Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:14])[C:3]1[NH:4][C:5]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[H-].[Na+].Cl[C:18]1[N:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[N:19]=1.O>CN(C=O)C>[F:14][CH:2]([F:1])[C:3]1[N:7]([C:18]2[N:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[N:19]=2)[C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:5]=2[N:4]=1
Reactant: COc1cccc2nc(C(F)F)[nH]c12
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)cc(Cl)n1
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
2-Difluoromethyl-4-methoxybenzimidazole (9.03 g, 45.6 mmol) was dissolved in DMF (100 ml), 60% NaH (1.82 g, 45.6 mmol) was added, and stirred for 30 minutes. The reaction mixture was added to a solution obtained by dissolving 2,4,6-trichloropyrimidine (15.7 g, 92.1 mmol) into DMF (100 ml) while cooling with ice, and stirred on an ice bath for 30 minutes and further at room temperature for 2 hours. Water was added to the reaction mixture, precipitated crystals were filtered, and washed well with hexane and ether, then air-dried to afford 2-(2-difluoromethyl-4-methoxybenzimidazol-1-yl)-4,6-dichloropyrimidine (12.3 g, yield 78%).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:12]([C:13](=O)[CH:14]=1)=[CH:11][CH:10]=[C:9]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=O)[CH3:30])=[C:25]([OH:32])[C:24]=1[CH2:33][CH2:34][CH3:35])[C:8]=2[CH2:36][CH2:37][CH3:38])([O:3][CH3:4])=[O:2]>C(O)(=O)C.[Pd]>[C:1]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:36][CH2:37][CH3:38])[C:9]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH3:30])=[C:25]([OH:32])[C:24]=3[CH2:33][CH2:34][CH3:35])=[CH:10][CH:11]=2)[O:6]1)([O:3][CH3:4])=[O:2]
Reactant: CCCc1c(OCCCCCOc2ccc3c(=O)cc(C(=O)OC)oc3c2CCC)ccc(C(C)=O)c1O
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCc1c(OCCCCCOc2ccc3c(c2CCC)OC(C(=O)OC)CC3)ccc(CC)c1O
Reaction time: 2 h
Yield: 35 %

Procedure:
5.25 (10 mmole) of the compound from Example 5, was dissolved in 125 ml of glacial acetic acid and 0.5 g of 5% palladium on carbon added. The resulting suspension was hydrogenated at 70° C. and 50 psi for two hours. The reaction mixture was cooled and filtered to remove catalyst. After removing the solvent by rotary evaporation, the residue was purified by high pressure liquid chromatography to furnish 1.76 g (35%) of the title compound as an oil. Calc: C, 72.26; H, 8.49; Found: C, 72.20; H, 8.59.
Reaction SMILES: [NH2:1][C:2]1[N:17]=[CH:16][C:15](Br)=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=1)=[O:5].[CH3:19][O:20][CH2:21][CH2:22][N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1>>[NH2:1][C:2]1[N:17]=[CH:16][C:15]([C:26]2[CH:25]=[N:24][N:23]([CH2:22][CH2:21][O:20][CH3:19])[CH:27]=2)=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=1)=[O:5]
Reactant: Cc1cc(NC(=O)c2cc(Br)cnc2N)ccn1
Reactant: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: COCCn1cc(-c2cnc(N)c(C(=O)Nc3ccnc(C)c3)c2)cn1

Procedure:
Reaction of 2-amino-5-bromo-N-(2-methyl-pyridin-4-yl)-nicotinamide with 1-(2-methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole gives the compound “A20”;
Reaction SMILES: [CH2:1]([N:5]1[C:10]([NH2:11])=[C:9]([NH2:12])[C:8](=[O:13])[NH:7][C:6]1=[O:14])[CH2:2][CH2:3][CH3:4].[C:15](O)(=O)[CH3:16]>>[CH2:1]([N:5]1[C:10]2[N:11]=[C:15]([CH3:16])[NH:12][C:9]=2[C:8](=[O:13])[NH:7][C:6]1=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(N)c(N)c(=O)[nH]c1=O
Reactant: CC(=O)O
Product: CCCCn1c(=O)[nH]c(=O)c2[nH]c(C)nc21

Procedure:
A solution of 7.6 g of 1-butyl-5,6-diamino-2,4-(1H,3H)-pyrimidinedione in 20 ml of acetic acid was refluxed for 2 hours. The solution was evaporated. The residue was refluxed in 40 ml of 2N NaOH for 2 hours and then neutralized with 5N HCl. The crystals were filtered off and recrystallized from 350 ml ethanol.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].CS([C:14]1[N:15]=[C:16]([CH2:40][CH2:41][CH3:42])[C:17]2[N:22]=[C:21]([C:23]3[CH:37]=[C:36]([CH3:38])[C:26]([O:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[C:25]([CH3:39])[CH:24]=3)[O:20][C:18]=2[N:19]=1)(=O)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH3:38][C:36]1[CH:37]=[C:23]([C:21]2[O:20][C:18]3[N:19]=[C:14]([O:5][CH2:4][CH2:3][C:2]([F:7])([F:6])[F:1])[N:15]=[C:16]([CH2:40][CH2:41][CH3:42])[C:17]=3[N:22]=2)[CH:24]=[C:25]([CH3:39])[C:26]=1[O:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]
Reactant: OCCC(F)(F)F
Reactant: CCCc1nc(S(C)(=O)=O)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc(OCCC(F)(F)F)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 10.1 %

Procedure:
116 mg of 3,3,3-trifluoropropan-1-ol were added to 46 mg of sodium hydride (60% pure in mineral oil) in 1.5 ml of dry N,N-dimethylformamide. After 5 min, 111 mg of tert-butyl [4-(5-methanesulfonyl-7-propyloxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethylphenoxy]acetate were added, and the reaction was stirred initially at room temperature for 2 h and then at 80° C. for 15 min. For work-up, saturated aqueous citric acid solution was added, and the reaction was extracted three times with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by preparative HPLC gave 12 mg (10%) of the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]1[N:15](C)[N:14]=[C:13]([CH2:17][OH:18])[N:12]=1)=O.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[BH4-].[Na+]>C(O)C>[C:23]1([CH2:22][NH:29][CH2:1][C:3]2[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=2)[O:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]2[NH:15][N:14]=[C:13]([CH2:17][OH:18])[N:12]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cn1nc(CO)nc1NCCCOc1cccc(C=O)c1
Reactant: NCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1n[nH]c(NCCCOc2cccc(CNCc3ccccc3)c2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 5-[[3-(3-formylphenoxy)propyl]amino]-1-methyl-1H-1,2,4-triazole-3-methanol (532 mg) in ethanol (15 ml) was treated with benzylamine (5 ml) and stirred at room temperature for 1.5 h. The solution was treated with sodium borohydride (500 mg) and stirred at room temperature for 16 h. The mixture was evaporated, and the residue partitioned between 2N hydrochloric acid and ethyl acetate. The aqueous layer was washed with ethyl acetate, neutralised with potassium carbonate, and extracted with ethyl acetate. The combined extracts were dried and evaporated in vacuo to yield an oil. This oil was chromatographed on silica gel, using a mixture of methanol-ethyl acetate (1:1) to give the title compound as an oil (315 mg).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[NH:6]1[C:16]2[C:11](=[CH:12][C:13]([S:17]([OH:20])(=O)=[O:18])=[CH:14][CH:15]=2)[C:9](=[O:10])[C:7]1=[O:8].[Na]>C1S(=O)(=O)CCC1>[O:8]=[C:7]1[C:9](=[O:10])[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([S:17]([Cl:3])(=[O:20])=[O:18])[CH:12]=2)[NH:6]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1Nc2ccc(S(=O)(=O)O)cc2C1=O
Agent: [Na]
Solvent: O=S1(=O)CCCC1
Product: O=C1Nc2ccc(S(=O)(=O)Cl)cc2C1=O
Temperature: 60 °C
Yield: 83 %

Procedure:
(16) Phosphorus oxychloride (13.2 mL, 141.6 mmol) was added to a solution of 5-isatinsulfonic acid (5), sodium salt hydrate (8.0 g, 30.0 mmol) in tetramethylene sulfone (40 mL). The mixture was heated to 60° C. for 3 h, then cooled to 0° C. The reaction mixture was poured into 150 g of ice. The solid was filtered out and washed with cold water, then the solid was dissolved in ethyl acetate (100 mL), washed with water (50 mL×2) and saturated NaCl (50 mL), and dried over Na2SO4. The ethyl acetate was evaporated in reduced pressure to afford 6.12 g (83%) of 6 as a pale yellow solid, mp 188.2-190.1° C. 1H NMR (300 MHz, DMSO) δ 11.1 (s, 1H), 7.82 (dd, J=8.4 Hz, J=1.8 Hz, 1H), 7.60 (s, 1H), 6.89 (d, J=8.1 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16](I)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1.[NH:31]1[CH2:35][CH2:34][CH:33]([NH:36][C:37](=[O:39])[CH3:38])[CH2:32]1>CN1CCCC1=O>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([N:31]3[CH2:35][CH2:34][CH:33]([NH:36][C:37](=[O:39])[CH3:38])[CH2:32]3)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Reactant: CC(=O)NC1CCNC1
Solvent: CN1CCCC1=O
Product: CC(=O)NC1CCN(c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc3c2C(C)(C)C(=O)N3)C1
Temperature: 150 °C

Procedure:
Under argon atmosphere, 200 mg (purity 62%, 0.24 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was suspended in 4 ml of absolute 1-methyl-2-pyrrolidone and 618 mg (4.82 mmol) of N-(pyrrolidin-3-yl)acetamide was added. The mixture was heated in the microwave at 150° C. for 3 h. After cooling, the reaction mixture was purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→100:0). 122 mg (98% of theor.) of the target compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=O)[CH3:11])[CH:5]=[CH:6][CH:7]=1.[NH2:19]/[C:20](/[CH3:26])=[CH:21]\[C:22]([O:24][CH3:25])=[O:23].C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:10]([CH3:11])[NH:19][C:20]([CH3:26])=[C:21]2[C:22]([O:24][CH3:25])=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)C(=Cc1cccc(Cl)c1)c1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(c2ccccc2)C1c1cccc(Cl)c1

Procedure:
12.82 g (50 mmol) of 1-(3-chlorophenyl)-2-phenyl-3-oxo-1-butene in 80 ml of ethanol are heated to reflux with 11.5 g (100 mmol) of methyl β-aminocrotonate and 6 ml (100 mmol) of acetic acid overnight. 11.5 g of methyl β-aminocrotonate and 6 ml of acetic acid are added once more, and the mixture is heated under reflux for 24 hours. On cooling, crystals are produced, and these are filtered off with suction and washed with ethanol. For complete purification, they are passed through a silica gel column using toluene/ethyl acetate 20:1. 5.3 g of a colorless substance, of melting point 191° C., are obtained.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:20][NH2:21].C(O)(=O)C.[C-:26]#[N:27].[K+]>CO>[CH:1]([N:14]1[CH2:17][C:16]([NH:27][CH3:26])([C:20]#[N:21])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: [C-]#N
Reactant: CN
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: CNC1(C#N)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1-benzhydrylazetidin-3-one (2.13 g, 8.98 mmol) in methanol (17 ml) was added methylamine hydrochloride (1.21 g, 18.0 mmol) and then acetic acid (1.03 ml, 18.0 mmol) at room temperature. After stirring for 5 minutes, solid KCN (1.17 g, 18.0 mmol) was added and the mixture was heated to 60° C. for 19 hours. The reaction was cooled; the solid product was collected by vacuum filtration, rinsed with methanol, and then dried, in vacuo, to afford I-(29A-7)a as a colorless solid (2.50 g, quantitative): +ES MS (M+1) 278.3; 1H NMR (400 MHz, CD2Cl2) δ 7.43 (d, J=7.5 Hz, 4H), 7.29 (t, J=7.5 Hz, 4H), 7.23 (t, J=7.3 Hz, 2H), 4.45 (s, 1H), 3.55 (d, J=7.5 Hz, 2H), 3.15 (d, J=7.1 Hz, 2H), 2.40 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1O)=[CH:11][C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:9][CH:8]=2)([O-:3])=[O:2].O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)[N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc2ccc(-c3ccccc3)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc2ccc(-c3ccccc3)cc2c1Cl

Procedure:
The title compound is prepared in analogy to Example 19e, starting from 900 mg (3.38 mmol) 3-nitro-6-phenyl-quinolin-4-ol (Example 53c) in 10 ml POCl3. The compound is crystallized from ethylacetate-hexane. mp: 144-145° C.; MS: 284 (M++1); HPLC: tret=140.51 min (Grad 1).
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:29]C(=O)OC(C)(C)C)([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=3)[CH:9]=2)[CH2:4][O:3]1.CO.Cl.O>>[NH2:29][C:5]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=3)[CH:14]=2)[CH:9]=1)([CH2:6][OH:7])[CH2:4][OH:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc3cc(Oc4cccc(C(F)(F)F)c4)ccc3c2)COC(C)(C)OC1
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(CO)(CO)c1ccc2cc(Oc3cccc(C(F)(F)F)c3)ccc2c1
Temperature: 50 °C
Yield: 90.2 %

Procedure:
tert-Butyl 2,2-Dimethyl-5-(6-(3-(trifluoromethyl)phenoxy)naphthalen-2-yl)-1,3-dioxan-5-ylcarbamate (35.0 mg, 0.0000676 mol) was dissolved in methanol (2 mL, 0.06 mol), followed by 2 M hydrogen chloride in water (2 mL, 0.004 mol). The reaction mixture was then heated at 50° C. for 3 hours. All solvents were removed to give a pure product (23 mg, 100%). 1H NMR (MeOD) δ: 8.00 (d, J=9.0 Hz, 1H), 7.96 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.54-7.64 (m, 2H), 7.42-7.48 (m, 2H), 7.24-7.37 (m, 3H), 4.05-4.13 (m, 2H), 3.94-4.03 (m, 2H). MS (M+1): 378.20.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19](=[O:31])[NH:20][CH2:21][CH2:22][C:23](=[O:30])[NH:24][CH2:25][CH:26]([OH:29])[CH2:27][CH3:28])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([O:18][C:19](=[O:31])[NH:20][CH2:21][CH2:22][C:23](=[O:30])[NH:24][CH2:25][C:26](=[O:29])[CH2:27][CH3:28])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCC(O)CNC(=O)CCNC(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCC(=O)CNC(=O)CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of oxalyl chloride (2 M in DCM) (13.35 ml, 26.5 mmol) in dry DCM at −78° C. is added dropwise DMSO (2.5 ml, 35.4 mmol). After stirring for 15 minutes, the reaction mixture is treated with a solution of [2-(2-hydroxy-butylcarbamoyl)-ethyl]-carbamic acid benzyl ester (step 1) (6.5 g, 22.1 mol) in dry DCM (40 ml). Triethylamine (13 ml) is added after 1 hour and after stirring at −78° C. for 90 minutes, the reaction mixture is allowed to warm to room temperature. The reaction is diluted with DCM (100 ml) and washed with HCl (1M, 200 ml), saturated sodium bicarbonate solution (200 ml), water (200 ml) and brine (200 ml). The organic portion is dried over MgSO4, filtered and concentrated in vacuo to yield the titled compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]3[N:9]2[C:12]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:13][N:14]=3)=[CH:4][CH:3]=1.[OH:21][C@@H:22]([CH3:26])[C:23](O)=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]3[N:9]2[C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:23](=[O:24])[C@@H:22]([OH:21])[CH3:26])[CH2:17][CH2:16]2)=[N:13][N:14]=3)=[CH:4][CH:3]=1
Reactant: Brc1ccc2ncc3nnc(C4CCNCC4)n3c2c1
Reactant: C[C@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](O)C(=O)N1CCC(c2nnc3cnc4ccc(Br)cc4n23)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66 %

Procedure:
A mixture of 8-bromo-1-(piperidin-4-yl)[1,2,4]triazolo[4,3-a]quinoxaline (250 mg, 0.75 mmol), (S)-2-hydroxypropanoic acid (75 mg, 0.83 mmol), HATU (346 mg, 0.90 mmol), and DIEA (116 mg, 0.90 mmol) in DMF (5 mL) was stirred at r.t. for 6 h. Then the solvents was removed, and the residue was purified by ISCO (MeOH/H2O=20%-90%) to afford (S)-1-(4-(8-bromo-[1,2,4]triazolo[4,3-a]quinoxalin-1-yl)piperidin-1-yl)-2-hydroxypropan-1-one as pale yellow solid (200 mg, yield 66.0%). MS (m/z): 404 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH2:4][C:5](=O)[CH2:6][CH3:7])[CH3:3].C(OC(=O)CC)(=[O:18])CC.[Cl-].C([Mg]Cl)C(C1C=CC=CC=1)(C)C>C1(C)C=CC=CC=1.C(OCC)C>[CH3:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH:4]=[CH:5][CH2:6][CH3:7])[CH2:3][OH:18]
Reactant: CCC(=O)OC(=O)CC
Reactant: CCC(=O)CC(C)(C)c1ccccc1
Agent: CC(C)(C[Mg]Cl)c1ccccc1
Agent: [Cl-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCC=CC(C)(CO)c1ccccc1

Procedure:
A process for preparing 2-methyl-2-phenyl-4-hexanone having the structure: ##STR47## comprising the step of intimately admixing propionic anhydride having the structure: ##STR48## with neophymagnesium chloride having the structure: ##STR49## in the presence of an inert solvent selected from the group consisting of diethylether, toluene and tetrahydrufuran, the reaction taking place in the presence of or in the absence of a cuprous chloride catalyst; the mole ratio of propionic anhydride:neophylmagnesium chloride being from 0.5:1 up to about 2:1; the temperature of reaction being from -10° C. up to 0° C.; the concentration of propionic anhydride in solvent being from about 1 up to about 5 moles of propionic anhydride per liter of solvent; the time of addition of one reactant to the other varying from 0.5 hours up to 4 hours and the time of aging of the reaction mass being from 0.5 up to 4 hours.
Reaction SMILES: CCCCC/C=C\C[C@@H](O)/C=[CH:11]/[CH:12]=[CH:13]/[CH:14]=[CH:15]\[C@@H:16](O)[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O.C1[O:27][C@H]1CO.O=C1O[C@H:36]([C@H:38]([CH2:40][OH:41])O)[C:34](O)=[C:32]1O.C#CCCCCC>CCOCC>[O:41]1[CH2:32][CH2:34][CH2:36][CH2:38][CH:40]1[O:22][CH2:20][C@H:19]([OH:27])[CH2:18][C:17]#[C:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: CCCCC/C=C\C[C@@H](O)/C=C/C=C/C=C\[C@@H](O)CCCC(=O)O
Reactant: OC[C@H]1CO1
Agent: C#CCCCCC
Solvent: CCOCC
Product: CCCCCC#CC[C@@H](O)COC1CCCCO1

Procedure:
The starting material for the process of this invention, compound 2, can be prepared as described in Nicolaou, K. C. et al., "A General and Stereocontrolled Total Synthesis of Leukotriene B4 and Analogues," J. Am. Chem. Soc., 106, 3548 (1984) or Hanson, R. M. and Sharpless, K. B., J. Org. Chem., 51 1922 (1986). Briefly, optically active (S)-glycidol THP ether is prepared from ascorbic acid as disclosed in Takano, S., Numata, H., Ogasawara, K., Heterocycles, 19, 237 (1982) and Baldwin, J. J., Raab, A. W., Mensler, K., Arison, B. H., McClure, D. E., J. Org. Chem., 43, 4876 (1978). The ether is reacted (-78°-25° C.) with two equivalents of the anion of 1-heptyne (1.0 equiv. of n-BuLi, 1.0 equiv. of TMEDA and THF, -78° C.) to afford a-[(tetrahydro-2H-pyran-2-yl)oxy]dec-4-yn-2(R)-ol which is then silylated (t-BuPh2SiCl, imidazole, DMF) to, compound 2.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=2)[C:12]#[N:13])=[CH:4][CH:3]=1.[N:17]1([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:21][CH2:20][CH2:19][CH2:18]1>CS(C)=O>[N:17]1([CH:22]2[CH2:27][CH2:26][N:25]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=4)[C:12]#[N:13])=[CH:4][CH:3]=3)[CH2:24][CH2:23]2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: N#Cc1ccc(-c2ccc(F)cc2)[nH]c1=O
Reactant: C1CCN(C2CCNCC2)C1
Solvent: CS(C)=O
Product: N#Cc1ccc(-c2ccc(N3CCC(N4CCCC4)CC3)cc2)[nH]c1=O

Procedure:
From 11.7 g. of 6-(p-fluorophenyl)-1,2-dihydro-2-oxonicotinonitrile and 16.7 g. of 4-(1-pyrrolidinyl)-piperidine in 150 ml. of dimethyl sulfoxide, there is obtained 6-[p-[4-(1-pyrrolidinyl)piperidino]phenyl]-1,2-dihydro-2-oxonicotinonitrile; m.p. 318°-326° (dec.).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:10][N:9]=1)=[O:7])C>CO>[O:14]([CH2:13][C:11]1[NH:10][N:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:12]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cc(COc2ccccc2)[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(COc2ccccc2)[nH]n1
Yield: 88.3 %

Procedure:
Freshly prepared aq. NaOH (10 M in H2O, 10.49 mmol) was added to a stirring, room temperature solution of 41 (0.5164 g, 2.10 mmol) in MeOH (5.2 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by HPLC (20 min): The reaction was concentrated and then dissolved in 4.2 mL H2O. 10% aq. HCl was added dropwise until the pH=2. The white solid that precipitated from the reaction was filtered off and washed with cold H2O. The solid was dried under vacuum overnight to obtain 0.4044 g (88.4%) of 42 as a white solid. Note: An undesired impurity that does not crash out of solution upon HCl addition has a retention time of 9.127 min by 1H (CDCl3, 400 MHz): δ 7.26 (2H, t, J=8.0 Hz), 6.99 (2H, d, J=8.3 Hz), 6.94 (1H, t, J=7.3 Hz), 6.85 (1H, s), 5.10 (2H, s) ppm. 13C (CDCl3, 100 MHz): δ 163.68, 159.73, 146.60, 141.13, 130.51, 122.27, 115.83, 108.88, 63.06 ppm. DEPT (CDCl3, 100MHz): CH2 carbons: 63.06; CH carbons: 130.51, 122.27, 115.83, 108.88 ppm. HPLC: 8.272 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.B(F)(F)F.[CH2:15](O)[CH3:16]>>[Cl:1][C:2]1[C:3]([C:8]([O:10][CH2:15][CH3:16])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncccc1Cl
Reactant: CCO
Agent: FB(F)F
Product: CCOC(=O)c1ncccc1Cl

Procedure:
3-Chloropicolinic acid is esterified using boron trifluoride and ethanol by the procedure described in Example 1 to give ethyl 3-chloropicolinate.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17]O)=[CH:11][C:10]=2[O:19][CH3:20])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS([Cl:32])(=O)=O.[NH4+].[Cl-]>ClCCl>[Cl:32][CH2:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=2)=[C:10]([O:19][CH3:20])[CH:11]=1
Reactant: COc1cc(C#CCO)ccc1Oc1cccc(F)n1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(CCCCl)ccc1Oc1cccc(F)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 169.1 %

Procedure:
To a solution of 3-{4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}prop-2-yn-ol (0.37 mmol; 102 mg) in dry dichloromethane (2 mL), under argon, cooled to −40° C., was added triethylamine (0.41 mmol; 56 μL) then methanesulfonyl chloride (0.39 mmol; 30 μL). The reaction mixture was allowed to stir for 6 hr, with gradual warming to room temperature. The reaction was hydrolysed with saturated NH4Cl, extracted with ethyl acetate. Combined organic phases were dried over Na2SO4, concentrated in vacuo. The title compound (185 mg; 47%) was obtained as a light oil, after purification on preparative TLC (cyclohexane/ethyl acetate: 7/3).