Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:26][CH3:27])=[C:9]([O:12][CH2:13][C@@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3C(OC(C)(C)C)=O)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:28][C:29]1[C:30]([F:36])=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32].Cl>C(#N)C>[ClH:1].[Cl:28][C:29]1[C:30]([F:36])=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH:32][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:26][CH3:27])=[C:9]([O:12][CH2:13][C@@H:14]3[CH2:18][CH2:17][CH2:16][NH:15]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1cccc(Cl)c1F
Reactant: COc1cc2ncnc(Cl)c2cc1OC[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC#N
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of 4-chloro-7-methoxy-6-{[(2S)-1-tert-butoxycarbonylpyrrolidin-2-yl]methoxy}quinazoline in acetonitrile (120 ml), 3-chloro-2-fluoroaniline (1.4 ml, 12.7 mmole) and hydrogen chloride (4.0M in 1,4-dioxane) (13 ml, 52 mmole) were added. This mixture was heated to reflux for one hour. After cooling to ambient temperature the precipitate was filtered off, washed with acetonitrile followed by diethylether and dried under vacuum to give 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-pyrrolidin-2-yl]methoxy}quinazoline hydrochloride as a yellow solid (5.73 g, 100%); 1H NMR Spectrum: (DMSO d6) 1.70-2.10 (m, 3H); 2.10-2.30 (m, 1H); 3.00-3.80 (m, 2H); 3.97-4.10 (m, 4H); 4.45-4.57 (m, 2H); 7.32-7.38 (m, 1H); 7.46 (s, 1H); 7.49-7.55 (m, 1H); 7.59-7.65 (m, 1H); 8.65 (s, 1H); 8.81 (s, 1H); 9.31 (bs, 1H); 9.67 (bs, 1H); 12.09 (bs, 1H); Mass Spectrum: (M+H)+ 403.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH:18]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][N:32]3[CH2:31][CH2:30][N:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][CH3:21])[CH2:34][CH2:33]3)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1ccc(C2=NOC(CCC=O)C2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C2=NOC(CCCN3CCN(c4ccccc4OC)CC3)C2)cc1OC
Yield: 59.4 %

Procedure:
3-[3-(3,4-Dimethoxyphenyl)-4,5-dihydroisoxazol-5-yl]propanal (25.8 mg, 0.096 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (20.0 mg, 0.087 mmol), molecular sieve (5 beads), NaBH(OAc)3 (55.5 mg, 0.262 mmol) and diisopropylethylamine (26.9 L, 0.087 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 22.7 mg (60.0%) of the target compound was obtained.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH2:35][CH2:36][CH3:37])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH2:35][CH2:36][CH3:37])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CCCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 5 was prepared from diphenylacetyl chloride and N-{3-[1-(3-amino propyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 7.49 (s, 1H), 7.35–7.23 (m, 12H), 7.20 (s, 1H), 6.95 (d, 2H, J=7.6 Hz), 4.90 (s, 1H), 3.41 (dd, 2H, J=5.6, 11.6 Hz), 2.94 (d, 2H, J=11.6 Hz), 2.48 (m, 1H), 2.40 (t, 2H, J=6.4 Hz), 2.34 (t, 2H, J=7.2 Hz), 1.98 (t, 2H, J=11.2 Hz), 1.82–1.60 (m, 8H), 1.02 (t, 3H, J=7.2 Hz); ESMS m/e: 498.3 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:8][CH:9]=1)([CH3:3])[CH3:2].C([O:37][C:38](=[O:41])[CH2:39]Br)(C)(C)C.C(O)(C(F)(F)F)=O>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:26][CH:27]=2)[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:39][C:38]([OH:41])=[O:37])=[CH:16][CH:15]=2)=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)c1ccc(N(CCCc2ccc(O)cc2)Cc2ccc(OC(F)(F)F)cc2)nc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc(N(CCCc2ccc(OCC(=O)O)cc2)Cc2ccc(OC(F)(F)F)cc2)nc1

Procedure:
Similarly prepared by alkylation of 4-(3-{(5-isopropylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}propyl)phenol with tert-butyl-bromo-acetate followed by standard TFA hydrolysis.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:24](O)=[O:25]>>[OH:9][C:4]1[CH:5]=[CH:6][C:7]([CH:24]=[O:25])=[CH:8][C:3]=1[C:2]([F:10])([F:11])[F:1]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1ccc(O)c(C(F)(F)F)c1
Yield: 36 %

Procedure:
A solution of 2-trifluoromethyl phenol (5.0 g, 30.86 mmol) and hexamethylenetetramine (8.64 g, 61.72 mmol) in trifluoracetic acid (50 mL) was heated at 65° C. for 18 h. At the end of this time the solution was concentrated and diluted with a 2N aqueious solution of hydrochloric acid. The acid phase was extracted twice with ethyl acetate and the combined organic extract dried over magnesium sulfate and concentrated. The residue was subjected to chromatography via Biotage (FLASH 40 M, silica, 20% ethyl acetate/hexane) to yield 2.1 g (36%) of 4-hydroxy-3-(trifluoromethyl)benzaldehyde. MS (ES) m/z 188.9; HRMS: calcd for C8H5F3O2, 190.0242; found (ESI, [M+H]+), 191.0324.
Reaction SMILES: N[C:2]1[N:18]=[C:5]2[CH:6]=[CH:7][CH:8]=[C:9](CN3CCNC(=O)C3)[N:4]2N=1.FC(F)(F)C(O)=O.C(OC([N:33]([C:51](OC(C)(C)C)=O)[C:34]1[N:50]=[C:37]2[CH:38]=[CH:39][CH:40]=[C:41]([CH2:42][N:43]3[CH2:48][CH2:47][NH:46][C:45](=[O:49])[CH2:44]3)[N:36]2[N:35]=1)=O)(C)(C)C>ClCCl>[NH:4]1[C:5]2=[N:18][CH:2]=[C:51]([NH:33][C:34]3[N:50]=[C:37]4[CH:38]=[CH:39][CH:40]=[C:41]([CH2:42][N:43]5[CH2:48][CH2:47][NH:46][C:45](=[O:49])[CH2:44]5)[N:36]4[N:35]=3)[CH:6]=[C:7]2[CH:8]=[CH:9]1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc2cccc(CN3CCNC(=O)C3)n2n1
Reactant: Nc1nc2cccc(CN3CCNC(=O)C3)n2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CN(Cc2cccc3nc(Nc4cnc5[nH]ccc5c4)nn23)CCN1
Temperature: 25 °C
Reaction time: 23 h
Yield: 97 %

Procedure:
4-((2-Amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)piperazin-2-one. Trifluoroacetic acid (2.55 mL, 33.1 mmol) was added to a stirred solution of N,N-di-tert-butoxycarbonyl-5-((3-oxopiperazinyl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (0.740 g, 1.657 mmol) in dichloromethane (18.5 mL). The resulting solution was capped and stirred at room temperature for 23 h. Most of the solvent was removed on a rotary evaporator. The residue was loaded onto two 5 g Strata X—C ion exchange columns from Phenomenex. The columns were washed successively with acetonitrile, water, acetonitrile, methanol, and then 10% ammonium hydroxide in methanol. The product came off with the 10% ammonium hydroxide in methanol eluent. The 10% ammonium hydroxide in methanol eluent from both runs was concentrated on a rotary evaporator and dried under high vacuum at 40° C. to give the desired product (0.406 g, 1.649 mmol, 97%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.82 (br s, 1H), 7.43 (dd, J=7.42, 8.59 Hz, 1H), 7.28 (d, J=8.59 Hz, 1H), 6.92 (d, J=7.03 Hz, 1H), 6.03 (s, 2H), 3.94 (s, 2H), 3.21 (br s, 2H), 3.12 (s, 2H), 2.71 (t, 2H); MS (ESI) m/z 247.3 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:14])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[S:10][CH:11]=[CH:12][N:13]=1.[CH:15](O)([CH3:17])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH:15]([CH3:17])[CH3:16])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[S:10][CH:11]=[CH:12][N:13]=1
Reactant: CC(C)O
Reactant: Oc1ccc(Oc2nccs2)c(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(Oc2nccs2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a mixture of Example 9B (2.3 g, 0.01 mol), isopropanol (1.2 mL, 0.015 mol) and triphenylphosphine (3.93 g, 0.015 mol) in dry tetrahydrofuran was added diethyl azodicarboxylate (2.61 g, 0.015 mol) drop wise and the reaction was stirred at room temperature overnight. The solvent was removed and the residue was purified on silica gel (ethyl acetate/hexane, 5˜35%) to give 2.4 g of product as a light yellow oil (89% yield), 1H NMR (300 MHz, CDCl3) δ ppm 1.35 (d, J=5.88 Hz, 6H) 4.42-4.57 (m, 1H) 6.76-6.86 (m, 2H) 6.99 (d, J=2.94 Hz, 1H) 7.19 (d, J=3.68 Hz, 1H) 7.23 (s, 1H), MS (ESI) m/z 269.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]([C:24]#[N:25])([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([O:22][CH3:23])[CH:14]=1)[CH2:7][CH2:8][C:9](OC)=[O:10].COCCOC.[H-].[Na+]>O>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][C:6]([C:24]#[N:25])([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([O:22][CH3:23])[CH:14]=2)[CH2:7][CH2:8][C:9]1=[O:10])=[O:26]
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc([N+](=O)[O-])c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)C1CC(C#N)(c2ccc([N+](=O)[O-])c(OC)c2)CCC1=O
Temperature: 25 °C

Procedure:
Into a 1-Neck round-bottom flask, 4-Cyano-4-(3-methoxy-4-nitro-phenyl)-heptanedioic acid dimethyl ester (4.20 g, 11.5 mmol), 1,2-Dimethoxyethane (80 mL, 800 mmol), and Sodium Hydride (60% dispersion mineral oil)(6:4, Sodium hydride:Mineral Oil, 1.38 g, 34.6 mmol) were added, and heated to reflux overnight. The reaction was cooled to room temperature. Water was added to quenched the excess NaH. 2N HCl was added to adjust pH to 2. The reaction was partitioned with water and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with hexane and EtOAc. The collected fractions afforded 5-Cyano-5-(3-methoxy-4-nitro-phenyl)-2-oxo-cyclohexanecarboxylic acid methyl ester as an off white solid (2.00, 59%).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].P(Cl)(Cl)(Cl)(Cl)[Cl:12].P(Cl)(Cl)(Cl)=O>>[Cl:12][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnccc1O
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnccc1Cl
Temperature: 135 °C
Yield: 45.1 %

Procedure:
4-Hydroxy-3-nitropyridine (10.0 g, 71.4 mmol) is added portionwise to a mechanically stirred mixture of phosphorous pentachloride (16.32 g, 78.6 mmol) and phosphorous oxychloride (16.2 mL) at 55-60° C. After the addition is complete, the temperature is raised to 130-140° C. for 4 hr. After cooling to room temperature, the phosphorous oxychloride is removed and the residue is cautiously treated with ice/water, made basic with sodium carbonate and extracted with ether. The combined extract is dried, filtered and concentrated to yield 4-chloro-3-nitropyridine (5.1 g, 45% yield) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOCCOC.Cl>[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([N:20]2[CH2:21][CH2:22][N:23]([C:2]3[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=3)[CH2:24][CH2:25]2)[CH:14]=1
Reactant: Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Cc1cc(C)nc(N2CCNCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Product: Cc1cc(C)nc(N2CCN(c3ccc([N+](=O)[O-])c(C)c3)CC2)c1
Yield: 44.4 %

Procedure:
A solution of 5-chloro-2-nitro-toluene (895 mg, 5.23 mmol) in diglyme (2.5 mL) was added to a stirred suspension of 1-(4,6-dimethyl-pyridin-2-yl)-piperazine (500 mg, 2.62 mmol) and potassium carbonate (900 mg, 6.54 mmol) in diglyme (5 mL) and heated at reflux overnight. The mixture was cooled, the inorganic salts filtered off and washed with ethyl acetate. The filtrate was concentrated to dryness under high vacuum to obtain a residue which was dissolved in 6N hydrochloric acid (10 mL) and washed with toluene. The aqueous layer was basified to pH 8 with ammonium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water, bicarbonate solution, and brine dried over sodium sulfate, filtered and concentrated to dryness to give the crude compound. Purification by column chromatography over silica gel (60-120 mesh) using 15% ethyl acetate in hexane as a eluent afforded 1-(4,6-dimethyl-pyridin-2-yl)-4-(3-methyl-4-nitro-phenyl)-piperazine (380 mg, 45%).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH:6]1[CH2:9][CH:8]([NH:10][C:11](=[O:36])[C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:22]3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH2:7]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:5][O:4][C:2]([N:6]1[CH2:9][CH:8]([NH:10][C:11](=[O:36])[C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:22]3)(=[O:19])=[O:20])=[CH:14][CH:13]=2)[CH2:7]1)=[O:3]
Reactant: O=C(NC1CNC1)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CC(NC(=O)c2ccc(S(=O)(=O)n3cc(-c4ccccc4)c4ccccc43)cc2)C1
Reaction time: 4 h
Yield: 68.6 %

Procedure:
Add methyl chloroformate (60 μL, 73 mg, 0.78 mmol, 3.1 equiv) to a suspension of N-azetidin-3-yl-4-(3-phenyl-indole-1-sulfonyl)-benzamide (108 mg, 0.250 mmol, 1 equiv) and triethylamine (140 μL, 100 mg, 1.0 mmol, 4.0 equiv) in anhydr CH2Cl2 (3 mL). Observe a vigorous gas evolution. After stirring 4 h, rotary evaporate the reaction solution. Transfer the resultant material to a column of silica gel (80 mm×20 mm dia.) and elute (20-60% EtOAc/hex) to yield 84 mg (69%) of 3-[4-(3-phenyl-indole-1-sulfonyl)-benzoylamino]-azetidine-1-carboxylic acid methyl ester as an off-white foam. MS (m/e): 489.96 (M+1); 488.09 (M−1).
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]#[C:16][CH3:17])[N:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>C(OCC)(=O)C>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])[N:8]=[CH:9][N:10]=1)[C:15]#[C:16][CH3:17]
Reactant: CCNCC
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCOc1cc(N(CC)CC)ncn1
Temperature: 50 °C
Reaction time: 4 h
Yield: 62.1 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 166 mg of potassium carbonate, and 73 mg of diethylamine, followed by stirring at a bath temperature of 50° C. for 4 hours. Then, 73 mg of diethylamine was further added, followed by stirring at a bath temperature of 50° C. for 5.5 hours. Then, 146 mg of diethylamine was further added, followed by stirring at a bath temperature of 40° C. for 6 hours. The reaction mixture was left for cooling to room temperature, diluted with ethyl acetate, and washed three times with an aqueous sodium chloride solution. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel thin layer chromatography to give 136 mg of 4-(2-butynyloxy)-6-(N,N-diethylamino)pyrimidine (the present compound (144)).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[C:18]([C:20]1[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1)#[N:19]>>[NH2:15][C:10]1[O:11][CH2:12][C@@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:23]3[CH:22]=[CH:21][C:20]([C:18]#[N:19])=[CH:25][N:24]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@H]1F
Product: C[C@]1(c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)N=C(N)OC[C@H]1F

Procedure:
The condensation of (4R,5S)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.1) and 5-cyano-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=372.2 [M+H]+.
Reaction SMILES: C(OC[C:6]([C@:8]1([OH:30])[C@:24]2([CH3:25])[C@H:11]([C@H:12]3[C@:21]([F:27])([C@@H:22]([OH:26])[CH2:23]2)[C@:20]2([CH3:28])[C:15](=[CH:16][C:17](=[O:29])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1)=[O:7])(=O)C.[OH-].[Na+].Cl.I(O)(O)(O)(O)(O)=[O:35]>CO.O>[F:27][C@@:21]12[C@:20]3([CH3:28])[C:15](=[CH:16][C:17](=[O:29])[CH2:18][CH2:19]3)[CH2:14][CH2:13][C@H:12]1[C@H:11]1[C@@:24]([CH3:25])([C@@:8]([OH:30])([C:6]([OH:35])=[O:7])[CH2:9][CH2:10]1)[CH2:23][C@@H:22]2[OH:26]
Reactant: [O-][I+](O)(O)(O)(O)O
Reactant: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CC[C@](O)(C(=O)O)[C@@]3(C)C[C@H](O)[C@@]12F
Reaction time: 0.17 h
Yield: 101.1 %

Procedure:
In a 1000 mL round-bottomed flask was suspended 2-((8S,9R,10S,11S,13S,14S,17R)-9-fluoro-11,17-dihydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl acetate (Fludrocortisone-21-acetate, 22.8 g, 53.97 mmol) in MeOH (200 mL) and the suspension was degassed with nitrogen. 2M sodium hydroxide (40.5 mL, 80.95 mmol) was added to the solution and the mixture was stirred for 10 minutes. To the solution was added 4M HCl (20 ml, 80 mmol) and MeOH was removed in vacuo. The obtained residue was dissolved in THF (200 ml), a solution of orthoperiodic acid (15.99 g, 70.16 mmol) in water (40 ml) was added at room temperature and the obtained mixture was stirred for 1 hour. 100 ml of water was added and the organic solvent was removed in vacuo. An additional 100 ml of water was added to the aqueous residue and the obtained solid was collected by filtration, was washed with water (2×200 ml) and was air dried on the sinter, followed by drying in vacuo to yield 20 g of the desired compound as an off-white solid. APCI-MS m/z: 367 [MH+].
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[NH:5][N:4]=1.C1C(=O)N([Cl:20])C(=O)C1>CC#N>[Cl:20][C:7]1[C:3]([C:2]([F:1])([F:11])[F:12])=[N:4][NH:5][C:6]=1[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)c1cc(C(F)(F)F)n[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CC(C)c1[nH]nc(C(F)(F)F)c1Cl

Procedure:
Following protocol L, to the solution of 3-trifluoromethyl-5-isopropyl-pyrazole (0.22 g, 1.23 mmol) in CH3CN (10 mL) was added NCS (0.19 g, 1.43 mmol) in portions with vigorous stirring. The reaction mixture was then heated under reflux for 14 h, cooled and the reaction quenched with saturated NaHCO3, extracted with methylene chloride (2×30 mL) and the combined organic extracts was washed with brine, dried with Na2SO4 and evaporated to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[F:9][C:10](Br)([F:12])[F:11].O>N1C=CC=CC=1.[Cu]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:10]([F:12])([F:11])[F:9])=[CH:4][N:3]=1
Reactant: FC(F)(F)Br
Reactant: Clc1ccc(I)cn1
Agent: [Cu]
Solvent: c1ccncc1
Solvent: O
Product: FC(F)(F)c1ccc(Cl)nc1
Yield: 13.6 %

Procedure:
In an autoclave were placed 2.9 g of 2-chloro-5-iodopyridine, 2.5 g of trifluoromethyl bromide dissolved in 100 ml of pyridine and 1.6 g of copper dust, and the mixture was reacted at 170° C. for 18 hours. After cooling the system, the reaction mixture was added to a suitable amount of water and extracted with methylene chloride. The extract was washed successively with water, 10% dilute hydrochloric acid, and water. After drying over anhydrous sodium sulfate, the extract was distilled to remove the methylene chloride and obtain 300 mg of 2-chloro-5-trifluoromethylpyridine.
Reaction SMILES: Cl[C:2]1[C:3]([C:10]([OH:12])=[O:11])=[CH:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1.[F:13][C:14]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:15]=1[NH2:16].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(OCC)(=O)C>Cl.O>[F:13][C:14]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:15]=1[NH:16][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[CH:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1
Reactant: Nc1ccc(I)cc1F
Reactant: Cn1cc(C(=O)O)c(Cl)cc1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Yield: 41.4 %

Procedure:
4-Chloro-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (133 mg, 0.709 mmol) and 2-fluoro-4-iodoaniline (172 mg, 0.726 mmol) were combined in a round bottom flask equipped with magenetic stir bar. The flask was immersed in an ice bath and lithium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 5.0 mL, 5.0 mmol) was added slowly (5 min) with vigorous stirring under an atmosphere of nitrogen. The reaction mixture was further stirred for 1 h at 0° C. and 1 h at ambient temperature. The reaction mixture was diluted with 1 M hydrochloric acid and water and was extracted with ethyl acetate (3×). The extracts were dried over magnesium sulfate and concentrated in vacuo. Upon concentrateion, 4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid (114 mg, 41% yield) was isolated directly from the ethyl acetate by filtration and drying in vacuo: 1H NMR (DMSO-d6, 400 MHz) δ 13.30 (v br s, 1H), 9.66 (s, 1H), 8.52 (s, 1H), 7.76 (dd, J=10.1, 1.9 Hz, 1H), 7.59 (br d, J=8.5 Hz, 1H), 7.31 (t, J=8.5 Hz, 1H), 5.49 (s, 1H), 3.41 (s, 3H); MS (APCI+) 388.9.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([O:11]CC)[CH3:10]>[Br-].[Zn+2].[Br-]>[C:1]1([C@H:9]([OH:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOCC
Reactant: Br[Mg]c1ccccc1
Agent: [Br-]
Agent: [Zn+2]
Product: C[C@@H](O)c1ccccc1
Temperature: -5 °C

Procedure:
Anhydrous zinc bromide (11.37 g) was charged to a dry, stirred 250 ml flask filled with nitrogen. Dried diethylether (75 ml) was added and the slurry heated to reflux until a homogenous solution. A 3molar ethereal solution of phenylmagnesium bromide (33.3 ml) was slowly added. Solvent was distilled from the reaction mixture at ambient pressure, whilst maintaining a constant volume by addition of toluene until a distillate temperature of 110° C. was reached. The hot slurry was screened under a nitrogen atmosphere using an in-line sintered glass filter. The filtrates were received into a dry, stirred 250 ml flask and cooled to −5° C. D(+) diethyinorephedrine (0.64 g) was added and the acetaldehyde (2.2 g) in toluene (5 ml) charged from a dropping funnel. The reaction mixture was warmed to ambient temperature, stirred for a total of 12 hours, then cooled on an ice bath and quenched by addition of dilute hydrochloric acid. The organic layer was separated, washed with an equal volume of water and concentrated to yield a crude product (4.62 g). This was further purified by chromatography to give 3.86 g (R)phenylethanol of 17% ee, measured by chiral GC. The product was identified by gas chromatographic comparison with authenticated material.
Reaction SMILES: [C:1]([C:4]1[NH:5][CH:6]=[NH+:7][C:8]=1[O-:9])(=[O:3])[NH2:2].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[C:10]([O:9][C:8]1[N:7]=[CH:6][NH:5][C:4]=1[C:1](=[O:3])[NH2:2])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)c1[nH]c[nH+]c1[O-]
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: NC(=O)c1[nH]cnc1OC(=O)c1ccccc1
Reaction time: 2 h

Procedure:
To a suspension of 455 mg of 4-carbamoylimidazolium-5-olate in 5 ml of dry pyridine was added 1.02 g of benzoyl chloride at a temperature below 5° C. After addition was over, the mixture was stirred under ice cooling for 2 hours. Then separated crystals were filtered off, washed with water and ether, dried to give 5-carbamoyl-1H-imidazol-4-yl benzoate, m.p. 204° C. (dec.).