Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([OH:16])=O)=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:17])[CH:3]=1.[CH:18]1([CH:21]([NH2:23])C)[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][NH:23][C:14]([C:10]2[S:9][C:8]([N:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][C:4]3=[O:17])=[N:12][C:11]=2[CH3:13])=[O:16])[CH2:20][CH2:19]1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)O
Reactant: CC(N)C1CC1
Product: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCC1CC1
Yield: 76 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with cyclopropylethanamine, the title compound was obtained as a colorless solid in 76% yield: mp 240-242° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 11.56 (br s, 1H), 8.58 (d, J=8.0 Hz, 1H), 8.26 (t, J=5.6 Hz, 1H), 6.25 (dd, J=8.0, 2.5 Hz, 1H), 5.81 (d, J=2.5 Hz, 1H), 3.05 (m, 2H), 2.51 (s, 3H), 1.05-0.92 (m, 1H), 0.43-0.36 (m, 2H), 0.20-0.15 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 167.9, 161.8, 161.6, 153.9, 149.7, 132.6, 124.0, 104.3, 98.0, 43.9, 17.4, 11.4, 3.7; MS (ES+) m/z: 306.2 (M+1).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][C:11]([N:16]=[C:17]=[S:18])=[CH:10][N:9]=2)[CH:7]=1>>[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[N:9]=[CH:10][C:11]([NH:16][C:17]([NH2:1])=[S:18])=[CH:12][C:13]=2[O:14][CH3:15])[CH:7]=1
Reactant: COc1cc(N=C=S)cnc1-n1cnc(Cl)c1
Reactant: N
Product: COc1cc(NC(N)=S)cnc1-n1cnc(Cl)c1
Reaction time: 16 h
Yield: 84.2 %

Procedure:
Step O (4): Methanolic ammonia (2.0 M, 25 mL, 50 mmol) was added to a flask charged with 2-(4-chloro-1H-imidazol-1-yl)-5-isothiocyanato-3-methoxypyridine (2.5 g, 9.37 mmol). After 16 h, the reaction mixture was concentrated in vacuo to afford 1-(6-(4-chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-yl)thiourea (2.24 g, 7.89 mmol, 84% yield). LC-MS (M+H)+ 283.9. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.24 (d, J=1.83 Hz, 1 H) 8.12 (d, J=2.14 Hz, 1 H) 8.09 (d, J=2.14 Hz, 1 H) 7.79-7.82 (m, 1 H) 3.90-3.95 (m, 3 H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.O>COCCO>[C:4]([C:3]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:2]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: C1CNCCN1
Solvent: O
Solvent: COCCO
Product: N#Cc1cc([N+](=O)[O-])ccc1N1CCNCC1
Temperature: 60 °C
Yield: 99.8 %

Procedure:
A mixture of 2-chloro-5-nitrobenzonitrile (1 g) and piperazine (2.12 g) in ethylene glycol monomethyl ether (5 mL) was heated at 60° C. for 30 minutes. After cooling to room temperature, H2O was added (50 mL) and the solution extracted with CH2Cl2 (3×25 mL). The combined organic layers were washed with H2O, dried over Na2SO4 and evaporated to dryness to give 1.27 g (99%) of the desired compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1>CN(C)C=O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCCCCBr
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCCCCCCBr

Procedure:
A solution of 8-bromooctan-1-ol (2.15 g, 10.3 mmol), t-butyldimethylsilyl chloride (1.7 g, 11.3 mmol) and imidazole (1.7 g, 25.0 mmol) in dimethylformamide (4 ml) was stirred at room temperature under argon for 48 hours. The reaction was quenched by the addition of water and extracted with hexane. The organic layer was washed with 5% hydrochloric acid, 5% sodium bicarbonate, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a colorless oil. Purification by flash chromatography (silica, 0 to 2% ethyl ether/hexane) gave the desired protected alcohol.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[CH:15]=O)(=[O:3])[CH3:2].Cl.[NH2:18][OH:19]>C(OCC)(=O)C>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[CH:15]=[N:18][OH:19])(=[O:3])[CH3:2]
Reactant: NO
Reactant: COC(=O)c1ccc(NC(C)=O)c(C=O)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC(C)=O)c(C=NO)c1
Yield: 52.9 %

Procedure:
A mixture of methyl 4-acetylamino-3-formylbenzoate (Gassman, P. G.; Drews, H. R. J. Am. Chem. Soc. 1978, 100, 7600-7610) (0.442 g, 0.002 mol) and hydroxylamine hydrochloride (0.174 g, 0.0025 mol) in ethyl acetate (10 mL) was heated at reflux for 16 h. White precipitate formed which was removed by filtration and the filtrate was concentrated to dryness. The residue was recrystallized from ethyl acetate-hexane to give 0.25 g (53%) of methyl 4-acetylamino-3-[(N-hydroxylimino)methyl]benzoate as a pale yellow powder, mp 200°-203° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([O:18][CH3:19])[C:15]=1[O:16][CH3:17])[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12].O1CCCC1.C([Li])(CC)C.[Si:30]([O:37][CH2:38][CH2:39][CH2:40]I)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([O:18][CH3:19])[C:15]=1[O:16][CH3:17])[CH2:6][N:7]1[CH2:11][CH2:10][CH:9]([CH2:40][CH2:39][CH2:38][O:37][Si:30]([C:33]([CH3:34])([CH3:36])[CH3:35])([CH3:31])[CH3:32])[C:8]1=[O:12]
Reactant: COc1cc(CN2CCCC2=O)cc(OC)c1OC
Reactant: CC(C)(C)[Si](C)(C)OCCCI
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(CN2CCC(CCCO[Si](C)(C)C(C)(C)C)C2=O)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzyl)-2-oxopyrrolidine (0.84 g, 3.16 mmol) and tetrahydrofuran (10 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of sec-butyl lithium (2.56 mL, 1.3 M in hexane, 3.33 mmol). After 30 minutes, add 3-(t-butyldimethylsilyloxy)propyl iodide (1.0 g, 3.33 mmol). After the addition is complete, warm to ambient temperature. After 2 hours, add water and extract three times with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5([C:28]#[N:29])[CH2:27][CH2:26]5)[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:31]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38](O)=[O:39].C(Cl)(=O)C(Cl)=O.O1CCCC1>CN(C)C=O.CN1CCCC1=O>[C:28]([C:25]1([C:21]2[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=2)[C:18]([NH:17][C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[O:10][C:7]2[CH:8]=[CH:9][C:4]3[N:5]([CH:31]=[C:2]([NH:1][C:38]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=4)=[O:39])[N:3]=3)[N:6]=2)=[O:30])[CH2:27][CH2:26]1)#[N:29]
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)cn5n4)c3)c2)CC1
Reactant: O=C(O)c1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)c6ccccn6)cn5n4)c3)c2)CC1
Yield: 66.4 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (150 mg, 0.365 mmol), pyridine-2-carboxylic acid (54 mg, 0.438 mmol), oxalyl chloride (63 μL), N,N-dimethylformamide (1 drop), tetrahydrofuran (3 mL) and N-methylpyrrolidone (5 mL) as starting materials and in the same manner as in Example 412, the title compound (125 mg, 67%) was obtained as a white powder.
Reaction SMILES: C([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[O:7]C1(C)C)(=O)CC.Cl>O>[CH3:21][S:18]([C:15]1[CH:14]=[CH:13][C:12]([C@@H:8]([OH:7])[C@H:9]([NH2:5])[CH2:10][F:11])=[CH:17][CH:16]=1)(=[O:20])=[O:19]
Reactant: CCC(=O)N1[C@H](CF)[C@@H](c2ccc(S(C)(=O)=O)cc2)OC1(C)C
Agent: Cl
Solvent: O
Product: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CF)cc1

Procedure:
(4S,5R)-3-acetyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound IX: R1 is methylsulfonyl; R2, R3 and R4 are methyl) (50.0 g, 0.1518 moles) hydrolyses in water (300 mL) containing 20% hydrochloric acid at 90 to 100° C. over about 1 hour. Washing with methylene chloride (200 mL), adjusting the pH to greater than 12 by addition of sodium hydroxide and extraction with methylene chloride (300 mL) yields (1R,2S)-1-[4-(methylsulfonyl)phenyl]-2-amino-3-fluoro-1-propanol (Compound Xa) in solution. Methanol (100 mL) replaces methylene chloride which distills off. Addition of methyl dichloroacetate (65.1 g, 0.4554 moles) and triethylamine (16.1 g, 0.1594 moles) with agitation for 12-16 hours at 20-25° C. then addition of water (175 mL) and toluene (100 mL) precipitates the crude product. Filtration, washing with water (100 mL) and toluene (174 mL) then dissolution in water (115 mL) and isopropanol (115 mL) at reflux, cooling to 20-25° C., filtration of the solids, washing with 1 to 1 water/isopropanol (50 mL) then drying gives pure (1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propanol (Florfenicol).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:13][O:14][CH2:15][P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH:10]([CH2:13][O:14][CH2:15][P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][O:12][S:37]([C:34]1[CH:35]=[CH:36][C:31]([CH3:41])=[CH:32][CH:33]=1)(=[O:39])=[O:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(COCC(CO)COCc1ccccc1)OCC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(COCC(COCc1ccccc1)COS(=O)(=O)c1ccc(C)cc1)OCC
Temperature: 25 °C
Reaction time: 14 h
Yield: 81.9 %

Procedure:
A solution of 2-benzyloxymethyl-3-diethylphosphonomethoxy-1-propanol (0.25 g, 0.72 mmol) in 5 mL of CH2Cl2 was cooled to 0° C. and treated with triethylamine (0.22 g, 2.16 mmol). A solution of p-toluenesulfonyl chloride (0.151 g, 0.79 mmol) in 2 mL of CH2Cl2 was added next and the reaction mixture allowed to warm gradually to room temperature. After 14 hours at room temperature, the mixture was diluted with CH2Cl2 and washed with two portions of 10% aqueous HCl and saturated sodium chloride solution, dried over MgSO4, filtered, and concentrated to give an orange oil. Purification by column chromatography on silica gel (1-3% ethanol in ethyl acetate) provided 0.295 g of 2-benzyloxymethyl-3-diethylphosphonomethoxy-1-(p-toluenesulfonyloxy)propane as a pale yellow oil.
Reaction SMILES: C(O[C:4](=[O:21])[CH2:5][N:6]1[CH2:10][C:9](=[CH2:11])[C@@H:8]([NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH2:7]1)C.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]2=[O:35])=[CH:25][C:24]=1[F:36]>>[F:36][C:24]1[CH:25]=[C:26]([N:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]2=[O:35])[CH:27]=[CH:28][C:23]=1[NH:22][C:4]([CH2:5][N:6]1[CH2:10][C:9](=[CH2:11])[C@@H:8]([NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH2:7]1)=[O:21]
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Reactant: C=C1CN(CC(=O)OCC)C[C@@H]1NC(=O)c1ccc(Cl)s1
Product: C=C1CN(CC(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1

Procedure:
39.4 Using general procedure F {(R)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methylene-pyrrolidin-1-yl}-acetic acid ethyl ester was reacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (CAS 536747-52-1, prepared according to WO 2003045912) to give 5-chloro-thiophene-2-carboxylic acid ((R)-1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-4-methylene-pyrrolidin-3-yl)-amide. Yellow solid. MS 487.2 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23]([OH:25])=O)[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.CN.C[CH2:38][N:39]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](=[O:25])[NH:39][CH3:38])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)NC
Yield: 77 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained by the method described in Example (68c) (100 mg, 0.20 mmol), methylamine hydrochloride (45 mg, 0.67 mmol), WSC hydrochloride (117 mg, 0.61 mmol) and HOBT (23 mg, 0.17 mmol), to obtain 78.6 mg of the title compound as a white solid (77%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH:28]([CH3:30])[CH3:29])[C@H:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:15]([CH2:25][CH2:26][OH:27])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]([Si:35]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)Cl)([CH3:34])([CH3:33])[CH3:32].N1C=CN=C1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]([CH:28]([CH3:30])[CH3:29])[C@H:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[C@@H:15]([CH2:25][CH2:26][O:27][Si:35]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N(C(=O)OCc1ccccc1)[C@@H]1CC[C@H](CCO)N(C(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)N(C(=O)OCc1ccccc1)[C@@H]1CC[C@H](CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
To a solution of tert-butyl (2R,5R)-5-[[(benzyloxy)carbonyl](isopropyl)amino]-2-(hydroxy-ethyl)piperidine-1-carboxylate (2.93 g) in methylene chloride (35 ml) were added tert-butyl diphenyl-chlorosilane (2.30 g) and imidazole (569 mg), and the mixture was stirred at room temperature for 4 hours. To the mixture was added a saturated aqueous sodium hydrogen carbonate solution (10 ml), and the mixture was extracted with chloroform (100 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/ethyl acetate=12/1) to give the title compound (4.42 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[OH:14])[N:10]=[C:9]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:8]=[C:7]2[N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH3:38])[CH:34]=3)[N:29]([CH3:39])[C:28]2=[O:40])[CH2:23][CH2:22]1)[CH3:2].[CH2:41](I)[CH2:42][CH3:43]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:41][CH2:42][CH3:43])[N:10]=[C:9]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:8]=[C:7]2[N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH3:38])[CH:34]=3)[N:29]([CH3:39])[C:28]2=[O:40])[CH2:23][CH2:22]1)[CH3:2]
Reactant: CCCI
Reactant: CCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1O
Product: CCCOc1cc2nc(N3CCOCC3)nc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OCC
Yield: 46 %

Procedure:
The same procedure as in Example 48 was repeated, using 335 mg (0.61 mmol) of Compound 47 obtained in Example 47, except that propyl iodide was used in place of methyl iodide, to give 164 mg (yield: 46%) of Compound 49 as white crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:25][CH3:26])[C:15]([NH:17][C:18]([CH2:22][O:23][CH3:24])([CH3:21])[CH2:19][OH:20])=[O:16])=[CH:8][CH:7]=2)#[CH:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:25][CH3:26])[C:15]([NH:17][C:18]([CH2:22][O:23][CH3:24])([CH3:21])[CH:19]=[O:20])=[O:16])=[CH:8][CH:7]=2)#[CH:2]
Reactant: C#Cc1cnc2ccc(OC(SC)C(=O)NC(C)(CO)COC)cc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C#Cc1cnc2ccc(OC(SC)C(=O)NC(C)(C=O)COC)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
A solution of 2-(3-Ethynyl-quinolin-6-yloxy)-N-(2-hydroxy-1-methoxymethyl-1-methyl-ethyl)-2-methylsulfanyl-acetamide (200 mg) in dry CH2Cl2 (15 ml) was treated with Dess-Martin periodinane (295 mg). The mixture was stirred at room temperature during 1 h then poured on sat aq NaHCO3. After separation the water phase was washed twice with CH2Cl2 The combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated. The crude residue was purified by column chromatography (cyclohexane/ethyl acetate 1:1) to give (3-Ethynyl-quinolin-6-yloxy)-N-(1-methoxymethyl-1-methyl-2-oxo-ethyl)-2-methylsulfanyl-acetamide (120 mg) as yellowish oil as a mixture of diastereoisomers.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:11]1[CH:12]=[C:13]([C:22]([N:24]2[CH2:27][CH:26]([OH:28])[CH2:25]2)=O)[CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])([CH3:10])([CH3:9])[CH3:8]>O1CCCC1>[C:18]([C:15]1[CH:14]=[C:13]([CH:12]=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:16]=1[OH:17])[CH2:22][N:24]1[CH2:27][CH:26]([OH:28])[CH2:25]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1cc(C(=O)N2CC(O)C2)cc(C(C)(C)C)c1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CN2CC(O)C2)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A suspension of lithium aluminium hydride (1,35 g, 36,7 mmoles) in anhydrous tetrahydrofuran (60 ml) was cooled to 0° C., and a solution of (3,5-di-tert-butyl-4-hydroxy-phenyl)-(3-hydroxy-azetidin-1-yl)-methanone (1,78 g, 6,12 mmoles) in anhydrous tetrahydrofuran (40 ml) was added. The cooling bath was removed, the mixture was stirred at room temperature overnight and then heated to reflux for 5 hours. The mixture was then cooled to 0° C. and the excess of the reducing agent was eliminated by the addition of a saturated solution of ammonium chloride. The mixture is filtered and the filtrate was evaporated to dryness by use of a rotavapor. The residue was dissolved in diethyl ether, the resulting solution washed with water, dried over sodium sulfate and evaporated to dryness with a rotavapor. The resulting crude solid was crystallized from chloroform/petrol ether to give 1,33 g (75% of theoretical yield) of the desired product having a melting point of 139–142° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].CSC.B.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH2:5][OH:6])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: O=C(O)c1ccc(F)c(Cl)c1F
Agent: B
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CSC
Product: OCc1ccc(F)c(Cl)c1F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3-Chloro-2,4-difluorobenzoic acid (5.37 g, 27.9 mmol) was dissolved in THF (20 mL) and the solution was cooled to 0 deg. Borane methylsulfide (2.0 M in THF, 55.8 ml, 112 mmol) was added. The resulting solution was warmed to rt and stirred for 14 h. The solution was cooled in an ice bath, and 10% aqueous Na2CO3 (7 mL) was added slowly. The material was concentrated on the rotovap to a white solid. The residue was acidified with 3M aqueous HCl (30 mL), diluted with dichloromethane (50 mL), and the mixture was filtered through Celite. The layers were separated, and the organic layer was dried over sodium sulfate and concentrated. The residue was purified through silica gel (500 mL) using 30% EtOAc-hexane, to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)=[O:11])=[N:7][CH:8]=1.Br[CH2:25][C:26](=O)[CH3:27].C([O-])(O)=O.[Na+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:25]=[C:26]([CH3:27])[C:9]=2[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)=[O:11])[CH:8]=1
Reactant: COc1ccc(CC(=O)c2cc(OC)c(OC)c(OC)c2)nc1
Reactant: CC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c(C)cn2c1
Yield: 95 %

Procedure:
A mixture of 2-(5-methoxypyridin-2-yl)-1-(3,4,5-trimethoxyphenyl)ethanone (0.200 g, 0.631 mmol), 1-bromo-2-propanone (0.171 g, 1.3 mmol), and NaHCO3 (0.212 g, 2.6 mmol) in acetone (5 mL) was refluxed for 20 h. The precipitate was removed by filtration. The filtrate was concentrated to give a residue, which was purified on a silica gel column eluting with CH2Cl2 to afford compound 5 (0.213 g, 95%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:13])[CH2:5][CH2:4][CH2:3]1.[BH4-].[Na+]>CO>[CH3:1][C:2]1([CH3:14])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]([OH:13])[CH2:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCCC(=O)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)CCCC(O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 9,9-dimethyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one (5.780 g, 30.70 mmol) in methanol (40 ml) was added sodium borohydride (1.16 g, 30.7 mmol) by small portions under ice-cooling, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, diluted with water, and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-6/1) to give the objective substance.