the resulting solution was stirred at RT for 2.3 h, a solution of the aniline prepared in Part B of Example 2 (84.3 mg, 0.465 mmol) in 1,2-dichloroethane (0.8 mL+0.4 mL rinse) was added. After heating at 80° C. with stirring for 16 h, the reaction was cooled to RT before being diluted first with water (30 mL) and then sat'd NaHCO3 (5.5 mL). Following extraction of the aqueous mixture (pH ˜9) with EtOAc (3×30 mL), the combined organic extracts were washed with water (20 mL), dried (Na2SO4) and evaporated. Chromatography (SiO2 230-400 mesh, 9/1 CH2Cl2/Ether) of the crude provided the desired amide (118.2 mg, 69% yield) as a yellow solid: MS (electrospray, + ions) m/z 417 (M+H).