Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:15]1[C@@H:20]2[C@H:21]([C:23]([OH:25])=O)[CH2:22][C@@:16]1([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@H:17]([O:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=1)[CH2:18][CH2:19]2)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N.O1CCOCC1.C([N:57](CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[CH2:8]([N:15]1[C@@H:20]2[C@H:21]([C:23]([NH2:57])=[O:25])[CH2:22][C@@:16]1([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C@H:17]([O:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:35])([F:37])[F:36])[CH:31]=[C:30]([C:38]([F:39])([F:41])[F:40])[CH:29]=1)[CH2:18][CH2:19]2)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Reaction time: 24 h
Yield: 56 %

Procedure:
A solution of (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octan-6-carboxylic acid trifluoroacetate (Example 53; 2.7 mmol) was treated with ammonia solution in dioxane (0.5M, 10 ml, 5 mmol), triethylamine (0.6 ml, 4.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (960 mg, 5.02 mmol), and 4-N,N-dimethylaminopyridine (120 mg, 1 mmol). The mixture was stirred for 24 hours, diluted with ethyl acetate (100 ml), washed with 10% aqueous citric acid, saturated aqueous NaHCO3, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (850 mg, 56%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1.CC(N(C)C)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: O=C(O)c1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 24 h
Yield: 94 %

Procedure:
10 g of 4-nitrobenzoic acid chloride are slowly introduced into 7.4 g of 4-aminobenzoic acid and 36 ml of dimethylacetamide while maintaining the temperature at less than 25° C. After stirring for 24 hours, 50 ml of methylene chloride are added at 10° C. in order to precipitate the desired product. After washing with water and drying, 14.5 g of product are isolated.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6](S(C3C=CC(C)=CC=3)(=O)=O)[S:7](=[O:10])(=[O:9])[O:8][C:4]=2[CH:3]=1.S(Cl)(Cl)(=O)=O.OC1C=C(C)C=CC=1NS(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][S:7](=[O:10])(=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2c3ccc(C)cc3OS2(=O)=O)cc1
Agent: Cc1ccc(S(=O)(=O)Nc2ccc(C)cc2O)cc1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)OS(=O)(=O)N2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
6-Methyl-3-(toluene-4-sulfonyl)-3H-benzo[1,2,3]oxathiazole 2,2-dioxide At-78° C., a solution of sulfuryl chloride (450 μl, 5.41 mmol) in CH2Cl2 (10 ml) is slowly added dropwise to a solution of N-(2-hydroxy-4-methylphenyl)-4-methyl-benzenesulfonamide (1.5 g, 5.41 mmol) and triethylamine (1.5 ml), and the mixture is stirred at −78° C. for one hour. After thawing to RT, the solvent is distilled off under reduced pressure and the residue is purified by RP chromatography.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][CH3:6].C[CH:8]([C@@H:12]1[CH2:17][CH2:16][NH:15][C@H:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[CH2:13]1)[C:9]([O-:11])=[O:10]>>[CH3:6][O:5][CH2:4][CH2:3][CH2:2][C@@H:14]([N:15]1[CH2:16][CH2:17][C@@H:12]([CH2:8][C:9]([OH:11])=[O:10])[CH2:13][C@H:14]1[C:18]1[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=1)[C:18]1[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=1
Reactant: CC(C(=O)[O-])[C@@H]1CCN[C@H](c2ccc(C(F)(F)F)cc2)C1
Reactant: COCCCBr
Product: COCCC[C@H](c1ccc(C(F)(F)F)cc1)N1CC[C@@H](CC(=O)O)C[C@H]1c1ccc(C(F)(F)F)cc1

Procedure:
The compound was prepared analogously to Example 160 using the Grignard reagent derived from 1-bromo-3-methoxypropane and starting with the chiral piperidine of Example 114 Step 1. M/Z (ES+) 518 (M+H).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40](=[O:46])[N:41]([CH2:43][CH2:44][OH:45])[CH:42]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:38]=[CH:39][C:40](=[O:46])[N:41]([CH2:43][CH2:44][OH:45])[CH:42]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: O=c1ccc(Br)cn1CCO
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(CCO)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 5-bromo-1-(2-hydroxyethyl)pyridin-2(1H)-one following a procedure analogous to that described in Example 20 Step 2. LC-MS Method 2 tR=1.08 min, m/z=513, 491; 1H NMR (CD3OD) δ 0.95 (s, 3H), 1.24 (s, 3H), 1.26 (s, 1H), 1.52 (d, 3H), 2.12 (s, 2H), 2.18 (m, 1H), 2.40-2.53 (m, 2H), 3.02 (m, 1H), 3.52 (m, 0.5H), 3.64 (m, 0.5H), 3.83 (t, 1H), 4.15 (t, 1H), 5.53 (m, 1H), 6.61 (m, 1H), 7.01 (d, 2H), 7.25-7.40 (m, 7H), 7.79 (m, 2H).
Reaction SMILES: [CH:1]1([C:6]2[CH:18]=[CH:17][C:9]([C:10]([CH2:12][CH2:13][C:14](O)=[O:15])=O)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:20][NH2:21]>C(O)C>[CH:1]1([C:6]2[CH:18]=[CH:17][C:9]([C:10]3[CH2:12][CH2:13][C:14](=[O:15])[NH:20][N:21]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: O=C(O)CCC(=O)c1ccc(C2CCCC2)cc1
Solvent: CCO
Solvent: O
Product: O=C1CCC(c2ccc(C3CCCC3)cc2)=NN1

Procedure:
A solution of 3-(p-cyclopentylbenzoyl)propionic acid (4.9 g.) in warm ethanol (50 ml.) was treated with hydrazine hydrate (1.1 g.) and the mixture heated on the steam bath for 1 hour. The colourless crystalline material which separated, was collected and recrystallised from ethanol to yield the product (4.2 g.) in large, colourless needles, m.p. 191°-192° C.
Reaction SMILES: [C:1]1([CH:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C(=O)C2=CC=CC=C2C1=O.O=O.OO>C(OCC)(=O)C>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])[CH3:8]
Reactant: CC(O)c1ccccc1
Agent: O=C1c2ccccc2C(=O)N1O
Agent: O=O
Agent: OO
Solvent: CCOC(C)=O
Product: CC(=O)c1ccccc1
Yield: 48 %

Procedure:
A mixture of 5 mmol of 1-phenylethanol, 0.5 mmol of N-hydroxyphthalimide, and 5 ml of ethyl acetate was stirred at 75° C. in an oxygen atmosphere (1 atm) for 18 hours. An iodometric analysis of a reaction mixture revealed that hydrogen peroxide was formed in yield of 40% (selectivity: 81%). Separately, a gas chromatographic analysis of the reaction mixture revealed that the conversion rate from 1-phenylethanol was 49%, and acetophenone was formed in yield of 48%.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[N:10][S:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:9]2[C:8]([C:6]([OH:7])=[O:5])=[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:11][N:10]=2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)c1c(-c2ccc(Cl)cc2)nsc1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1c(-c2ccc(Cl)cc2)nsc1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.7 %

Procedure:
To a solution of 11 (2.35 g) in CH2Cl2 (25 ml) is added 25 ml of TFA and the mixture is stirred at room temperature for 24 h. The mixture is then concentrated and the residue is dissolved in ether (250 ml). Water (225 ml) is added followed by 1N NaOH (25 ml). After washing and separation, the basic water layer is extracted once more with ether. The water layer is acidified with conc. HCl and the precipitated product is extracted with ether (2×150 ml). The combined organic layers are washed with brine, dried and concentrated. 1.85 g of 12 is obtained as a cream colored solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([F:12])([F:11])[F:10].[OH:13][CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1>>[F:8][C:4]1[C:3]([C:9]([F:12])([F:11])[F:10])=[C:2]([N:16]2[CH2:17][CH2:18][CH:14]([OH:13])[CH2:15]2)[CH:7]=[CH:6][CH:5]=1
Reactant: OC1CCNC1
Reactant: Fc1cccc(Br)c1C(F)(F)F
Product: OC1CCN(c2cccc(F)c2C(F)(F)F)C1
Yield: 24 %

Procedure:
The title compound (6.2 g, yield 24%) was obtained from 1-bromo-3-fluoro-2-(trifluoromethyl)benzene and 3-hydroxypyrrolidine by a method similar to that in Reference Example 1.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]3[N:20]=[C:21]([CH:24]=[CH:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[O:22][CH:23]=3)=[O:18])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[OH-].[K+].I[CH3:39]>CC(C)=O>[CH3:39][N:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)=[CH:11][CH:12]=1)[C:17]([C:19]1[N:20]=[C:21]([CH:24]=[CH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=2)[O:22][CH:23]=1)=[O:18]
Reactant: CI
Reactant: O=C(Nc1ccc(CCCCn2ccnn2)cc1)c1coc(C=Cc2ccc(C(F)(F)F)cc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CN(C(=O)c1coc(C=Cc2ccc(C(F)(F)F)cc2)n1)c1ccc(CCCCn2ccnn2)cc1

Procedure:
2-[2-(4-Trifluoromethyl-phenyl)-vinyl]-oxazole-4-carboxylic acid [4-(4-[1,2,3]triazol-1-yl-butyl)-phenyl]-amide (40 mg, 0.083 mmol) is dissolved in acetone (0.6 ml), treated with KOH (17 mg, 0.3 mmol) and iodomethane (17.7 mg, 0.12 mmol) and heated to reflux for 5 min. After cooling the mixture is concentrated, taken up in water (10 ml) and extracted with dichloromethane (2×10 ml). The organic layers are dried over sodium sulfate, concentrated in vacuo and purified by flash column chromatography (ethyl acetate/heptane 9:1) yielding 2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazole-4-carboxylic acid methyl-[4-(4-[1,2,3]triazol-1-yl-butyl)-phenyl]-amide 12 as a colorless solid. Yield 30 mg (73%); m.p. 127–129° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:12]2[N:13]=[CH:14][N:15]=[C:16](N)[C:17]=2[N:18]=1)[C@@H:4]1[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[CH2:5]1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:22]>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[NH2:1][C:2]1[N:3]([C:12]2[N:13]=[CH:14][N:15]=[C:16]([OH:22])[C:17]=2[N:18]=1)[C@@H:4]1[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[CH2:5]1
Reactant: Nc1ncnc2c1nc(N)n2[C@H]1C[C@H](O)[C@@H](CO)O1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: Nc1nc2c(O)ncnc2n1[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 37 °C
Reaction time: 72 h

Procedure:
In a round-bottom flask 2 g (7.5 mmol) of 8-amino-2′-deoxyadenosine (Long R. A. et al ref. 36 and Example 2) were dissolved with 150 ml of 0.1 M aqueous sodium phosphate buffer (pH 7.5). Adenosine deaminase (150 mg of crude powder from calf intestinal mucosa) was added. The resulting solution was stirred at 37° C. for 72 hrs. A precipitate was formed that was the desired product. Completion of the reaction was checked by TLC (ethanol/dichloromethane 1:4). It was observed the disappearance of the starting material to produce a more polar compound. The precipitate was filtered yielding 1.8 g (6.7 mmol, 89% yield) of 8-amino-2′-deoxyinosine.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[NH2:10][C:11]1[C:12]2[C:17]([C:18]3[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[CH:21]=[CH:22][C:23]=3[CH:24]=1)=[CH:16][C:15]([CH3:29])=[CH:14][CH:13]=2.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[C:30]([NH:10][C:11]1[C:12]2[C:17]([C:18]3[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[CH:21]=[CH:22][C:23]=3[CH:24]=1)=[CH:16][C:15]([CH3:29])=[CH:14][CH:13]=2)(=[O:32])[CH3:31]
Reactant: COc1ccc2cc(N)c3ccc(C)cc3c2c1OC
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2cc(NC(C)=O)c3ccc(C)cc3c2c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
105.7 ml (0.750M) of N-ethyl-N,N-diisopropyl-amine are added to a solution of 100.2 g (0.375M) of 9-amino-3,4-dimethoxy-6-methyl-phenanthrene in 1000 ml methylene chloride. To the resulting mixture is added dropwise over 30 minutes a solution of 34.5 ml (0.450M) of acetyl chloride in 250 ml methylene chloride. During the addition, the temperature of the reaction mixture is maintained at 20° by cooling with ice. The reaction mixture is stirred for 2 hours at room temperature and extracted with methylene chloride. The organic phases are washed with ice cooled 2N hydrochloric acid, water and 2N sodium bicarbonate, dried over sodium sulfate and evaporated, to give the title compound. M.pt. 190°-192° after crystallization from acetone/ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].Br[CH2:24][Cl:25]>O>[Cl:25][CH2:24][S:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: ClCBr
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)(CCl)c1ccc(F)cc1
Temperature: 100 °C

Procedure:
A stirred mixture of 4-fluoro-benzenesulfonyl chloride (10.16 g, 52.2 mmol), sodium sulfite (12.25 g, 97.1 mmol) and sodium bicarbonate (8.02 g, 95.5 mmol) in water (55 mL) is heated at 100° C. for 1 h. The crude sodium sulfinate solution is allowed to cool for 30 min and then treated with bromochloromethane (60 mL) and tetra-N-butyl ammonium bromide (1.68 g, 5.22 mmol). The resulting mixture is heated at 75° C. overnight. The organic layer was separated. The aqueous solution was extracted with CH2Cl2 (×2). The combined organics were washed with water and brine, and dried over anhydrous MgSO4. The filtration through Celite-silica gel pad and concentration in vacuo gave the desired product without further purification. 1H NMR (300 MHz, CDCl3) 8.00 (m, 2H), 7.30 (m, 2H), 4.53 (s, 2H).
Reaction SMILES: [P:1]([OH:13])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)(O)[O-].[Na+].S([O-])(O)(=O)=O.S(Cl)(O[CH2:28][Cl:29])(=O)=O>O.ClCCl>[P:1]([O:13][CH2:28][Cl:29])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:2]
Reactant: CC(C)(C)OP(=O)(O)OC(C)(C)C
Reactant: O=S(=O)(Cl)OCCl
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Yield: 52.3 %

Procedure:
To a well stirred suspension of di-tert-butyl hydrogen phosphate (4.7 g, 22.47 mmol) in water (186 ml) was added sodium bicarbonate (7.5 g, 89.52 mmol) followed by tetra-n-butylammomium hydrogen sulphate (760 mg, 2.238 mmol). The reaction mixture was stirred at room temperature for 15 min. To the reaction mixture was added dichloromethane (112 ml) at 0° C. and it was stirred for 10 min followed by the addition of chloromethyl chlorosulphate (4.4 g, 26.85 mmol) in dichloromethane (75 ml) at same temperature. The resultant mixture was vigorously stirred overnight at room temperature. The organic layer was separated, washed with brine and evaporated under reduced pressure to yield 3.04 g of product as pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:11][N:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]1=[O:1]
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc([N+](=O)[O-])ccc1=O
Reaction time: 8 h
Yield: 68.2 %

Procedure:
To a solution of 2-hydroxy-5-nitropyridine (600 mg, 4.28 mmol, 1 eq) in DMF (5 mL) was added cesium carbonate (1.67 g, 5.16 mmol, 1.2 eq), followed by methyl iodide (0.4 mL, 6.42 mmol, 1.5 eq). After stirring overnight, the reaction mixture was quenched with water and extracted with ethyl ether (5×20 mL). The ether was dried over Na2SO4 and concentrated under reduced pressure. The crude material was column chromatographed, eluting with 50% EtOAc/hexanes to give 450 mg of compound 50B.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([CH3:19])[C:5]([NH:7][C:8]1[CH:12]=[C:11]([C:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][CH3:16])[O:10][N:9]=1)=[O:6].[OH-].[K+]>O.C(O)C>[CH3:17][C:13]([C:11]1[O:10][N:9]=[C:8]([N:7]2[CH2:2][CH2:3][CH:4]([CH3:19])[C:5]2=[O:6])[CH:12]=1)([CH3:18])[CH2:14][CH2:15][CH3:16]
Reactant: CCCC(C)(C)c1cc(NC(=O)C(C)CCCl)no1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCC(C)(C)c1cc(N2CCC(C)C2=O)no1
Yield: 20 %

Procedure:
1-[5-(1,1-Dimethylbutyl)-3-isoxazolyl]-3-methyl-2-pyrrolidinone was prepared by reacting 17.2 g of 4-chloro-N-[5-(1,1-dimethylbutyl)-3-isoxazolyl]-2-methylbutanamide with 6.72 g of potassium hydroxide in 30 ml water and 75 ml ethanol by the general method of Example 3. Weight 4 g (Yield 20%). mp 30°-31° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:16](N)=[NH:17]>C(O)C>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:17][CH:16]=[N:1]2)=[CH:7][CH:8]=1
Reactant: N=CN
Reactant: Nc1cc(F)ccc1C(=O)O
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2cc(F)ccc12
Yield: 82.4 %

Procedure:
25.0 g (0.156 mol) of 2-amino-4-fluorobenzoic acid and 33.0 g (0.317 mol) of formamidine acetate were suspended in 250 ml of ethanol. The reaction mixture was subsequently stirred under reflux for 16 h. Conventional work-up gave 21.1 g (Y=82%) of 7-fluoro-3H-quinazolin-4-one.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]#[N:30])[CH:28]=1)C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:2].[Br-].C(C1C=C(C=C(C#N)C=1)C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#N.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>>[C:29](#[N:30])[C:27]1[CH:26]=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:28]=1
Reactant: N#Cc1cc(C#N)cc(C=P(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N#Cc1cc(C#N)cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Product: N#Cc1cccc(C#N)c1

Procedure:
(kk) by using 3,5-dicyanobenzylidenetriphenylphosphorane prepared in situ by means of 3,5-dicyanobenzyltriphenylphosphonium bromide and sodium bis(trimethylsilyl)amide there is obtained 5-[(Z)-2-(1R,4S,5S,8R)-4,8-dimethyl-7-oxo-2,3-dioxabicyclo[3.3.1]nonan-4-yl]vinyl]isophthalonitrile [m.p. 185°]:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.N1C=CC=NC=1.[H-].[Na+].[O:32]1[CH2:36][CH2:35][C@@H:34](C2C=C(S([O-])(=O)=O)C(C)=CC=2)[CH2:33]1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C.CO>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[CH:9][N:8]([CH:34]3[CH2:35][CH2:36][O:32][CH2:33]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccc([C@@H]2CCOC2)cc1S(=O)(=O)[O-]
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: c1cncnc1
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCOC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a stirred suspension of 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine (4.83 g, 16 mmol) in N,N-dimethylformamide (80 mL), under an d]pyrimidine (4.83 g, 16 mmol) in N,N-dimethylformamide (80 mL), under an atmosphere of nitrogen, was added 60% sodium hydride in mineral oil (0.75 g, 19 mmol), and the mixture stirred at room temperature for 30 minutes. The resultant dark solution was treated with a solution of 4-{(S)-tetrahydrofuran-3-yl}toluenesulphonate (4.20 g, 18 mmol) in N,N-dimethylformamide (20 mL) in 2 mL aliquots. The resultant solution was stirred at room temperature for 30 minutes, then at 95 deg. C. for 18 hours. The solution was allowed to cool to ambient temperature, then poured onto ice/water (200 mL). The aqueous was extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with water (4×150 mL), dried over sodium sulphate, and the solvent was removed under reduced pressure. The residue was warmed with dichloromethane (1000 mL) until a solution was obtained, cooled to ambient temperature, and purified by chromatography with a Biotage 40M column using ethyl acetate/triethylamine (95:5), then ethyl acetate/triethylamine/methanol (90:5:5) as a mobile phase, to yield R-(+)-4-[4-amino-5-(4-phenoxyphenyl)-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidine as an off-white solid (4.35 g, 12 mmol) melting point 165-166 deg. C., LC/MS: Hypersil BDS c18 (100×2.1 mm) 0.1M ammoniumacetate/acetonitrile, 10-100% acetonitrile in 8 min.) MH+373 tr=4.44 minutes. [ ]D+20.5±0.6 (dichloromethane, 22.6 deg. C.)
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[C:22]([C:23]2[CH:28]=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:26]=[CH:25][C:24]=2[F:38])=[CH:21][C:20]([C:39]#[N:40])=[CH:19][CH:18]=1>>[F:16][C:17]1[C:22]([C:23]2[CH:28]=[C:27]([C:2]3[C:3]4[C:8](=[N:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=4)[N:9]=[CH:10][CH:11]=3)[CH:26]=[CH:25][C:24]=2[F:38])=[CH:21][C:20]([C:39]#[N:40])=[CH:19][CH:18]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3cc(C#N)ccc3F)c2)OC1(C)C
Product: N#Cc1ccc(F)c(-c2cc(-c3ccnc4nc(C(F)(F)F)ccc34)ccc2F)c1
Yield: 26.5 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 6,2′-difluoro-5′-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)biphenyl-3-carbonitrile (96 mg, 0.28 mmol) as described in Example 7 part g), affording 6,2′-difluoro-5′-(7-trifluoromethyl[1,8]naphthyridin-4-yl)biphenyl-3-carbonitrile (24 mg, 27%). δH (400 MHz, CDCl3) 7.35 (1H, t, J 9.0), 7.45 (1H, t, J 9.0), 7.52-7.61 (3H, m), 7.74-7.78 (1H, m), 7.83 (1H, dd, J 1.4 and 6.5), 7.87 (1H, d, J 8.6), 8.54 (1H, d, J 8.2), 9.30 (1H, d, J 4.3). m/z (ES) 412 [MH]+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[C:20]([O:30][CH3:31])[CH:19]=3)=[C:15]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43])=[CH:34][CH:33]=3)[S:14][C:13]=2[CH:46]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C1COCC1.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[C:20]([O:30][CH3:31])[CH:19]=3)=[C:15]([C:32]3[CH:33]=[CH:34][C:35]([O:38][CH2:39][CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43])=[CH:36][CH:37]=3)[S:14][C:13]=2[CH:46]=1
Reactant: COC(=O)CCCOc1ccc(-c2sc3cc(OCc4ccccc4)ccc3c2Cc2ccc(CN3CCCC3)c(OC)c2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)CCCOc1ccc(-c2sc3cc(O)ccc3c2Cc2ccc(CN3CCCC3)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.6 %

Procedure:
6-Benzyloxy-3-[3-methoxy-4-(1-pyrrolidinylmethyl)benzyl]-2-[4-(4-methoxy-4-oxobutoxy)phenyl]benzo[b]thiophene (147 mg) in THF (3.0 mL) was treated sequentially with a solution of ammonium formate (25% in H2O, 2.0 mL) and 10% palladium on carbon (100 mg) at ambient temperature. The resulting mixture was stirred at ambient temperature under argon for 3 h before it was filtered through diatonaceous earth followed by rinsing with dichloromethane and methanol. The filtrate was extracted with dichloromethane (20 mL×3) from water (30 mL). The combined organic layers were dried with sodium sulfate and concentrated under reduced pressure. Chromatography with Et3N:EtOAc (0-5%) afforded the product (108 mg).