Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1)=[O:10].[C:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>>[C:18]([C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[O:10])(=[O:29])=[O:28])=[CH:25][CH:26]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(C(=O)c2cc(Cl)ccc2N)cn1
Product: CC(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccc(C)nc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and 4-acetyl-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3) δ 9.54 (br s, 1, NH), 8.30 (m, 1), 7.77 (d, 2, J=8.8 Hz), 7.71 (d, 2, J=8.8 Hz), 7.69 (m, 1), 7.54 (dd, 1, J=8.8 Hz, J=2.2 Hz), 7.33 (d, 1, J=2.2 Hz), 7.26 (m, 1), 7.21 (d, 1, J=8.0 Hz), 2.63 (s, 3), 2.52 (s, 3). MS: m/z 429 (M+1).
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[N:26]1([NH:25][C:3]([C:5]2[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: NN1CCOCC1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)n[nH]1
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)NN2CCOCC2)[nH]n1
Yield: 94 %

Procedure:
As described for example 17e, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (50 mg, 0.15 mmol) was converted, using 4-aminomorpholine instead of 2,2,2-trifluoroethylamine, to the title compound (57 mg, 94%) which was obtained as a colorless oil. MS: m/e=403.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]([OH:14])=O)=[N:6][CH:7]=1.Cl.[F:24][C:25]([F:32])=[C:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C@H:11]([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]([N:29]2[CH2:30][CH2:31][C:26](=[C:25]([F:32])[F:24])[CH2:27][CH2:28]2)=[O:14])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCc1cnc(N)cn1)C(=O)O
Reactant: FC(F)=C1CCNCC1
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@@H](CCCc1cnc(N)cn1)C(=O)N1CCC(=C(F)F)CC1
Yield: 81.8 %

Procedure:
The process is performed in the same way as in Example 1.4, and starting with 2.32 g (7.5 mmol) of (S)-5-(5-amino-2-pyrazinyl)-2-[[(1,1-dimethylethoxy)carbonyl]amino]pentanoic acid and 1.9 g (11.25 mmol) of 4-(difluoromethylene)piperidine hydrochloride, to give 2.61 g of 1,1-dimethylethyl (S)-[4-(5-amino-2-pyrazinyl)-1-[[4-(difluoromethylene)piperid-1-yl)carbonyl]butyl]carbamate in the form of an amorphous powder.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[C:10]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH3:10][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[CH3:9]
Reactant: Cc1cc(Br)ccc1N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNc1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 2.03 g (10.91 mmol) of 4-bromo-2-methylaniline in 40 ml of DMF was added 2.07 g (14.98 mmol) of K2CO3 and 0.63 ml (10.12 mmol) of iodomethane, and the mixture was stirred at room temperature for 14 hours. After this time, the reaction mixture was quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel (hexanes:EtOAc, 20:1) to give the title compound. 1H-NMR (CDCl3) δ 2.18 (s, 3H), 2.90 (s, 3H), 3.60 (brs, 1H), 6.49 (d, J=8.6 Hz, 1H), 7.19 (s, 1H), 7.29 (d, J=8.5 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([NH:12][C:13](=[O:15])[CH3:14])=[CH:7][C:6]=1[CH3:16])=O.[NH2:17][C:18]([NH2:20])=[S:19]>CCO>[NH2:20][C:18]1[S:19][CH:2]=[C:3]([C:5]2[C:10]([CH3:11])=[CH:9][C:8]([NH:12][C:13](=[O:15])[CH3:14])=[CH:7][C:6]=2[CH3:16])[N:17]=1
Reactant: CC(=O)Nc1cc(C)c(C(=O)CBr)c(C)c1
Reactant: NC(N)=S
Solvent: CCO
Product: CC(=O)Nc1cc(C)c(-c2csc(N)n2)c(C)c1
Yield: 86.4 %

Procedure:
A mixture of N-(4-(2-bromoacetyl)-3,5-dimethylphenyl)acetamide (7.34 g, 25.9 g mmol) and thiourea (1.97 g, 25.9 mmol) in 95% EtOH (36.9 mL) was heated at reflux for 120 min. The solution was concentrated and added with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (50 mL). The solids were filtered and dried under vacuum to give N-(4-(2-aminothiazol-4-yl)-3,5-dimethylphenyl)acetamide (5.83 g) as yellow solids in 86% yield: 1H NMR (500 MHz, DMSO-d6) δ 9.80 (s, 1 H), 7.26 (s, 2 H), 6.90 (s, 2 H), 6.30 (s, 1 H), 2.06 (s, 6 H), 2.02 (s, 3 H).
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:12]=[C:11]([OH:13])[C:10](=[O:14])[CH:9]=[C:8]2[CH3:15])[CH:2]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:12]=[C:11]([O:13][CH2:30][C:27]3[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[C:10](=[O:14])[CH:9]=[C:8]2[CH3:15])[CH:2]=1
Reactant: Cc1cc(=O)c(O)cn1-c1cccc(-c2ccccc2)c1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2cn(-c3cccc(-c4ccccc4)c3)c(C)cc2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4.8 g (17.4 mmol) l-biphenyl-3-yl-5-hydroxy-2-methylpyridin-4(1H)-one in 150 ml of DMF was added 4.1 g (26.1 mmol) PMBCl, and 12.0 g (87.0 mmol) K2CO3. The reaction was stirred at rt for 2 h, after which time water was added and a precipitate formed. The solid was collected by filtration and purified by flash chromatography (100 g silica gel, 0-20% MeOH;EtOAc) to afford 1-biphenyl-3-yl-5-[(4-methoxybenzyl)oxy]-2-methylpyridin-4(1H)-one.  H NM δ (ppm)(DMSO-d6): 7.84 (1H, d, J=7.86 Hz), 7.77 (2H, d, J=7.71 Hz), 7.73 (1H, s), 7.64 (1H, t, J=7.84 Hz), 7.53-7.47 (3H, m), 7.46-7.39 (2H, m), 7.38-7.30 (3H, m), 6.93 (2H, d, J=8.32 Hz), 6.23 (1H, s), 4.89 (2H, s), 3.77-3.70 (3H, m), 2.03 (3H, s). LCMS (M+H)+=398.3.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:48])[CH2:16][N:17]1[C:26](=[O:27])[C:25]2[N:24]([CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])[C:23]([N:33]3[CH2:38][CH2:37][CH2:36][CH:35]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:34]3)=[N:22][C:21]=2[N:20]([CH3:47])[C:18]1=[O:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:6]([O:5][C:3]([CH2:2][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:48])[CH2:16][N:17]1[C:26](=[O:27])[C:25]2[N:24]([CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])[C:23]([N:33]3[CH2:38][CH2:37][CH2:36][CH:35]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:34]3)=[N:22][C:21]=2[N:20]([CH3:47])[C:18]1=[O:19])=[O:4])[CH3:7]
Reactant: CC(C)=CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)c1ccccc1O)c(=O)n2C
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccccc1C(=O)Cn1c(=O)c2c(nc(N3CCCC(NC(=O)OC(C)(C)C)C3)n2CC=C(C)C)n(C)c1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
63 mg of ethyl bromoacetate are added to a mixture of 200 mg of 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine and 63 mg of potassium carbonate in 3 ml N,N-dimethylformamide. The reaction mixture is stirred for five hours at ambient temperature. For working up it is combined with water and the precipitate formed is suction filtered, washed with water and dried for three hours at 80° C. in the drying cupboard.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:22]([CH2:23][OH:24])=[C:21]([CH:25]([CH3:27])[CH3:26])[N:20]=[C:19]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])[N:18]=2)=[CH:13][CH:12]=1.CC1C=CN=C(N)C=1C.[P:43](Cl)([O:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([O:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:44]>ClCCl>[P:43]([O:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)([O:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)([O:24][CH2:23][C:22]1[C:17]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)=[N:18][C:19]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])=[N:20][C:21]=1[CH:25]([CH3:27])[CH3:26])=[O:44]
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CO
Agent: Cc1ccnc(N)c1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1COP(=O)(Oc1ccccc1)Oc1ccccc1
Reaction time: 0.5 h

Procedure:
Diisopropyl ethyl amine (84.12 g) was slowly added to a mixture of N-[4-(4-fluorophenyl)-5-(hydroxymethyl)-6-(propan-2-yl)pyrimidin-2-yl]-N-methylmethanesulfonamide (commercially available; 100 g) and dimethyl aminopyridine (5 g) and diphenyl chlorophosphate (123.2 g) in dichloromethane (500 mL) at 0° C. to 5° C. The reaction mixture was stirred for 30 minutes at the same temperature to give [4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-(propan-2-yl)pyrimidin-5-yl]methyl diphenyl phosphate. To this mixture was added 2-mercapto-5-methyl-1,3,4-thiadiazole (41 g) at 0° C. to 5° C. followed by slow addition of diisopropyl ethyl amine (36.5 g). The resultant mixture was stirred for 2 hours at 0° C. to 5° C. After completion of the reaction, the mixture was quenched with de-ionized water (500 mL) and acidified to pH 3.5 using hydrochloric acid (6N). The organic layer was separated and washed with sodium bicarbonate (5%) at room temperature. The organic layer was separated and dichloromethane was recovered at 45° C. to give oily residue. Methanol (300 mL) was added to resulting oily residue and the mixture was stirred at room temperature for one hour to give N-[4-(4-fluorophenyl)-5-{[(5-methyl-1,3,4-thiadiazol-2-yl)sulfanyl]methyl}-6-(propan-2-yl)pyrimidin-2-yl]-N-methylmethanesulfonamide, which was filtered, washed with methanol (100 mL) and dried at 45° C. for 2 hours.
Reaction SMILES: C([O-])(=O)C.[NH4+].[CH3:6][C:7]1([CH3:15])[C:12](=O)[CH:11]([CH3:14])[CH2:10][NH:9][CH2:8]1.C([BH3-])#[N:17].[Na+]>CO>[NH2:17][CH:12]1[CH:11]([CH3:14])[CH2:10][NH:9][CH2:8][C:7]1([CH3:15])[CH3:6]
Reactant: CC1CNCC(C)(C)C1=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC1CNCC(C)(C)C1N
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ammonium acetate (2.5 g, 32.46 mmol) was added to the stirred solution of 3,3,5-trimethyl-4-piperidone (0.8 g, 5.67 mmol) in methanol (20 ml) and stirring was continued for 3 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (0.25 g, 3.96 mmol) was added to it. Cooling was removed after 10 min. and resulting mixture was stirred for 6 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer, was basified with 1 M sodium hydroxide solution (pH 10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 4-amino-3,3,5-trimethylpiperidine. Yield 0.45 g (54%), C8H18N2, m/z 143 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19]([CH:21]=[CH2:22])[CH:18]=[C:17]([CH:23]=O)[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.[Na].Cl>CO.C(O)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19]([CH:21]=[CH2:22])[CH:18]=[C:17]([CH2:23][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: C1CCNC1
Reactant: C=Cc1cc(C=O)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: C=Cc1cc(CN2CCCC2)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Eine suspension von 200 mg of the aldehyde described in Example 80.1 and 0.062 ml of pyrrolidine in 2 ml of MeOH was adjusted to pH 6 by the dropwise addition of acetic acid. Then, 46 mg of sodium cyanoborhydride were added and the mixture was stirred overnight at room temperature. It was acidified to pH 3 with 1N HCl and subsequently evaporated. The crude product was isolated by extraction and purified by chromatography on silica gel gereinigt. There were obtained 200 mg of methyl (RS)-(4-cyano-phenylamino)-(3-pyrrolidin-1-ylmethyl-5-vinyl-phenyl)-acetate as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][CH:14]([C:19](=O)[CH2:20][CH3:21])[C:15](=O)[CH2:16][CH3:17])=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH:26][NH2:27])[CH2:24][CH3:25]>>[CH2:1]([N:8]1[C:12]([CH2:13][C:14]2[C:19]([CH2:20][CH3:21])=[N:27][N:26]([CH2:23][CH2:24][CH3:25])[C:15]=2[CH2:16][CH3:17])=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCNN
Reactant: CCC(=O)C(Cc1cncn1Cc1ccccc1)C(=O)CC
Product: CCCn1nc(CC)c(Cc2cncn2Cc2ccccc2)c1CC

Procedure:
4-(3-Benzyl-3H-imidazol-4-ylmethyl)-3,5-diethyl-1-propyl-1H-pyrazole was prepared from 4-(3-benzyl-3H-imidazol-4-ylmethyl)-heptane-3,5-dione and propylhydrazine in analogy to Example 55 b): off-white solid; MS (ISP): 337.1 ((M+H)+.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH:17]1[CH2:20][N:19]([C:21]([N:23]2[CH2:29][CH2:28][CH2:27][N:26]([CH:30]3[CH2:33][CH2:32][CH2:31]3)[CH2:25][CH2:24]2)=[O:22])[CH2:18]1)(=O)=O>CS(C)=O.CCOC(C)=O>[CH:30]1([N:26]2[CH2:27][CH2:28][CH2:29][N:23]([C:21]([N:19]3[CH2:20][CH:17]([O:9][CH2:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:18]3)=[O:22])[CH2:24][CH2:25]2)[CH2:31][CH2:32][CH2:33]1
Reactant: CS(=O)(=O)OC1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Reactant: OCc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(N1CCCN(C2CCC2)CC1)N1CC(OCc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.1 %

Procedure:
To a stirred solution of (4-fluorophenyl)methanol (27 mg, 0.2 mmol) in DMSO (1.5 mL) was added NaH (8.5 mg, 0.2 mmol, 60% purity) at RT. The mixture was stirred for 1 h and a solution of 1 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-yl methanesulfonate (33 mg, 0.1 mmol) in DMSO (0.5 mL) was added. The resulting mixture was stirred at 100° C. overnight, cooled to RT and diluted with EtOAc. The crude mixture and washed with water/brine; 1/1 solution, dried (Na2SO4), filtered and concentrated at reduced pressure. Purification by preparative HPLC provided the title compound as colourless oil (8 mg, 18%).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].O=C1CCCCC1C(OCC)=O.[Cl:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[C:22]([Cl:29])[C:21]=1I.[F:31][C:32]([F:36])([F:35])[CH2:33][OH:34]>CS(C)=O.CC(=O)OCC>[Cl:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[C:22]([Cl:29])[C:21]=1[O:34][CH2:33][C:32]([F:36])([F:35])[F:31]
Reactant: O=[N+]([O-])c1cc(Cl)c(I)c(Cl)c1
Reactant: OCC(F)(F)F
Agent: CCOC(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(Cl)c(OCC(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.4 %

Procedure:
A Mixture of Cs2CO3 (17.22 g, 52.84 mmol), CuBr (361 mg, 2.52 mmol) and ethyl 2-oxocyclohexanecarboxylate (856 mg, 5.03 mmol) in DMSO (30 mL) under N2 was stirred for 0.5 h at rt. Then a solution of 1,3-dichloro-2-iodo-5-nitrobenzene (8.0 g, 25.16 mmol) and 2,2,2-trifluoroethanol (3.02 g, 30.19 mmol) in DMSO (20 mL) was added to it. The reaction mixture was stirred at 80° C. for 18 h and cooled to room temperature, and then directly passed through celite. After rinsed with 250 ml of EA, the combined filter was washed by brine, dried over anhydrous Na2SO4, concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (100:1) to provide 1,3-dichloro-5-nitro-2-(2,2,2-trifluoroethoxy)benzene (1.93 g, yield 12.6%) as pale yellow solid.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.[OH-].[Na+].[CH:9]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:17](Cl)=[O:18])=[CH:11][CH:10]=1>O.O1CCCC1>[OH:6][CH:4]1[CH2:5][N:2]([C:17]([O:16][CH2:15][C:12]2[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=2)=[O:18])[CH2:3]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC1CNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)N1CC(O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
To a solution of azetidin-3-ol hydrochloride (2 g, 18.26 mmol, 1.00 equiv) and sodium hydroxide (1.53 g, 38.25 mmol, 2.10 equiv) in water (10 mL) and tetrahydrofuran (25 mL) was added Cbz-Cl (3.27 g, 19.17 mmol, 1.05 equiv) dropwise with stirring at 0° C. over 30 min. The resulting solution was stirred for 3 h at room temperature. The reaction was then quenched by the addition of 20 mL of water. The mixture was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×40 mL of sodium chloride (sat.). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). Purification afforded 2.0 g (53%) of benzyl 3-hydroxyazetidine-1-carboxylate (50.2) as a light yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH2:12][N:13]3[CH:17]=[N:16][CH:15]=[N:14]3)[C@H:10]([CH3:11])[O:9]2)=[CH:4][CH:3]=1.[F:18][C:19]([F:36])([O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:34]=[CH:33][NH:32][C:31]2=[O:35])=[CH:26][CH:25]=1)[CH:20]([F:22])[F:21].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([OH:9])([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[C@H:10]([N:32]2[CH:33]=[CH:34][N:30]([C:27]3[CH:26]=[CH:25][C:24]([O:23][C:19]([F:36])([F:18])[CH:20]([F:22])[F:21])=[CH:29][CH:28]=3)[C:31]2=[O:35])[CH3:11])=[CH:4][CH:3]=1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1
Reactant: O=c1[nH]ccn1-c1ccc(OC(F)(F)C(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 36.9 %

Procedure:
(2R,3S)-2-(4-Fluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (1.5 g), 2.66 g of 1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone and 6.3 g of cesium carbonate were added to 25 ml of N,N-dimethylformamide. The mixture was stirred at 80° C. for five hours. After cooling, the reaction solution was diluted with 100 ml of ethyl acetate, and washed with water (100 ml×2) and a saturated aqueous solution of sodium chloride (100 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=2/3) to give 1.21 g of 1-[(1R,2R)-2-(4-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone as colorless powdery crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:19]=[C:18]([CH2:20][CH2:21][CH3:22])[C:13]([C:14]([NH:16][CH3:17])=[O:15])=[CH:12][N:11]=2)[CH2:6][CH2:5]1.S(=O)(=O)(O)O.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[C:28]([O:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:19]=[C:18]([CH2:20][CH2:21][CH3:22])[C:13]([C:14]([NH:16][CH3:17])=[O:15])=[CH:12][N:11]=2)[CH2:8][CH2:9]1)(=[O:30])[CH3:29]
Reactant: CCCc1cc(N2CCN(CCO)CC2)ncc1C(=O)NC
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CCCc1cc(N2CCN(CCOC(C)=O)CC2)ncc1C(=O)NC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
6-[4-(2-Hydroxyethyl)piperazin-1-yl]-N-methyl-4-propylnicotinamide (477 mg, 1.56 mol) was dissolved in acetic anhydride (1.5 mL), added sulfuric acid (50 μL) under ice-cold conditions, and stirred at room temperature for 10 minutes. The reaction solution was concentrated in vacuo, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The title compound (496 mg (yield 91%)) was obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])=[O:7].[CH3:23][NH:24][CH3:25].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([N:24]([CH3:25])[CH3:23])=[O:13])=[O:7]
Reactant: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)O)c1
Reactant: CNC
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CN(C)C(=O)c1cccc(NC(=O)COc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Yield: 55.7 %

Procedure:
To solution of 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid (100 mg, 0.29 mmol), dimethylamine (0.031 ml, 0.59 mmol) in DMF 3.0 mL was added EDC (83.4 mg, 0.44 mmol), HOBt (58.9 mg, 0.44 mmol) and DIPEA (0.076 ml, 0.44 mmol). Reaction mixture was stirred at room temperature, and separated by EtoAC and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=30:1) to give 3-[2-(2,4-dichloro-phenoxy)acetylamino]-N,N-dimethyl-benzamide as a white solid (59.3 mg, 56% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1C(O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](OC1C(OC(=O)C)=C(I=O)C=CC=1)(=[O:21])C.II.CO>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[O:21][CH3:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(=O)Oc1cccc(I=O)c1OC(C)=O
Agent: II
Solvent: ClCCl
Solvent: CO
Product: COC1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.3 %

Procedure:
To a mixture of (S)-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (purchased at Fluka, Ref 97090, 6 g, 1.0 eq.) in dichloromethane (300 mL) was added diacetoxyiodosobenzene (15.8 g, 2 eq.) and iodine (3.0 eq., 0.5 eq.). The mixture was stirred 5 h at room temperature. Methanol (12 mL) was added and the reaction mixture was stirred for an additional 1.5 h at room temperature, partitioned between an aqueous solution of sodium sulfite and dichloromethane. The organic layer was washed with an aqueous solution of sodium sulfite, brine, evaporated in vacuo and purified on silica eluting with 9:1 cyclohexane/ethyl acetate to yield 5.0 g (88%) of the desired product as light yellow oil. MS (m/e): 235.5 (MH+, 100%)