Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=O)[CH2:3]1.C(N)CN.[N+:16]([CH3:19])([O-:18])=[O:17]>>[N+:16]([CH2:19][C:4]1[CH2:3][C:2]([CH3:11])([CH3:1])[CH2:7][C:6]([CH3:9])([CH3:8])[CH:5]=1)([O-:18])=[O:17]
Reactant: C[N+](=O)[O-]
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Solvent: NCCN
Product: CC1(C)C=C(C[N+](=O)[O-])CC(C)(C)C1
Yield: 61 %

Procedure:
A solution of 3,3,5,5-tetramethylcyclohexanone (2-13) (1.54 g, 10 mmol) and ethylenediamine (60 mg) in nitromethane (45 ml) was refluxed in argon atmosphere for 25 h. Excess of nitromethane was then removed in vacuo and the residue was purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate (6:1). 1.2 g (61%) of 6 was obtained as an oil.
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].CO[C:22](OC)([CH3:24])[CH3:23].CC(C)=O>CCCCCC>[CH3:23][C:22]1([CH3:24])[O:3][CH:2]2[CH:4]([CH:6]([CH2:7][OH:8])[O:9][CH:1]2[N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:5]1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: COC(C)(C)OC
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CC1(C)OC2C(CO)OC(n3cnc4c(N)ncnc43)C2O1
Reaction time: 3 h

Procedure:
A solution of adenosine (43 g) and 2,2-dimethoxypropane (5 eq.) in acetone (75 eq.) was treated with D-camphorsulphonic acid (1 eq) at and the resulting reaction was allowed to stir for 3 hr. The reaction mixture was concentrated in vacuo and diluted with a mixture of saturated aqueous NaHCO3 (250 mL) and ethyl acetate (250 mL). The resulting solution was transferred to a separatory funnel and the organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to provide a solid residue. The solid residue was suspended in hexane, filtered, washed with hexane and dried to provide 2′,3′-Isopropylidene-adenosine (43 g). 1H NMR (DMSO-d6, 300 MHz): δ 4.12-4.17 (m, 1H), 4.22-4.26 (m, 1H), 4.59 (d, J=4.8 Hz, 1H), 4.74-4.85 (m, 2H), 5.49-5.52 (m, 1H), 5.51 (d, J=5.1 Hz, 1H), 5.84 (d, J=5.1 Hz, 1H), 7.85 (s, 2H), 8.33 (s, 1H). MS m/z 347.11 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([O:21][CH3:22])=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.[CH3:23][N:24](C)C=O>[Pd].C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:7]1[C:6]2[CH:20]=[C:2]([C:23]#[N:24])[C:3]([O:21][CH3:22])=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][N:8]=1
Reactant: COc1cc2c(cc1Br)C(c1ccccc1Cl)=NCC(=O)N2
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1C#N)C(c1ccccc1Cl)=NCC(=O)N2
Temperature: 110 °C

Procedure:
5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-methoxy-2H-1,4-benzodiazepin-2-one (Ib) was prepared from 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-8-methoxy-2H-1,4-benzodiazepin-2-one (Id) by reaction with zinc cyanide in the presence of a palladium catalyst (tetrakistriphenyl phosphine palladium) according to conditions similar to those described by Tschaen et al., Synthetic Communications, 24:887-90 (1994). A mixture of 0.9491 g (0.0025 mole) of 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-8-methoxy-2H-1,4-benzodiazepin-2-one (Id), 0.176 g (0.0015 mole) of zinc cyanide, 4 mL of dimethylformamide and 0.289 g (0.00025 mole) of tetrakistriphenyl phosphine palladium was heated at 110° C. under an argon atmosphere for 24 hours. The mixture was then cooled, taken up in ethyl acetate and washed with 0.2 M sodium carbonate solution. The aqueous phase was reextracted with ethyl acetate, and the ethyl acetate layers washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate-hexane (4:1) to give 0.620 g of 5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-methoxy-2H-1,4-benzodiazepin-2-one (Ib). MH+/Z=326.
Reaction SMILES: C[O:2][C:3](=[O:35])[C@H:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15]([C:17]2[C:18]([O:24][C:25]3[CH:33]=[CH:32][C:28]4[O:29][CH2:30][O:31][C:27]=4[CH:26]=3)=[N:19][CH:20]=[C:21]([F:23])[CH:22]=2)=[O:16])=[C:9]([F:34])[CH:8]=1)[CH3:5].COC(=O)COC1C=CC(CNC(C2C(OC3C=CC4OCOC=4C=3)=NC=CC=2)=O)=C(F)C=1>>[O:29]1[C:28]2[CH:32]=[CH:33][C:25]([O:24][C:18]3[C:17]([C:15]([NH:14][CH2:13][C:10]4[CH:11]=[CH:12][C:7]([O:6][C@H:4]([CH3:5])[C:3]([OH:35])=[O:2])=[CH:8][C:9]=4[F:34])=[O:16])=[CH:22][C:21]([F:23])=[CH:20][N:19]=3)=[CH:26][C:27]=2[O:31][CH2:30]1
Reactant: COC(=O)[C@@H](C)Oc1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc3c(c2)OCO3)c(F)c1
Agent: COC(=O)COc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1
Product: C[C@@H](Oc1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc3c(c2)OCO3)c(F)c1)C(=O)O

Procedure:
The compound of Formula (5.5.12) was prepared in a manner analogous to that described in Example 1, substituting (R)-2-[4-({[2-(benzo[1,3]dioxol-5-yloxy)-5-fluoro-pyridine- 3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid methyl ester for the corresponding [4-({[2-(benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-acetic acid methyl ester material.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C2[N:32]=NN(O)C2=CC=1.O.C(Cl)CCl.[NH4+].[OH-]>CN(C=O)C.CCOC(C)=O.O>[NH2:32][C:10](=[O:12])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccncc2)cc1)C(=O)O
Reactant: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccncc2)cc1)C(N)=O
Reaction time: 18 h
Yield: 61.9 %

Procedure:
A solution of (R)-2-(tert-butoxycarbonylamino)-3-(4-(pyridin-4-yl)phenyl)propanoic acid (141 mg, 0.412 mmol), HOBt monohydrate (100 mg, 0.653 mmol) and EDC (120 mg, 0.625 mmol) in DMF (2 mL) was stirred at room temperature for 45 min, conc. NH4OH (0.300 mL, ca. 4.20 mmol) was added. The mixture was stirred for 18 h. Water and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give (R)-tert-butyl 1-amino-1-oxo-3-(4-(pyridin-4-yl)phenyl)propan-2-ylcarbamate (87 mg).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].S1C=CN=C1N.[CH3:21][C:22]1[N:23]=[C:24]([NH:27][C:28]2[N:33]=[CH:32][C:31]([S:34]CCC(OC)=O)=[CH:30][C:29]=2[O:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[S:25][CH:26]=1.CC([O-])(C)C.[K+].CS(O[CH:59]([CH:61]1[CH2:66][CH2:65][N:64](C(OC(C)(C)C)=O)[CH2:63][CH2:62]1)[CH3:60])(=O)=O.[NH4+].[Cl-]>C1COCC1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[CH3:21][C:22]1[N:23]=[C:24]([NH:27][C:28]2[C:29]([O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:30][C:31]([S:34][CH:59]([CH:61]3[CH2:62][CH2:63][NH:64][CH2:65][CH2:66]3)[CH3:60])=[CH:32][N:33]=2)[S:25][CH:26]=1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(Oc2ccccc2)c1
Reactant: CC(OS(C)(=O)=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)[O-]
Agent: Nc1nccs1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1csc(Nc2ncc(SC(C)C3CCNCC3)cc2Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.01 h
Yield: 14.8 %

Procedure:
Preparation of 4-methyl-N-(3-phenoxy-5-(1-piperidin-4-yl)ethylthio)pyridin-2-yl)thiazol-2-amine bis(2,2,2-trifluoroacetate): A nitrogen purged vial was charged with methyl 3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate (0.150 g, 0.374 mmol) and THF (5 mL). Potassium 2-methylpropan-2-olate (0.934 mL, 0.934 mmol) was added and stirred at ambient temperature for 30 seconds. Tert-butyl 4-(1-(methylsulfonyloxy)ethyl)piperidine-1-carboxylate (0.144 g, 0.467 mmol) was added and stirred at ambient temperature under nitrogen for 20 hours. Saturated NH4Cl was added and extracted with CH2Cl2. The organic layer was dried, filtered, and concentrated. The residue was dissolved in CH2Cl2 (5 mL) and TFA (2 mL) was added and stirred for 1 hour. The reaction was concentrated and purified by reverse phase chromatography (with 0.1% TFA) to provide the title compound (0.0363 g, 14.8% yield). 1H NMR (d6-DMSO) δ 8.57 (bs, 1H), 8.23 (bs, 1H), 8.18 (d, 1H), 7.42 (t, 2H), 7.34 (d, 1H), 7.19 (t, 1H), 7.07 (d, 2H), 6.64 (s, 1H), 3.26 (d, 2H), 3.13 (m, 1H), 2.80 (m, 2H), 2.24 (s, 3H), 1.87 (m, 2H), 1.67 (m, 1H), 1.47 (m, 2H), 1.15 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:12])[C:7]=1[CH2:8][C:9]([OH:11])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]([CH2:36][CH2:37][CH3:38])[CH2:34][NH2:35])[CH:30]=[CH:31][CH:32]=1>C1COCC1>[Cl:12][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]([NH:35][CH2:34][CH:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH3:25])[CH:28]=1)[CH2:36][CH2:37][CH3:38])=[O:11]
Reactant: CCCC(CN)c1cccc(OC)c1
Reactant: O=C(O)Cc1c(Cl)cncc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCC(CNC(=O)Cc1c(Cl)cncc1Cl)c1cccc(OC)c1
Yield: 97 %

Procedure:
By working in a way similar to that described in example 4 but using (3,5-dichloro-pyridin-4-yl)-acetic acid (2.06 g, 10 mmoles), carbonyldiimidazole (1.78 g, 11 mmoles), THF (30 ml) and 2-(3-methoxy-phenyl)-pentylamine (1.93 g 10 mmoles), obtained as described in example 17, 3.7 g of the title compound were obtained (yield: 97%), m.p.: 97-98° C.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:21][CH2:22][CH2:23][Si:24]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]>O1CCCC1>[C:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][O:17][CH2:21][CH2:22][CH2:23][Si:24]([O:25][CH2:26][CH3:27])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1ccc(CO)cc1)c1ccccc1
Reactant: CCO[Si](CCCI)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCO[Si](CCCOCc1ccc(OC(=O)c2ccccc2)cc1)(OCC)OCC
Yield: 30.1 %

Procedure:
4-(Hydroxymethyl)phenyl benzoate (1 g, 4.39 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran and cooled in an ice bath. A suspension of sodium hydride (60% suspension, 175 mg, 4.39 mmol) in 5 mL of anhydrous tetrahydrofuran was added dropwise under stirring. The resultant mixture was stirred at 0° C. for 1 hour. (3-Iodopropyl)triethoxysilane (1.46 g, 4.39 mmol) was added and the mixture was refluxed for 36 hours. The reaction crude was filtered, the solvent was removed under reduced pressure, and the resultant oil was chromatographed (hexane/ethyl acetate 8:2) thus affording 570 mg (1.32 mmol, yield=30%) of the title compound (HPLC purity=99.2%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([NH:8][CH3:9])[CH:7]=1.[NH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([OH:21])=[CH:16][C:15]=1[CH3:22].CC(C)([O-])C.[K+].O>CN(C)C(=O)C>[NH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([O:21][C:2]2[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([NH:8][CH3:9])[CH:7]=2)=[CH:16][C:15]=1[CH3:22]
Reactant: CNc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Cc1cc(O)cc(C)c1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CNc1cc(Oc2cc(C)c(N)c(C)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a solution of N-(5-chloro-2-nitrophenyl)-N-methylamine (4.0 g) in N,N-dimethylacetamide (56 ml) were added 4-amino-3,5-dimethylphenol (2.9 g) and potassium t-butoxide (2.9 g) with stirring under ice-cooling, and the resulting mixture was stirred at 75-80° C. for 1 hour. After stirring, water (74 ml) was added to the reaction mixture, and the resulting mixture was cooled gradually to room temperature. The crystals precipitated were collected by filtration and dried in vacuo to afford the title compound (4.9 g, yield: 80%) as a yellow crystalline solid.
Reaction SMILES: [C@@H:1]12[O:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[C:8](OCC)=[O:9].[BH4-].[Na+]>C(O)C>[C@@H:1]12[O:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[CH2:8][OH:9]
Reactant: CCOC(=O)[C@@H]1C[C@@H]2CC[C@H]1O2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC[C@@H]1C[C@@H]2CC[C@H]1O2
Temperature: 0 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
(1R,2R,4S)-ethyl 7-oxabicyclo[2.2.1]heptane-2-carboxylate (3.63 g, 21.33 mmol) was dissolved in ethanol (107 ml) and cooled to 0° C. Sodium borohydride (4.84 g, 128 mmol) was added portionwise and the reaction was warmed to room temperature and stirred overnight. The reaction was quenched with saturated NH4Cl solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 40 g, gradient elution 0-100% EtOAc:Heptane) to afford (1R,2S,4S)-7-oxabicyclo[2.2.1]heptan-2-ylmethanol (0.973 g, 7.59 mmol, 35.6% yield) as a clear colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ=4.57 (t, J=5.0 Hz, 1H), 4.49 (d, J=5.1 Hz, 1H), 3.78 (dd, J=6.8, 10.7 Hz, 1H), 3.57 (dd, J=9.3, 10.6 Hz, 1H), 3.51-3.42 (m, 2H), 2.44-2.31 (m, 1H), 2.00-1.92 (m, 1H), 1.85-1.79 (m, 1H), 1.76-1.69 (m, 2H), 1.60 (dd, J=8.6, 12.1 Hz, 1H), 1.49-1.43 (m, 2H), 1.39-1.31 (m, 1H), 1.29-1.24 (m, 1H), 0.94 (dd, J=5.1, 11.9 Hz, 1H)
Reaction SMILES: Cl[CH:2]1[C:11]2[C:6](=[C:7]([O:12][C:13]3[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=3)[CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.[C:23]1([O-:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[CH3:22][O:21][C:15]1[CH:16]=[C:17]([O:19][CH3:20])[N:18]=[C:13]([O:12][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[C:4](=[O:5])[O:3][CH:2]3[O:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:14]=1
Reactant: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3Cl)n1
Reactant: [O-]c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3Oc2ccccc2)n1
Reaction time: 19 h

Procedure:
A mixture of 1.4 g of 3-chloro-7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-phthalide (see Example 85) and 0.63 g of potassium phenolate is heated at reflux temperature in the presence of a spatula tip of 18-crown-6 in 15 ml of acetonitrile. After 19 hours, the reaction mixture is filtered through Celite® and concentrated by evaporation, and the crude product is purified by column chromatography (eluant 25% ethyl acetate/n-hexane) to yield 7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-3-phenoxy-phthalide in the form of white crystals, m.p. 155°-157° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[F:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.O>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[F:16][C:17]1[CH:24]=[CH:23][C:20]([C:21](=[NH:22])[NH:9][C:8]2[CH:10]=[CH:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:19][CH:18]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CS(=O)(=O)c1ccc(NC(=N)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline (3.53 g, 20.2 mmol) in toluene (100 mL), trimethylaluminum (15.2 ml, 2M solution in toluene, 30.2 mmol) was added over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. A solution of 4-fluorobenzonitrile (5 g, 40.3 mmol) in toluene (100 mL) was added over 10 minutes and the reaction mixture heated to 80–85° C. After 20 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol (2/1). The combined filtrates were concentrated in vacuo and the resulting yellowish solid stirred with a mixture of hexane/ether (2/1, 1000 mL). The intermediate was filtered and concentrated. The pale yellow solid 4-fluoro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (5.25 g, 87%) was used in the next reaction without further purification: mp (DSC) 206.2° C. Anal. Calc'd for C14H13N2FSO3.1.25 H2O: C, 53.41; H, 4.91; N, 8.90. Found: C, 53.08; H, 4.50; N, 8.61.
Reaction SMILES: [CH3:1][C:2]1[CH:7]([OH:8])[C:6](=[O:9])[CH:5]=[CH:4][N:3]=1.Br[CH2:11]Br.[H-].[Na+]>CS(C)=O.[Cl-].[Na+].O>[CH3:1][C:2]1[C:7]2[O:8][CH2:11][O:9][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: BrCBr
Reactant: CC1=NC=CC(=O)C1O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nccc2c1OCO2
Reaction time: 72 h

Procedure:
2-Methyl-3-hydroxy-4-pyridone (1.25 g, 10 mmol) was dissolved in dry DMSO (20 ml). Dibromomethane (3.5 g, 20 mmol) was added followed by sodium hydride (1 g, >20 mmol, 50-60% in oil). The mixture was left at ambient temperature under stirring for 3 days whereupon it was poured into brine (50 ml). The water-DMSO solution was extracted with methylene chloride (3×50 ml) and the collected extracts were used directly in the next step. A sample for NMR analysis was withdrawn.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:12][C:11]([C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[N:10]1.ClC1C=CC=C(C(OO)=[O:43])C=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:27])=[O:43])=[CH:22][CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:12][C:11]([C:28]([F:33])([F:34])[C:29]([F:32])([F:30])[F:31])=[N:10]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(Cl)cc3Cl)c2)cc1
Product: CS(=O)c1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(Cl)cc3Cl)c2)cc1

Procedure:
The compound of Example 42 was prepared in accordance with the same procedures as in Example 37, using the compound prepared in Example 25 and meta-chloroperbenzoic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:13])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C>C(O)C.[Pd]>[F:12][C:8]1[C:7]([F:13])=[C:6]2[C:11]([CH:2]=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1cnc2c(F)c(F)ccc2c1Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cnc2c(F)c(F)ccc2c1
Yield: 92 %

Procedure:
A solution of 21.9 g of ethyl 4-chloro-7,8-difluoroquinoline-3-carboxylate in 7300 cm3 of ethanol in the presence of 8.8 g of triethylamine and 2.2 g of 5% palladium on carbon was hydrogenated at atmospheric pressure for 1 hour. The solid residue obtained was recrystallized from 300 cm3 of hexane. 17.6 g of ethyl 7,8-difluoroquinoline-3-carboxylate was obtained in the form of white crystals, which melted at 118° C.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH:13][CH:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9]([N:16]1[CH2:17][CH2:18][CH2:19][CH:14]([OH:13])[CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC1CCCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCCC(O)C1
Reaction time: 3 h

Procedure:
Benzylchloroformate (15 ml) was added dropwise to a stirred suspension of 3-hydroxypiperidine hydrochloride (13,7 g) and triethylamine (30 ml) in dichloromethane (150 ml),maintaining the temperature below 15° C. throughout. Stirring was continued for three hours,then the solution was washed with water (4×100 ml) and saturated aqueous sodium chloride (100 ml),dried (PS paper) and concentrated. The residual oil was dissolved in ether (300 ml),washed with dilute hydrochloric acid (2×100 ml) and water (100 ml),dried (PS paper) and concentrated. The residue was purified by flash column chromatography,eluting first with hexane/ether (1: 1) then ether to give 1-benzyloxycarbonylpiperidine-3-ol (7.1 g) as a colourless oil. NMR (d6DMSO) δ1.2-1.4(2H,m); 1.6-1.9(1 H,m +1 H,m); 2.8(1H,br s); 2.95(1 H,m); 3.45(1 H,m); 3.65(1H,brd); 3.8(1H,dd); 4.85(1H,d); 5.1(2H,s); 7.3(5H,m); m/e 236(M+H)+.
Reaction SMILES: [Cl-:1].[C:2]([CH2:5][O:6][C:7](=[O:30])[CH2:8][C:9]1[CH:10]=[C:11]([S+:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:19]3[CH:26]=[CH:27][CH:28]=[CH:29][C:18]2=3)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])([OH:4])=[O:3].Br[CH2:32][C:33]([O:35][C:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([CH3:38])[CH3:37])=[O:34].[I-].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl-:1].[CH3:16][O:15][C:14]1[CH:13]=[CH:12][C:11]([S+:17]2[C:18]3[CH:29]=[CH:28][CH:27]=[CH:26][C:19]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]2=3)=[CH:10][C:9]=1[CH2:8][C:7](=[O:30])[O:6][CH2:5][C:2](=[O:4])[O:3][CH2:32][C:33](=[O:34])[O:35][C:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([CH3:37])[CH3:38]
Reactant: COc1ccc(-[s+]2c3ccccc3c3ccccc32)cc1CC(=O)OCC(=O)O
Reactant: CC(C)(OC(=O)CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(-[s+]2c3ccccc3c3ccccc32)cc1CC(=O)OCC(=O)OCC(=O)OC(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5-(3-(2-(carboxymethoxy)-2-oxoethyl)-4-methoxyphenyl)dibenzothiophenium chloride (25 g, 59.2 mmol), 2-phenylpropan-2-yl 2-bromoacetate (15.2 g, 59.2 mmol), sodium iodide (17.7 g, 0.118 mmol), and cesium carbonate (38.4 g, 0.118 mmol) are dissolved in DMF (200 mL) and stirred at 25° C. for 4 h. The reaction mixture is quenched with water (500 mL), extracted with DCM (2×200 mL), the combined organic layers washed with water (4×200 mL), concentrated to a viscous oil and precipitated from MTBE (1 L) to afford the title compound as a white solid.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH:9]([CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]1)[CH2:8][CH2:7]2.CI.[CH3:30]CN(CC)CC.Cl>C1COCC1>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[C:9]([CH3:30])([CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]1)[CH2:8][CH2:7]2
Reactant: CCN(CC)CC
Reactant: COc1ccc2c(c1)CCC(CN1CCC(c3ccccc3)CC1)C2=O
Agent: Cl
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC(C)(CN1CCC(c3ccccc3)CC1)C2=O
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of the title compound of Example 1 (379 mg, 1.084 mmol, free base) in THF (10 mL) at -78° C. under nitrogen with stirring was added a solution of KN(SiMe3)2 (0.5 M in toluene, 2.39 mL, 1.19 mmol). The reaction mixture was stirred at -78° C. for 5 minutes followed by the addition of methyl iodide (0.223 mL, 3.58 mmol). The mixture was stirred at -78° C. for another 15 minutes, then kept at -16° C. for 0.5 hours followed by the addition of Et3N (0.832 mL, 5.96 mmol). The mixture was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to afford a thick gummy residue. This was converted to its hydrochloride by treatment with hydrochloric to afford the title compound as a white solid, mp 185-186° C.
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[C:1]([NH:9][CH:10]([C:11]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)=[O:12])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCC(=O)c1ccco1)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)c1ccccc1)C(=O)c1ccco1
Yield: 72.7 %

Procedure:
4.0 g of N-benzoyl-(2-furylcarbonyl)methylamine, 0.8 g of 61% sodium hydride and 3.2 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(2). 4.0 g of ethyl 3-benzoylamino-3-(2-furylcarbonyl)propionate are thereby obtained. Yield: 72.7%