Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC([C:5]1[N:6]([CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([F:20])([F:19])[C:11]2([CH3:22])[CH3:21])[CH:7]=[N:8][CH:9]=1)=O.[CH3:23][Mg]Br.C([O:28][CH2:29][CH3:30])C>C1COCC1>[F:20][C:12]1([F:19])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([N:6]2[C:5]([C:29]([OH:28])([CH3:30])[CH3:23])=[CH:9][N:8]=[CH:7]2)[C:11]1([CH3:22])[CH3:21]
Reactant: COC(=O)c1cncn1C1c2ccccc2C(F)(F)C1(C)C
Reactant: CCOCC
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(O)c1cncn1C1c2ccccc2C(F)(F)C1(C)C
Reaction time: 1 h

Procedure:
To a solution of 3-(3,3-difluoro-2,2-dimethyl-indan-1-yl)-3H-imidazole-4-carboxylic acid methyl ester (300 mg, 0.98 mmol), which can be prepared as described in Example 18, in THF (10 mL) at 0° C. is added a 3.0 M solution of methylmagnesium bromide in diethyl ether (1.63 mL, 4.9 mmol). After one hour of stirring the reaction is quenched with saturated aqueous NH4Cl. The reaction is extracted three times with ethyl acetate and the organic extracts are combined, washed with brine, dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0:1 to 1:5) to afford 2-[3-(3,3-difluoro-2,2-dimethyl-indan-1-yl)-3H-imidazol-4-yl]-propan-2-ol; HRMS: (ESI) m/z 307.1628 [(M+H)+: Calcd for C17H21N2OF2: 307.1622]; 1H NMR (400 MHz, CDCl3) δ ppm 0.97 (d, J=2.53 Hz, 3 H), 1.29 (d, J=3.28 Hz, 3 H), 1.79 (s, 6 H), 6.16 (d, J=3.79 Hz, 1 H), 6.89 (s, 1 H), 7.03 (s, 1 H), 7.33-7.41 (m, 1 H), 7.47-7.59 (m, 2 H), 7.62-7.72 (m, 1 H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1.C(Cl)Cl>CCCCCC>[C:15]([Si:12]([O:5][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:2][Cl:1])([CH3:14])[CH3:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC(CCCl)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OC(CCCl)c1ccccc1
Reaction time: 1 h
Yield: 74.9 %

Procedure:
3-Chloro-1-phenyl-propan-1-ol (3.87 g, 22.6 mmol), tert-butyldimethylsilyl chloride (3.75 g, 24.9 mmol), imidazole (2.00 g, 29.3 mmmol), and methylene chloride (50 mL) are combined and stirred for 1 hour. The mixture is quenched with saturated aqueous sodium bicarbonate and diluted with methylene chloride (100 mL). The mixture is washed with saturated aqueous ammonium chloride, water, and brine, then is dried over magnesium sulfate, filtered, and concentrated to a crude oil. Purification by flash chromatography, eluting with ethyl acetate:hexane gave 4.82 g (75% yield) of the title compound as a transparent oil. 1HNMR (DMSO-d6) 7.76–7.84 (m, 4H), 7.68–7.74 (m, 1H), 5.39 (dd, J=4, 4 Hz, 1H), 4.19–4.22 (m, 1H), 4.00–4.08(m, 1H), 2.55–2.65 (m, 1H), 2.38–2.48 (m, 1H), 1.34 (s, 9H), 0.53 (s, 3H), 0.28 (s, 3H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])[CH:5]=[C:6](F)[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][CH2:15][CH2:16][CH2:17][C@@H:10]2[CH2:9]1.[F:27]C1C=CC(C(C2C=CC(F)=CC=2)=O)=CC=1>>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]([C:4]2[CH:5]=[CH:6][C:7]([N:8]3[CH2:13][CH2:12][N:11]4[CH2:14][CH2:15][CH2:16][CH2:17][C@@H:10]4[CH2:9]3)=[CH:2][CH:3]=2)=[O:20])=[CH:26][CH:25]=1
Reactant: O=C(c1ccccc1)c1cc(F)c(N2CCN3CCCC[C@@H]3C2)c(F)c1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Product: O=C(c1ccc(F)cc1)c1ccc(N2CCN3CCCC[C@@H]3C2)cc1

Procedure:
340 mg of the title compound were prepared as described for [3,5-difluoro-4-((R)-octahydropyrido[1,2-a]pyrazin-2-yl)phenyl]-[phenyl]methanone, using 4,4′-difluorobenzophenone instead of 3,4,5-trifluorobenzophenone.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[C:7]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.O(Cl)[Cl:24].[P+5].[Na]>O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([C:7]2[CH:8]=[N:9][C:10]3[C:5]([C:6]=2[Cl:24])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=3)(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: ClOCl
Reactant: O=S(=O)(c1ccc(Cl)cc1)c1cnc2cc(Cl)ccc2c1O
Agent: [Na]
Agent: [P+5]
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)c1cnc2cc(Cl)ccc2c1Cl
Yield: 85 %

Procedure:
7-Chloro-3-(4-chloro-benzenesulfonyl)-4-hydroxyquinoline (4.25 g, 12 mmol) in phosphorus(V) oxychloride (5.6 ml, 60 mmol) was refluxed for 3 h. The reaction mixture was poured into water (50 ml) and was alkalized with 5M sodium hydroxyde solution. After cooling the precipitate was filtered and washed with water to obtain 3.8 g of the title compound in 85.0% yield.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])[C:5](=[S:18])[NH:4][CH2:3]1.[O:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:31][C:30]([CH:32]=O)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[CH3:20].NCCC(O)=O.CO.C(Cl)Cl>C(O)(=O)C>[CH3:20][O:19][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[S:31][C:30]([CH:32]=[C:3]3[C:2](=[O:1])[N:6]([CH:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([OH:10])=[O:9])[C:5](=[S:18])[NH:4]3)=[CH:29][CH:28]=2)=[CH:25][CH:26]=1
Reactant: COc1ccc(-c2ccc(C=O)s2)cc1
Reactant: O=C(O)C(Cc1ccccc1)N1C(=O)CNC1=S
Agent: NCCC(=O)O
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(-c2ccc(C=C3NC(=S)N(C(Cc4ccccc4)C(=O)O)C3=O)s2)cc1
Temperature: 170 °C

Procedure:
To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.080 g, 0.303 mmol) and 5-(4-methoxylphenyl)thiophene-2-carbaldehyde (0.066 g, 0.303 mmol) in acetic acid 5 mL is added β-alanine (2.69 mg, 0.030 mmol) and heat to 170° C. for 30 min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.075 g, 0.162 mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system. 1H-NMR (CD3OD/300 MHz): 7.62 (m, 2H), 7.45 (m, 1H), 7.33 (m, 5H), 7.27 (d, J=13.2 Hz, 1H), 6.94 (d, J=6.9 Hz, 2H), 6.70 (s, 1H), 5.50 (m, 1H), 3.82 (s, 3H), 3.53 (m, 2H). MS (ES+, m/z): 465.1 (M++1, 20.0).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH:7]([O:18][Si](C)(C)C)[CH2:8][P:9]([CH2:14][CH2:15][CH2:16][CH3:17])(=[O:13])[O:10]CC)C(=O)C2=CC=CC=C12.[ClH:29]>>[ClH:29].[NH2:5][CH2:6][CH:7]([OH:18])[CH2:8][P:9]([CH2:14][CH2:15][CH2:16][CH3:17])(=[O:10])[OH:13]
Reactant: CCCCP(=O)(CC(CN1C(=O)c2ccccc2C1=O)O[Si](C)(C)C)OCC
Agent: Cl
Product: CCCCP(=O)(O)CC(O)CN
Temperature: 25 °C

Procedure:
The solution of 2.4 g of ethyl 3-phthalimido-2-trimethylsilyloxy-propyl(n-butyl)phosphinate in 50 ml of concentrated aqueous hydrochloric acid is heated to reflux for 20 hours. After this time the suspension is cooled to room temperature and filtered. The filtrate is evaporated to dryness and the resulting semi-solid is co-evaporated with water (5×50 ml) and absolute ethanol (5×100 ml) and the white solid dried in high vacuum overnight. Crystallisation from absolute ethanol affords 3-amino-2-hydroxy-propyl(n-butyl)phosphinic acid hydrochloride, m.p. 158-160°.
Reaction SMILES: [CH:1]([N:4]([C:11]([C:13]1[N:22]=[C:21]2[N:15]([CH2:16][CH2:17][O:18][C:19]3[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:20]=32)[CH:14]=1)=O)[NH:5][C:6](=O)[CH2:7][O:8][CH3:9])([CH3:3])[CH3:2].C(O)(=O)C.[Cl-].[NH4+:33]>O(Cl)Cl.[P+5]>[Br:27][C:25]1[CH:24]=[CH:23][C:20]2[C:21]3[N:15]([CH2:16][CH2:17][O:18][C:19]=2[CH:26]=1)[CH:14]=[C:13]([C:11]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([CH2:7][O:8][CH3:9])[N:33]=1)[N:22]=3
Reactant: [NH4+]
Reactant: COCC(=O)NN(C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2)C(C)C
Agent: ClOCl
Agent: [Cl-]
Agent: [P+5]
Solvent: CC(=O)O
Product: COCc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid N-isopropyl-N′-(2-methoxy-acetyl)-hydrazide (1.00 g, 2.29 mmol) was suspended in phosphorus (V) oxychloride (23 mL) then stirred at 100° C. for 18 h. The reaction mixture was concentrated in vacuo and the residue then azeotroped with toluene (×3) giving a brown solid. To the brown solid was added acetic acid (23 mL) and ammonium chloride (1.76 g, 22.9 mmol), the resultant mixture was stirred at 125° C. for 2.5 h then further ammonium chloride (0.88 g, 11.4 mmol) added, the reaction was stirred at 125° C. for 1 h, then concentrated in vacuo. The resultant residue was treated with water and extracted with DCM (×3). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution then followed by brine then dried (Na2SO4) and concentrated in vacuo. The resultant solid was triturated with diethyl ether to give 8-Bromo-2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene as a light brown solid (0.73 g, 1.74 mmol, 76%). LCMS RT=4.95 min, [M+H]+=418/420. 1H NMR 400 MHz (DMSO-d6) δ: 8.29 (1H, d, J=8.65 Hz), 7.93 (1H, s), 7.31 (1H, dd, J=8.66, 2.05 Hz), 7.25 (1H, d, J=2.05 Hz), 5.79-5.78 (1H, m), 4.49 (4H, s), 4.33 (2H, s), 3.27 (3H, s), 1.43 (6H, d, J=6.60 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[S:11][C:7]=2[C:6]([C:18]([OH:20])=O)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[CH3:27][C:28]1[C:32]([NH2:33])=[C:31]([CH3:34])[O:30][N:29]=1>CN(C)C=O.ClCCl.C(N(CC)CC)C>[CH3:27][C:28]1[C:32]([NH:33][C:18]([C:6]2[C:7]3[S:11][C:10]([N:12]4[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]4)=[N:9][C:8]=3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:20])=[C:31]([CH3:34])[O:30][N:29]=1
Reactant: Cc1noc(C)c1N
Reactant: COc1ccc(C(=O)O)c2sc(N3CCCCC3)nc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2c(C)noc2C)c2sc(N3CCCCC3)nc12
Yield: 9.1 %

Procedure:
Starting from 4-methoxy-2(piperidin-1-yl)benzothiazole-7-carboxylic acid (0.24 g), oxalyl chloride (2.0 ml), dichloromethane (20 ml) and dimethylformamide (1 drop), followed by 3,5-dimethylisoxazol-4-amine (0.10 g), triethylamine (0.25 ml) and dichloromethane (20 ml). Purification by flash chromatography (eluent 5% methanol in dichloromethane) yielded the title compound as a white solid (29 mg). TLC Rf 0.49 (ethyl acetate); MS found M+1 387.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:24])[CH:4]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]#[C:22][CH3:23])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[C:25]1([CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:26]([C:31](O)=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=1>>[CH2:20]([O:19][C:16]1[CH:15]=[CH:14][C:13]([S:10]([CH:4]([C:3](=[O:24])[NH:2][OH:1])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:31](=[O:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:11])=[O:12])=[CH:18][CH:17]=1)[C:21]#[C:22][CH3:23]
Reactant: O=C(O)c1ccccc1CCc1ccccc1
Reactant: CC#CCOc1ccc(S(=O)(=O)C(CCCCN)C(=O)NO)cc1
Product: CC#CCOc1ccc(S(=O)(=O)C(CCCCNC(=O)c2ccccc2CCc2ccccc2)C(=O)NO)cc1

Procedure:
6-Amino-2-(4-but-2-ynoxy-benzenesulfonyl)-hexanoic acid hydroxyamide resin (0.33 g, 1.1 meq/g) prepared in step B was acylated with 2-bibenzylcarboxylic acid (1.6 g, 4.0 eq) according to the procedure in Example 13, Step E to give N-[5-(4-but-2-ynyloxy-benzenesulfonyl)-5-hydroxycarbamoyl-pentyl]-2-phenethyl-benzamide resin.
Reaction SMILES: [Cl:1][C:2]1[C:3](=O)[NH:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C)C=O.C(Cl)([Cl:17])=O.N>C1(C)C=CC=CC=1.O>[Cl:17][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1
Reactant: O=C(Cl)Cl
Reactant: O=c1[nH]cc(Cl)cc1Cl
Agent: N
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1cnc(Cl)c(Cl)c1

Procedure:
According to a preferred embodiment of the process of the invention, 3,5-dichloro-2-pyridone is suspended in toluene, the water present is separated by azeotropic distillation, 0.05-0.15 mol of N,N-dimethylformamide per mol of 3,5-dichloro-2-pyridone is added, and 1.0-1.3 mols of phosgene per mol of 3,5-dichloro-2-pyridone are introduced at 75°-80° C. After the addition of phosgene has been completed, the reaction mixture is allowed to react for a further one hour at 75°-80° C., and the excess phosgene is subsequently reacted with aqueous ammonia. The phases are afterwards separated, the solvent is distilled off from the organic phase, and 2,3,5-trichloropyridine is obtained as a melt.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([SH:7])[CH:2]=1.[C:9]([OH:13])(=[O:12])[CH:10]=[CH2:11].[Br:14]Br.S([O-])(O)=O.[Na+]>C(O)(=O)C.C(N(CC)CC)C>[Br:14][C:6]1[CH:5]=[CH:4][C:3]([S:7][CH2:11][CH2:10][C:9]([OH:13])=[O:12])=[CH:2][C:1]=1[CH3:8]
Reactant: Cc1cccc(S)c1
Reactant: BrBr
Reactant: C=CC(=O)O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Cc1cc(SCCC(=O)O)ccc1Br
Temperature: 50 °C

Procedure:
A one-liter, three-necked flask was charged with 0 g (0.4 mol) of m-toluenethiol, 29 g (0.4 mol) of acrylic acid and 1.0 ml of triethylamine and the mixture was allowed to react at 150° C. for 1 hour. After the reaction mixture was allowed to cool, 200 ml of acetic acid was added to the reaction mixture, and the mixture was heated up to 50° C. to form a complete solution. Then, 21 ml of bromine was gradually added over 30 minutes, and the mixture was further allowed to react at 50° to 50° C. for 1 hour. After the reaction was completed, the reaction mixture was poured into 1.5 liters of a 1% sodium hydrogensulfite aqueous solution, and the formed solid was recovered by filtration and dried to give 110 g of 3-(4-bromo-3-methylphenylthio)propionic acid as a crude product.
Reaction SMILES: C([CH:3]1[CH2:11][N:10]2[C:5](=[CH:6][C:7]([CH:13]([O:19][C:20]([C@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])=[O:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][C:9]2=[O:12])[C:4]21[O:40][CH2:39][CH2:38][O:37]2)#N.[H-].[Na+].[CH2:43](I)[CH3:44].[CH3:46][N:47](C)C=O>C(Cl)(Cl)Cl>[C:46]([C:8]1[C:9](=[O:12])[N:10]2[C:5](=[CH:6][C:7]=1[C@:13]([CH2:43][CH3:44])([O:19][C:20]([C@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[S:27]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)(=[O:28])=[O:29])=[O:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:4]1([O:37][CH2:38][CH2:39][O:40]1)[CH2:3][CH2:11]2)#[N:47]
Reactant: CCOC(=O)C(OC(=O)[C@H]1CCCN1S(=O)(=O)c1ccc(C)cc1)c1cc2n(c(=O)c1)CC(C#N)C21OCCO1
Reactant: CN(C)C=O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@](CC)(OC(=O)[C@H]1CCCN1S(=O)(=O)c1ccc(C)cc1)c1cc2n(c(=O)c1C#N)CCC21OCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dissolved in 28 ml of anhydrous N,N-dimethylformamide was 3.50 g of the compound (XII) obtained in the above procedure (2), followed by an addition of 248 mg of 60% NaH. After stirring the resultant mixture at room temperature for 1 hour, 5 ml of ethyl iodide was added and the resulting mixture was stirred at room temperature for 3 hours. After concentration of the reaction mixture under reduced pressure, the residue was dissolved in chloroform and the resulting chloroform solution was washed first with a 10% citric acid solution and then with water. The chloroform solution was dried over anhydrous sodium sulfate and then concentrated. The residue was subjected to column chromatography on silica gel and then developed with a 3:1 mixed solvent of benzene and ethyl acetate. A fraction containing the intended product was concentrated. The residue was crystallized from 2-propanol to obtain 2.07 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8]3[NH:9][CH:10]([C:16]4[N:17]=[C:18]([CH:21]([CH3:23])[CH3:22])[S:19][CH:20]=4)[CH2:11][C:12](=[O:15])[C:13]=3[O:14][C:6]=2[CH:5]=[CH:4][C:3]=1[O:24][CH3:25].O>O1CCOCC1>[OH:15][C:12]1[CH:11]=[C:10]([C:16]2[N:17]=[C:18]([CH:21]([CH3:23])[CH3:22])[S:19][CH:20]=2)[N:9]=[C:8]2[C:7]3[C:2]([Br:1])=[C:3]([O:24][CH3:25])[CH:4]=[CH:5][C:6]=3[O:14][C:13]=12
Reactant: COc1ccc2oc3c(c2c1Br)NC(c1csc(C(C)C)n1)CC3=O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2oc3c(O)cc(-c4csc(C(C)C)n4)nc3c2c1Br
Temperature: 110 °C
Yield: 60.9 %

Procedure:
A mixture of 15B (2.0 g, 4.7 mmol), FeCl3.6H2O (6 g) in 1,4-dioxane (20 mL) was heated to 110° C. and reacted overnight. TLC monitored the reaction. After the reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 15C (1.2 g, 60.2% yield).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[C:12]([NH2:14])[N:11]=[C:10]([NH2:15])[CH:9]=1)=[O:5].C1(C)C=C(C)C=C(C)C=1S([NH:31]O)(=O)=O.[CH3:34][C:35]1[O:39][C:38]([CH:40]=O)=[CH:37][CH:36]=1>>[NH2:15][C:10]1[N:11]2[N:31]=[C:40]([C:38]3[O:39][C:35]([CH3:34])=[CH:36][CH:37]=3)[N:14]=[C:12]2[CH:13]=[C:8]([CH2:7][NH:6][C:4](=[O:5])[C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=2[Br:1])[CH:9]=1
Reactant: Nc1cc(CNC(=O)c2ccccc2Br)cc(N)n1
Reactant: Cc1ccc(C=O)o1
Reactant: Cc1cc(C)c(S(=O)(=O)NO)c(C)c1
Product: Cc1ccc(-c2nc3cc(CNC(=O)c4ccccc4Br)cc(N)n3n2)o1
Yield: 21 %

Procedure:
The title compound was prepared in accordance with the general method of example 365 from 2-bromo-N-(2,6-diamino-pyridin-4-ylmethyl)-benzamide, o-mesitylene-sulfonylhydroxylamine, and 5-methyl-2-furaldehyde. The purification was performed with column chromatography on silica eluting with dichloromethane/ethylacetate 1:2.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:14]([NH2:26])[CH2:15][C:16]1[CH:25]=[CH:24][C:21]([O:22][CH3:23])=[C:18]([O:19][CH3:20])[CH:17]=1.C(N(CC)CC)C>C(OCC)(=O)C.C(OCC)C>[CH3:20][O:19][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][NH:26][C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:12])[CH:25]=[CH:24][C:21]=1[O:22][CH3:23]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(CCN)cc1OC
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(CCNC(=O)C23CC4CC(CC(C4)C2)C3)cc1OC

Procedure:
Subject 2.0 g. of adamantane carboxylic acid chloride 1.8 g. (10.0 mmoles) of homoveratrylamine and 5.0 ml. of triethylamine to the process of Example 11. Crystallize the residue obtained thereby from an ethyl acetate-ethyl ether mixture to obtain the title product, m.p, 132°-133° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=2)[NH2:9])=[CH:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][S:23][CH2:24][C:25](O)=[O:26])=[C:16]([C:29]([O:31]C)=[O:30])[CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][S:23][CH2:24][C:25]([NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)[CH:7]=2)=[O:26])=[C:16]([CH:15]=1)[C:29]([OH:31])=[O:30]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CSCC(=O)O
Reactant: Nc1cccc(-c2ccoc2)c1
Product: O=C(CSCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2ccoc2)c1

Procedure:
Using the same method as in Example 15-(ii), 3-(furan-3-yl)aniline was reacted with the [(2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethyl)sulfanyl]acetic acid obtained in Example 12-(i) to give 5-chloro-2-(([(2-([3-(furan-3-yl)phenyl]amino)-2-oxoethyl)sulfanyl]acetyl)amino)benzoic acid.methyl ester (yield: 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[CH:22][N:21]=1>>[F:29][CH:27]([F:28])[O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:16]2[CH:11]([C:4]3[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]2=[O:17])=[N:21][CH:22]=1
Reactant: FC(F)Oc1ccc(CBr)nc1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(OC(F)F)cn1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with 2-(bromomethyl)-5-(difluoromethoxy)pyridine. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions B): tR=0.82 min.; [M+H]+: 393.28 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.C(N(C(C)C)CC)(C)C.Cl[C:38]([O:40][CH2:41][C:42]1[CH:47]=[C:46]([Cl:48])[CH:45]=[C:44]([Cl:49])[CH:43]=1)=[O:39]>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:38]([O:40][CH2:41][C:42]2[CH:43]=[C:44]([Cl:49])[CH:45]=[C:46]([Cl:48])[CH:47]=2)=[O:39])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.101 g, 0.26 mmol) and diisopropylethylamine (0.23 mL, 1.32 mmol) in CH2Cl2 (1 mL) was added 3,5-dichlorobenzyl chloroformate (1.06 mmol) in CH2Cl2, and the reaction was stirred at room temperature for 5 minutes. The mixture was diluted with H2O and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, decanted, and concentrated, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][N:10]=2)[N:6]=[CH:5]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].CO>C(Cl)Cl>[CH3:19][S:20]([O:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][N:10]=2)[N:6]=[CH:5]1)(=[O:22])=[O:21]
Reactant: COC(=O)c1ccnc(-c2cn(CCO)cn2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of methyl 2-[1-(2-hydroxyethyl)-1H-imidazol-4-yl]pyridine-4-carboxylate (500 mg, 2 mmol) in DCM (10 mL) was added TEA (255 mg, 2.5 mmol) followed by drop-wise addition of a solution of methanesulfonyl chloride (255 mg, 2.22 mmol) in DCM (2 mL). The solution was stirred at 0° C. for 1 hr and then allowed to warm to r.t. where stirring was continued for 1 hr. MeOH (1 mL) was then added and stirring was continued for 30 min. The solution was diluted with DCM (50 mL), washed with water (50 mL), dried (MgSO4), filtered, and concentrated to give the title compound as an oily residue (649 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH:11]([C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH2:13])[CH:10]([CH:18]([O:20]C(OCC2C=CC=CC=2)=O)[CH3:19])[C:9]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.N1C=CN=C1.[Si:42](Cl)([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43]>CO.[Pd]>[CH2:1]([N:8]1[CH:11]([CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH3:13])[CH:10]([CH:18]([O:20][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH3:19])[C:9]1=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C(=O)OC)C1C(C(C)OC(=O)OCc2ccccc2)C(=O)N1Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Pd]
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)C(C)C1C(C(C)O[Si](C)(C)C(C)(C)C)C(=O)N1Cc1ccccc1
Temperature: 0 °C
Yield: 77.5 %

Procedure:
To a solution of 28 mg (0.07 mmol) of 1-benzyl-3-(1-benzyloxycarbonyloxyethyl)-4-(1-methoxycarbonylethenyl)-2-azetidinone dissolved in 2 ml of methanol, 5 mg of 5% palladium charcoal was added and the mixture was stirred under hydrogen atmosphere for a night. The reaction solution was filtered with selite and the filtrate was washed with ethyl acetate and concentrated. To the concentrate were added 1 ml of DMF, 20 mg (0.3 mmol) of imidazole and 45 mg (0.3 mmol) of t-butyldimethylsilylchloride and the mixture was stirred for a night. Ice water was added to the reaction solution and the resultant was extracted with ether, washed with a saturated solution of NaCl, dried with magnesium sulfate, concentrated and purified with 2 g of silica-gel column (hexane:ether 1:1) to give 22 mg of 1-benzyl-4-(1-methoxycarbonylethyl)-3-(1-t-butyldimethylsilyloxyethyl)-2-azetidinone (yield: 84%). Comparison with the NMR data showed α:β=1:1.