Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=1N)([O-])=O.[C:16]([CH2:18]C(OCC1C=CC=CC=1)=O)#N.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CN(C=O)C>[F:13][C:12]([F:15])([F:14])[O:11][C:9]1[CH:10]=[C:4]2[C:5]([CH:16]=[CH:18][NH:1]2)=[CH:7][CH:8]=1
Reactant: N#CCC(=O)OCc1ccccc1
Reactant: Nc1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: FC(F)(F)Oc1ccc2cc[nH]c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a suspension of t-BuONO (8.01 mL, 67.5 mmol) and CuCl2 (7.26 g, 54 mmol) in acetonitrile (50 mL), at 61° C. with gentle stirring, is added 2-nitro-4-trifluoromethoxyaniline (10.0 g, 45.0 mmol) portionwise. The mixture is stirred at this temperature for 2 h after the addition. The solvent is removed on a rotorvap and the residue is treated with HCl (6 N, 200 mL), and extracted with dichloromethane (3×100 mL). The extracts are combined, dried over anhydrous Na2SO4, and passed through a short silica gel pad. The solvent is removed and the residue is added to a suspension of benzyl cyanoacetate (7.88 g, 45 mmol) and K2CO3 (12.42 g, 90 mmol) in DMF (100 mL). This mixture is then stirred at 45° C. overnight and poured into ice-water (700 mL), and extracted with dichloromethane (3×100 mL). The organics are dried over anhydrous Na2SO4 and again passed through a short silica gel pad, eluting with ethyl acetate. The solvent is then replaced with EtOH (160 mL), acetic acid (16 mL) and water (16 mL), and the reaction mixture is hydrogenated over 5% Pd/C (2.80 g) at 50 psi overnight. The mixture is filtered over Celite and the volatiles are removed in vacuo. The residue is dissolved in dichloromethane (200 mL), washed with Na2CO3 (2 M, 2×50 mL), water (2×50 mL), brine (50 mL) and dried over anhydrous Na2SO4. The crude product, obtained after the removal of the solvent, is chromatographed (silica gel, DCM/Hexanes, 1/1) to provide 6-trifluoromethoxyindole (5.70 g, 63% based on 2-nitro-4-trifluoromethoxyaniline).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:17]([O-])=O)[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[CH2:9][CH2:8][CH2:7]2.[H][H]>[Pd].C(O)C>[CH3:15][N:14]([CH3:16])[CH2:13][CH2:12][N:10]1[C:11]2[C:6](=[CH:5][C:4]([NH2:17])=[CH:3][C:2]=2[F:1])[CH2:7][CH2:8][CH2:9]1
Reactant: CN(C)CCN1CCCc2cc([N+](=O)[O-])cc(F)c21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCN1CCCc2cc(N)cc(F)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(8-Fluoro-6-nitro-3,4-dihydroquinolin-1(2H)-yl)-N,N-dimethylethanamine (340 mg, 1.27 mmol) was weighed into a round bottom flask equipped with a stir bar. Ethanol (8 mL) was added, followed by Pd (10 wt. % on activated carbon). The flask was fitted with a balloon of hydrogen, evacuated of air and backfilled with hydrogen. The reaction mixture was stirred for 2 h at room temperature under balloon pressure. The reaction mixture was then filtered through a pad of celite and the pad washed with methanol. The filtrate was concentrated, then chromatographed on silica gel using 0-10% (2M NH3 in MeOH) in dichloromethane. Yield: 270 mg, 89%. ESI-MS: 238 (MH+, 100), 193 (37), 147 (31).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:45])[CH:6]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][N:20]([C:22]([C:24]3[O:25][C:26]4[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=4[C:28]=3[CH2:29][CH2:30][CH2:31][CH3:32])=[O:23])[CH3:21])[CH:15]=2)[C:10]=1[Br:37].O.Cl>CO>[CH2:38]([CH:6]([CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][N:20]([C:22]([C:24]3[O:25][C:26]4[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=4[C:28]=3[CH2:29][CH2:30][CH2:31][CH3:32])=[O:23])[CH3:21])[CH:15]=2)[C:10]=1[Br:37])[C:5]([OH:45])=[O:4])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCCCc1c(C(=O)N(C)Cc2ccc3c(Br)c(OCC(Cc4ccccc4)C(=O)OC)ccc3c2)oc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCc1c(C(=O)N(C)Cc2ccc3c(Br)c(OCC(Cc4ccccc4)C(=O)O)ccc3c2)oc2ccccc12
Reaction time: 8 h
Yield: 41.5 %

Procedure:
A mixture of 1 N NaOH (2.5 mL, 2.5 mmol) and 2-benzyl-3-(1-bromo-6-{[(3-butyl-benzofuran-2-carbonyl)-methyl-amino]-methyl}-naphthalen-2-yloxy)-propionic acid methyl ester (769 mg, 1.22 mmol), prepared in the previous step, in 30 mL of methanol plus 2 mL of water was stirred under nitrogen at room temperature for 6 h. By TLC starting material remained. An additional 2.5 mL (2.5 mmol) of 1 N NaOH was added and the stirring continued at room temperature overnight. 1 N HCl (5.1 mL, 5.1 mmol) was added and the reaction concentrated under reduced pressure to remove the methanol. The solid that formed was collected by filtration and dried under reduced pressure to give the title compound (318 mg, 42%) as a white solid, mp 64-68° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:9][C:10]([F:17])([CH3:16])[C:11](OCC)=[O:12])[C:5]([N+:23]([O-])=O)=[CH:4][N:3]=1.Cl>C(O)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:23][C:11](=[O:12])[C:10]([F:17])([CH3:16])[CH2:9][N:8]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:6]=2[N:7]=1
Reactant: CCOC(=O)C(C)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Agent: Cl
Solvent: CC(=O)O
Product: CC1(F)CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Temperature: 60 °C
Reaction time: 18 h
Yield: 23.1 %

Procedure:
To a suspension of ethyl 3-((2-chloro-5-nitropyrimidin-4-yl)(cyclopentyl)amino)-2-fluoro-2-methylpropanoate (3.4 g, 9 mmol), reduced iron (1.2 g, 23 mmol) in acetic acid (20 ml) was added dropwise concentrated hydrochloric acid (2 ml) at 0° C. The reaction mixture was stirred at 60° C. for 18 h. It was then concentrated in vacuo, diluted to EtOAc, basified with 10% NaOH solution at 0° C. The whole was filtered through celite, washed with EtOAc. The filtrate was then separated. The organic layer was dried over Na2SO4. The solution was concentrated in vacuo followed by precipitation from ether to afford the product (620 mg, 23% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42-1.67 (m, 7 H) 1.72 (d, J=4.0 Hz, 2 H) 1.77-1.91 (m, 2 H) 3.58-3.77 (m, 2 H) 5.01 (t, J=8.2 Hz, 1 H) 7.97 (s, 1 H) 10.36 (s, 1 H). [M+H] calc'd for C13H16ClFN4O, 299; found 299.
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([N:16]3[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=O)OC(C)(C)C)[CH2:17]3)[C:10]=2[CH:9]=[CH:8]1.ClC1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][N:33]=1.CCN(C(C)C)C(C)C>Cl.O>[CH3:29][Si:2]([CH3:30])([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([N:16]3[CH2:20][CH2:19][C@@H:18]([NH:21][C:22]4[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][N:33]=4)[CH2:17]3)[C:10]=2[CH:9]=[CH:8]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(N3CC[C@@H](Nc4ccc(C#N)cn4)C3)ncnc21
Temperature: 120 °C
Reaction time: 14 h

Procedure:
A solution of (R)-tert-butyl 1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-ylcarbamate (700 mg, 1.61 mmol) in HCl (in MeOH, 6 N, 5 mL) was stirred at ambient temperature for 3 hours. The volatiles were removed under reduced pressure. The residue was dissolved in DMSO (3 mL). 6-chloronicotinonitrile (323 mg, 2.41 mmol), KI (10 mg, 0.06 mmol) and DIPEA (311 mg, 2.41 mmol) were then added. The reaction mixture was stirred at 120° C. for 14 h, cooled to ambient temperature, diluted with H2O (20 mL), and extracted with EtOAc (3×40 mL). The combined extracts were washed with brine (3×10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography to give the title compound. MS (m/z): 436 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=2[N:5]([S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:6][CH2:7][C:8]=1C(OCC)=O>C(O)(=O)C.Cl.C(O)C.S(=O)(=O)(O)O>[S:14]([N:5]1[CH2:6][CH2:7][CH2:8][C:2](=[O:1])[C:3]2[CH:27]=[CH:26][CH:25]=[CH:24][C:4]1=2)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:15])=[O:16]
Reactant: CCOC(=O)C1=C(O)c2ccccc2N(S(=O)(=O)c2ccc(C)cc2)CC1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)N2CCCC(=O)c3ccccc32)cc1
Temperature: 25 °C
Yield: 552.1 %

Procedure:
To a suspension of ethyl 5-hydroxy-1-tosyl-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate (30 g, 8.04 mmol) in glacial acetic acid (180 mL), conc. hydrochloric acid (30 mL), ethanol (60 mL) water (30 mL) and conc. sulphuric acid (15 mL) were added at 10-15° C. The reaction mixture was warmed to room temperature and then heated to reflux for 15-16 h. The reaction mixture was cooled to room temperature and poured on to ice. A precipitate formed which was filtered and washed with water (200 mL×3) and dried under reduced pressure to afford 1-tosyl-3,4-dihydro-1H-benzo[b]azepin-5(2H)-one (14 g, 56%). 1H NMR: (400 MHz, CDCl3) δ: 7.71-7.69 (1H, d, J=9.6 Hz), 7.60 (2H, d, J=8.4 Hz), 7.54 (1H, t, J=8.4 Hz), 7.48 (1H, d, J=7.2 Hz), 7.40 (1H, t, J=7.2 Hz), 7.28 (2H, d, J=8.4 Hz), 3.87 (2H, t, J=6.4 Hz), 2.42 (3H, s), 2.42 (2H, m), 1.98 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]#[N:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]3[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]=3[N:23]=[CH:24][N:25]=2)=[CH:16]1.N12CCCN=C1CCCCC2>C(#N)C>[C:13]([CH2:12][C:10]1([N:15]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]4[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:16]2)[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)#[N:14]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cc[nH]c3)ncnc21
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2ccc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)c2)C1
Yield: 82.8 %

Procedure:
A 100 mL round bottom flask fitted with overhead stirring, septa and nitrogen inlet was charged with tert-butyl-3-(cyanomethylene)azetidine-1-carboxylate (1.8 g, 9.5 mmol), 4-(1H-pyrrol-3-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 9.5 mmol) and acetonitrile (60 mL). The resulting solution was heterogeneous. 1,8-Diazabicyclo[5.4.0]undec-7-ene (1.4 mL, 9.5 mmol) was added portionwise via a syringe over 3 minutes at room temperature. The solution slowly becomes homogeneous and yellow in color. The reaction was allowed to stir at room temperature for 3 hours. The solution was concentrated by rotary evaporation to remove acetonitrile. EtOAc (100 mL) and brine (100 mL) were added. The organic phase was separated and the aqueous layer was extracted with 3×30 mL EtOAc. The combined extracts were dried over anhydrous MgSO4, filtered and concentrated in vacuo to yield an orange oil which was purified by flash chromatography (120 grams silica, 30-55% EtOAc/hexane, loaded with CH2Cl2). Desired fractions were combined and concentrated to yield a yellow oil which was placed on a high vacuum pump to give 4 g (83%) of tert-butyl 3-(cyanomethyl)-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidine-1-carboxylate as a white foam. LC-MS: [M+H]+=509.3.
Reaction SMILES: C([O:5][C:6]([C:8]1([N:18]([C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21])[CH3:19])[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])(C)(C)C.[O:27]1CCOC[CH2:28]1>Cl>[CH2:23]([O:22][C:20]([N:18]([CH3:19])[C:8]1([C:6]([OH:5])=[O:7])[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([O:27][CH3:28])[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:21])[CH:24]([CH3:25])[CH3:26]
Reactant: CC(C)COC(=O)N(C)C1(C(=O)OC(C)(C)C)CCc2ccccc2C1
Reactant: C1COCCO1
Agent: Cl
Product: COc1cccc2c1CC(C(=O)O)(N(C)C(=O)OCC(C)C)CC2
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
The t-butyl ester from Example 33E was dissolved in 4 N HCl in dioxane (10 mL) and the resulting mixture was stirred at r.t for 16 h and at 60° C. for 1.5 h. The volatiles were removed to give the titled acid.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:7]([CH3:9])[N:8]=1)[NH2:2].[CH:16](=O)[CH2:17][CH3:18]>Cl.CO>[CH3:9][C:7]1[N:8]=[C:3]([NH:1][N:2]=[CH:16][CH2:17][CH3:18])[N:4]=[N:5][C:6]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1nc(NN)nnc1-c1ccccc1
Reactant: CCC=O
Agent: Cl
Solvent: CO
Product: CCC=NNc1nnc(-c2ccccc2)c(C)n1
Reaction time: 0.08 h

Procedure:
C.hydrochloric acid (1 drop) was added to a stirred solution of 3-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (4.12 g) and propionaldehyde (4 ml) in methanol (15 ml) at room temperature, and the stirring was continued for 5 minutes. The reaction mixture was evaporated and the resultant residue was triturated with diethyl ether. The precipitates were collected by filtration to give 5-methyl-6-phenyl-3-(2-propylidenehydrazino)-1,2,4-triazine (3.89 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([CH3:10])[CH:4]=1.C([O:13][CH:14]=[C:15]([C:21](OCC)=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>>[CH2:19]([O:18][C:16]([C:15]1[C:14](=[O:13])[C:8]2[C:6](=[C:5]([CH3:10])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=2)[NH:7][CH:21]=1)=[O:17])[CH3:20]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(N)c(C)c1
Product: CCOC(=O)c1c[nH]c2c(C)cc(OC)cc2c1=O
Yield: 59.5 %

Procedure:
4-Methoxy-2-methylaniline (3.0 g) and diethyl ethoxymethylenemalonate (5.7 g) were reacted in the same manner as in Experimental Example 1 to obtain 3-ethoxycarbonyl-6-methoxy-8-methyl-4(1H)-quinolone (3.4 g). The compound (2.0 g) was subjected to hydrolysis and decarboxylation in the same manner as in Experimental Example 2 to obtain 6-methoxy-8-methyl-4(1H)-quinolone (compound 20, 0.7 g).
Reaction SMILES: [H-].[K+:2].[C:3]1([OH:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[H][H]>O1CCCC1>[C:3]1([O-:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[K+:2]
Reactant: Oc1cccc2ccccc12
Reactant: [H][H]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: [O-]c1cccc2ccccc12

Procedure:
Potassium hydride (93.6 mg as a 35% oil dispersion, 0.82 mmol) was suspended in anhydrous tetrahydrofuran (2.5 mL) under nitrogen. 1-Naphthol (72 mg, 0.5 mmole) was added and the mixture was stirred until hydrogen evolution ceased (about 5 minutes) to produce potassium naphtholate. N-Fluoro-N-t-butyl-p-toluenesulfonamide (122 mg, 0.5 mmole) was dissolved in anhydrous tetrahydrofuran (2.5 mL) and the solution was added dropwise to the potassium naphtholate. After 20 minutes the reaction mixture was diluted with ether (100 mL), washed with aqueous 1N oxalic acid solution (30 mL), water (30 mL), and saturated aqueous sodium chloride solution (30 mL), and then dried over anhydrous magnesium sulfate. Filtration, removal of solvent under reduced pressure, and purification by flash column chromatography (silica, 25% methylene chloride in hexane) yielded 2-fluoro-1-naphthol (49 mg, 60% yield) as a white crystalline solid. This material, and an additional sample prepared by this procedure, were analyzed and provided the following results: 1H NMR (90 MHz, CDCl3) δ5.58 (b, 1H, OH), 7.00-8.30 (m, 6H, aromatic); 19F NMR (94.1 MHz, CDCl3) -146.78(m); HRMS calcd. for C10H7OF: 162.0480; found: 162.0439.
Reaction SMILES: [CH2:1]([C:5]([CH2:7][CH2:8][CH2:9][CH3:10])=[O:6])[CH2:2][CH2:3][CH3:4].[C:11]([NH2:20])(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:5]1([CH2:7][CH2:8][CH2:9][CH3:10])[NH:20][C:11](=[O:19])[C:12]2[CH:13]=[CH:15][CH:16]=[CH:17][C:18]=2[O:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: NC(=O)c1ccccc1O
Reactant: CCCCC(=O)CCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCC1(CCCC)NC(=O)c2ccccc2O1
Yield: 92.5 %

Procedure:
A mixture of 20 g of dibutylketone, 19.3 g of salicylamide and 2.7 g of p-toluenesulfonic acid monohydrate is added to 300 ml of toluene and the mixture is refluxed overnight by making use of a dehydrator of Dean Stark. After cooling, the reaction mixture is washed, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; hexane:ethyl acetate=95:5) to obtain 34 g of 2,2-dibutyl-4-oxo-2,3-dihydro-4H-1,3-benzoxazine as a yellow oil.
Reaction SMILES: N#N.[OH:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11](=[O:13])[CH3:12])[CH:6]=1.CCN(CC)CC.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:11]([C:7]1[CH:6]=[C:5]([CH2:4][O:3][S:21]([CH3:24])(=[O:23])=[O:22])[CH:10]=[CH:9][N:8]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)c1cc(CO)ccn1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cc(COS(C)(=O)=O)ccn1
Temperature: 0 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(4-hydroxymethyl-pyridin-2-yl)-ethanone (165 mg, 1.09 mmol) in dry CH2Cl2 (5 mL) was treated at 0° C. with Et3N (0.20 mL, 1.43 mmol) followed by DMAP (13 mg, 0.10 mmol) and Ms-Cl (0.11 mL, 1.39 mmol). After stirring at 0° C. for 1 h30, the reaction was quenched with water (5 mL). The org. layer was dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give crude methanesulfonic acid 2-acetyl-pyridin-4-ylmethyl ester as a brown oil. The crude material (250 mg) was dissolved in acetone (8 mL) under inert atmosphere (N2). 4-Nitro-1H-pyrazole (139 mg, 1.09 mmol) was added followed by K2CO3 (761 mg, 5.45 mmol) and TBA bromide (70 mg, 0.22 mmol). The reaction mixture was stirred at rt for 2 h and concentrated to dryness. The residue was partitioned between water (5 mL) and EA (10 mL). The layers were separated and the aq. layer extracted with EA (2×10 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification of the residue by FC (10:1 to 2:1 hept-EA) gave the title compound as a yellow oil. TLC: rf (1:2 hept-EA)=0.41. LC-MS-conditions 02: tR=0.84 min, [M+H]+=247.33.
Reaction SMILES: [N:1]([C:3]1[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:5][N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12)=O.C(=O)(O)[O-].[Na+].[C:23](O)(=[O:25])[CH3:24]>[Zn]>[C:23]([NH:1][C:3]1[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:5][N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12)(=[O:25])[CH3:24]
Reactant: O=Nc1c(-c2ccccc2)nn2ccccc12
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Product: CC(=O)Nc1c(-c2ccccc2)nn2ccccc12

Procedure:
A mixture of 3-nitroso-2-phenylpyrazolo[1,5-a]pyridine (0.81 g) and zinc powder (0.95 g) in acetic acid (10 ml) was heated under reflux for 2.5 hours. The reaction mixture was poured onto ice-water (100 ml) and neutralized with saturated aqueous sodium bicarbonate solution. Resultant precipitates were collected by filtration, washed with water, and recrystallized from ethyl acetate to give crystals of 3-acetamido-2-phenylpyrazolo[1,5-a]pyridine (304 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[O:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:13])[C:10]=2[C:11]=1[CH3:12].[CH3:15][NH2:16]>>[CH3:15][N:16]1[C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:13])[C:10]=2[C:11]([CH3:12])=[C:2]([CH3:1])[C:3]1=[O:4]
Reactant: CN
Reactant: Cc1c2c(oc(=O)c1C)CCCC2=O
Product: Cc1c2c(n(C)c(=O)c1C)CCCC2=O

Procedure:
Prepared from 3,4-dimethyl-5,6,7,8-tetrahydro-cumarin- 5-one and methanolic methylamine solution over a period of 15 hours at ambient temperature.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4](Cl)=[N:5][C:6]([Cl:10])=[N:7][C:8]=1[Cl:9].C(O)=O.[S-:15][C:16]#[N:17].[K+]>O>[Cl:10][C:6]1[N:7]=[C:8]([Cl:9])[C:3]([S:2][CH3:1])=[C:4]([S:15][C:16]#[N:17])[N:5]=1
Reactant: CSc1c(Cl)nc(Cl)nc1Cl
Reactant: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: O=CO
Product: CSc1c(Cl)nc(Cl)nc1SC#N
Temperature: 25 °C
Yield: 92.8 %

Procedure:
In a 50-ml four-necked flask equipped with a thermometer, reflux condenser and stirrer, were charged 2.30 g (0.010 mole) of 5-methylthio-2,4,6-trichloropyrimidine and 15 ml of formic acid. While stirring the contents at room temperature, 1.07 g (0.011 mole) of potassium thiocyanate was added. Then, the resulting mixture was heated and was then stirred at 50° C. for 1 hour. After cooling the reaction mixture, it was poured into a great deal of water. The precipitated solid was collected by filtration and dried to obtain 2.34 g of crude crystals (yield: 92.9%). A portion of the crude crystals was recrystallized from ethyl acetate, thereby obtaining a purified product. m.p. 143°-144.5° C.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].C([Li])CCC.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([CH2:34][CH2:35][CH2:36][C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH2:28][CH2:29][C:30](OC)=[O:31])(=[O:21])=[O:20])=[CH:15][CH:14]=1>O1CCCC1.CCCCCC>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([CH2:34][CH2:35][CH2:36][C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH2:28][CH2:29][C:30]([O:4][CH2:3][C:2]([CH3:6])([CH3:5])[CH3:1])=[O:31])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: CC(C)(C)CO
Reactant: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1

Procedure:
To a solution of 0.378 g of 2,2-dimethylpropanol in 3 ml tetrahydrofuran is added 0.003 ml of 2.5M n-butyllithium in hexane. To this solution is added 0.332 g methyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanoate and the mixture is refluxed for 20 h. The reaction is quenched by addition of 3 ml of saturated ammonium chloride solution. It is then extracted with methylene chloride (3×10 ml). The combined organic extracts are dried, filtered and evaporated to dryness to give a clear oil which is purified by preparative thin layer chromatography to obtain 2,2-dimethylpropyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanoate as a pale yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]([O:21][CH3:22])[C:8]([Cl:23])=[C:7]([CH3:24])[C:6]=1[C:25](=[O:27])[CH3:26].Cl.[F:29][C:30]1([F:34])[CH2:33][NH:32][CH2:31]1>>[Cl:23][C:8]1[C:7]([CH3:24])=[C:6]([C:25](=[O:27])[CH3:26])[C:5]([O:4][CH2:3][CH2:2][N:32]2[CH2:33][C:30]([F:34])([F:29])[CH2:31]2)=[C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]=1[O:21][CH3:22]
Reactant: FC1(F)CNC1
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCCc1ccccc1
Agent: Cl
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN2CC(F)(F)C2)c1OCCCc1ccccc1
Yield: 20 %

Procedure:
Example 34b (105 mg, 0.23 mmol) was reacted with 3,3-difluoroazetidine hydrochloride (2.0 eq.) as described under General Procedure J and the crude mixture was purified by flash chromatography (silica gel, hexane/Et2O 70:30) to afford the title compound (21 mg, 20%) as a light orange oil. 1H NMR (300 MHz, CDCl3) δ 7.33-7.20 (m, 5H), 4.07 (t, J=6.5 Hz, 2H), 4.01 (t, J=5.6 Hz, 2H), 3.88 (s, 3H), 3.63 (t, J=12.0 Hz, 4H), 2.85-2.80 (m, 4H), 2.51 (s, 3H), 2.20 (s, 3H), 2.12-2.06 (m, 2H). MS (ES+) m/z 468.2 (M+H+).