Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:5]=[C:4]([OH:15])[CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([CH2:26][CH2:27][CH2:28][CH2:29]Br)=[O:25])[CH:20]=[CH:21][C:22]=1[Cl:23]>>[Br:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7]([CH3:13])([CH3:14])[C:6]=2[CH:5]=[C:4]([O:15][CH2:29][CH2:28][CH2:27][CH2:26][S:24]([C:19]2[CH:20]=[CH:21][C:22]([Cl:23])=[C:17]([Cl:16])[CH:18]=2)=[O:25])[CH:3]=1
Reactant: CC1(C)OC(=O)Nc2c(Br)cc(O)cc21
Reactant: O=S(CCCCBr)c1ccc(Cl)c(Cl)c1
Product: CC1(C)OC(=O)Nc2c(Br)cc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 4 from 8-bromo-6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-(3,4-dichloro-phenylsulfinyl)-butylbromide.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:48]([F:49])=[CH:47][CH:46]=[C:45]([F:50])[C:4]=2[S:5][C:6]=1[C:7]([N:9]([CH2:25][C:26]1[CH:27]=[C:28]([C:34]2[CH:39]=[CH:38][C:37]([CH2:40][S:41]([CH3:44])(=[O:43])=[O:42])=[CH:36][CH:35]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:10]1[CH2:15][CH2:14][CH:13]([N:16](C)[C:17](=O)OC(C)(C)C)[CH2:12][CH2:11]1)=[O:8].Cl.CC(OC)(C)C>C(Cl)Cl>[ClH:1].[CH3:44][S:41]([CH2:40][C:37]1[CH:38]=[CH:39][C:34]([C:28]2[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:26]([CH2:25][N:9]([CH:10]3[CH2:11][CH2:12][CH:13]([NH:16][CH3:17])[CH2:14][CH2:15]3)[C:7]([C:6]3[S:5][C:4]4[C:45]([F:50])=[CH:46][CH:47]=[C:48]([F:49])[C:3]=4[C:2]=3[Cl:1])=[O:8])[CH:27]=2)=[CH:35][CH:36]=1)(=[O:42])=[O:43]
Reactant: COc1ccc(-c2ccc(CS(C)(=O)=O)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CNC1CCC(N(Cc2cc(-c3ccc(CS(C)(=O)=O)cc3)ccc2OC)C(=O)c2sc3c(F)ccc(F)c3c2Cl)CC1

Procedure:
tert-Butyl carbamate 199 (224 mg, 0.30 mmol) is deprotected using Method F. On removal of the solvents in vacuo, the residue is suspended in aqueous NaHCO3 (20 mL) and extracted into DCM (3×20 mL). The combined DCM phases are washed with water (2×20 μL) and brine (20 mL) then dried (Na2SO4) and reduced in vacuo. The free base thus obtained is converted to the HCl salt by Method H. The isolated salt is then dissolved in the minimum amount of DCM and added dropwise to cold (0° C.) TBME (25 mL). The resultant pale yellow precipitate is isolated by filtration, washed with TBME (10 mL) and diethyl ether (10 mL) and dried to afford the title compound.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(O[CH:12]=[CH:13][C:14]#[N:15])C>C(O)CCCC>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[N:1]1[C:14]([NH2:15])=[CH:13][CH:12]=[N:2]1
Reactant: CCOC=CC#N
Reactant: NNc1ccccn1
Solvent: CCCCCO
Product: Nc1ccnn1-c1ccccn1

Procedure:
A solution of 2-hydrazinopyridine (38.9 g, 453 mmol) was slowly added to a solution of 3-ethoxyacrylonitrile (31.5 g, 324 mmol) in pentanol (155 ml). The reaction mixture was brought to reflux for 5 h. 2-Hydrazinopyridine (10.6 g, 97 mmol) was again added and the reaction was allowed to continue to reflux for 4 h. The progress of the reaction is observed by TLC and, when the reaction is complete, the mixture is concentrated under reduced pressure until the excess hydrazinopyridine has precipitated. The filtrate was purified by column chromatography to give 2-pyridin-2-yl-2H-pyrazol-3-ylamine in the form of a white solid (2.75 g, 5.3%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.CCCCCC>N1C=CC=CC=1.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reaction time: 15 h
Yield: 85.9 %

Procedure:
To a well-stirred solution of 2-(R)-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (compound (2), 15 g, 75 mmol) in 42 mL of pyridine and 100 mL of dichloromethane at 0° C. was added a solution of 4toluenesulfonyl chloride (15.68 g, 82.55 mmol) in 75 mL of dichloromethane in a dropwise manner while maintaining the reaction temperature below 0° C. After the addition was complete, the temperature of the reaction was allowed to rise to ambient temperature (˜23° C.) and the reaction was stirred for 5 hours, at which time another 5 grams of 4-toluenesulfonyl chloride was added. The reaction was stirred for 15 hours. The reaction mixture was poured into 150 mL of a 2:1 mixture of dichloromethane and hexane. The mixture was washed twice with a mixture of 100 mL of saturated NaH2PO4 (pH=4.1) solution and water, and then washed with 500 mL of a mixture of 100 mL of Na2HPO4 and water. The organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography, eluting with 15% EtOAc in hexane to give a clear oil (22.9 g, 86% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].Br[C:21]1[CH:26]=[CH:25][C:24]([N:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([N:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:25][CH:26]=1
Reactant: Brc1ccc(N(c2ccccc2)c2ncccn2)cc1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Product: COC(=O)C(C/C=C/c1ccc(N(c2ccccc2)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 42.1 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (52.4 mg) was reacted with N-(4-bromophenyl)-N-phenylpyrimidin-2-amine (56.6 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(phenyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (40.0 mg). Column chromatography (silica gel, eluent: chloroform/cyclohexane=1/1→chloroform) and thin layer chromatography (silica gel, developing solvent: cyclohexane/ethyl acetate=1/2) were used for purification.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:13])[C:10](Cl)=[O:11].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C:22]1[CH2:26][NH:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=1>ClCCl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C:22]1[CH2:26][N:25]([C:10]([N:9]([CH3:13])[CH3:8])=[O:11])[CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=1
Reactant: Fc1ccc(Cl)c(C2=CC(c3ccccc3)NC2)c1
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N1CC(c2cc(F)ccc2Cl)=CC1c1ccccc1
Reaction time: 2 h

Procedure:
Triethylamine (0.600 mL, 4.28 mmol, 5.00 equiv) and dimethylcarbamoyl chloride (0.080 mL, 0.86 mmol, 1.00 equiv) were added to a solution of 4-(2-chloro-5-fluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole (1-5, TFA salt, 0.856 mmol, 1 equiv) in dichloromethane (50 mL) at 23° C., and the resulting mixture was stirred for 2 h, then concentrated. The residue was partitioned between saturated aqueous sodium bicarbonate solution (75 mL) and ethyl acetate (100 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was suspended in ethyl ether (2 mL) and the precipitate filtered to provide 4-(2-chloro-5-fluorophenyl)-N,N-dimethyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (1-6) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 7.40-7.30 (m, 5H), 7.26 (m, 1H), 7.03 (dd, 1H, J=9.0,2.9 Hz), 6.97.(m, 1H), 6.24 (m, 1H), 6.15 (m, 1H), 4.86 (ddd, 1H, J=13.9, 5.6, 2.2 Hz), 4.49 (dt, 1H, J=13.9, 2.0 Hz), 2.86 (s, 6H). LRMS m/z (M+H) 345.0 found, 345.1 required.
Reaction SMILES: C([O:3][C:4](=[O:50])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])[CH:25]=[C:24]([C:34]3[CH:42]=[CH:41][C:37]4[O:38][CH2:39][O:40][C:36]=4[CH:35]=3)[CH:23]=2)[C:10]=1[CH2:43][CH2:44][C:45]([O:47]CC)=[O:46])C.[OH-].[Na+]>>[O:38]1[C:37]2[CH:41]=[CH:42][C:34]([C:24]3[CH:23]=[C:22]([CH:27]=[C:26]([S:28]([CH:31]([CH3:33])[CH3:32])(=[O:29])=[O:30])[CH:25]=3)[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]3[C:10]([CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[C:9]([CH:14]=[CH:13][CH:12]=3)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:50])=[O:3])=[CH:35][C:36]=2[O:40][CH2:39]1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc4c(c3)OCO4)cc(S(=O)(=O)C(C)C)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CC(C)S(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3c(c2)OCO3)c1
Yield: 34.6 %

Procedure:
A similar procedure as described in Example 40, step 8 was used, starting from 4-[3-{6-[3-benzo[1,3]dioxol-5-yl-5-(propane-2-sulfonyl)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (135 mg, 0.19 mmol) and 1.0 N aqueous sodium hydroxide (1.9 mL) to afford 4-[3-[6-(3-benzo[1,3]dioxol-5-yl-5-(propane-2-sulfonyl)-phenoxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (43 mg, 34%) as a white sticky solid: ES(+)-HRMS m/e calcd for C35H42O10S (M+Na)+ 677.2391, found 677.2386.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][CH2:9][CH2:8][CH:7]=1)=[O:5])[CH3:2].[C-:11]#[N:12].[Na+].O>CN(C)C=O>[C:11]([C@H:7]1[C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:10][CH2:9][CH2:8]1)#[N:12]
Reactant: CCOC(=O)C1=CCCS1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1SCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 22.2 %

Procedure:
To a stirred solution of 5-ethoxycarbonyl-2,3-dihydrothiophene (500 mg) in dimethylformamide (3 ml), sodium cyanide (187 mg) was added under nitrogen atmosphere and the mixture was stirred for 2 days at room temperature. Water was added to the mixture and extracted with diethyl ether. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 130 mg (24%) of trans-4-cyano-5-ethoxycarbonyltetrahydrothiophene.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]([CH:6]=O)=[CH:4][C:3]=2[O:2]1.[C:15](#[N:19])[CH2:16][C:17]#[N:18].NCCC(O)=O.O>C(O)C>[CH2:1]1[O:11][C:10]2[CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]([CH:6]=[C:16]([C:15]#[N:19])[C:17]#[N:18])=[CH:4][C:3]=2[O:2]1
Reactant: N#CCC#N
Reactant: O=Cc1cc2c(cc1[N+](=O)[O-])OCO2
Agent: NCCC(=O)O
Solvent: O
Solvent: CCO
Product: N#CC(C#N)=Cc1cc2c(cc1[N+](=O)[O-])OCO2
Yield: 80.6 %

Procedure:
1 g (5.1 mmol) 3,4-Methylenedioxy-6-nitrobenzaldehyde, 0.4 g (6 mmol) malononitrile and 0.2 g β-alanine in 30 ml ethanol were stirred 16 hours at room temperature, 50 ml H2O was added and the reaction mixture was filtered, giving 1 g (80% yield) of a bright yellow solid, m.p. 104° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:29][C:30]1[CH:31]=[N:32][CH:33]=[N:34][CH:35]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:22][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)=[N:7][C:2]([NH:29][C:30]2[CH:31]=[N:32][CH:33]=[N:34][CH:35]=2)=[N:3][CH:4]=1
Reactant: Nc1cncnc1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3cncnc3)ncc2Cl)CC1
Yield: 21 %

Procedure:
A suspension of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.100 g, 0.297 mmol), Cs2CO3 (0.291 g, 0.892 mmol) and 5-aminopyrimidine (56.6 mg, 0.595 mmol) in 1,4-dioxane (3 mL) was sonicated for 10 minutes. Xantphos (6.9 mg, 12 μmol) and Pd(II) acetate (1.3 mg, 5.9 μmol) were added and the reaction was irradiated in the microwave at 120° C. for 20 minutes. The resulting mixture was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C. then 0-40% MeOH in EtOAc) to give a solid which was suspended in 0.5 M aqueous citric acid (50 mL) and sonicated for 10 minutes. The precipitate was collected by filtration and the filter cake was washed with 2 M aqueous NaOH (100 mL), cyclohexane (100 mL) and air dried to give the title compound 12 as a yellow solid (25 mg, 21%). LCMS-B: rt 4.89 min; m/z 395.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[C:16]([C:17]3[CH:18]=[N:19][NH:20][CH:21]=3)=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C@H:11]([CH3:26])[N:12]3[C:22]([O:24][CH3:25])=[O:23])=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].CS(O[CH:41]1[CH2:44][N:43]([CH:45]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:42]1[CH3:58])(=O)=O>O>[CH:45]([N:43]1[CH2:44][CH:41]([N:20]2[CH:21]=[C:17]([C:16]3[C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=4)=[C:8]4[C:13](=[CH:14][CH:15]=3)[N:12]([C:22]([O:24][CH3:25])=[O:23])[C@@H:11]([CH3:26])[CH2:10][CH2:9]4)[CH:18]=[N:19]2)[CH:42]1[CH3:58])([C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: COC(=O)N1c2ccc(-c3cn[nH]c3)c(Oc3ccc(F)cc3)c2CC[C@@H]1C
Reactant: CC1C(OS(C)(=O)=O)CN1C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N1c2ccc(-c3cnn(C4CN(C(c5ccccc5)c5ccccc5)C4C)c3)c(Oc3ccc(F)cc3)c2CC[C@@H]1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.5 %

Procedure:
A 100-mL round-bottom flask was charged with (S)-methyl 5-(4-fluorophenoxy)-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.300 g, 0.79 mmol) and N,N-dimethylformamide (10 mL), and the solution was cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 0.047 g, 1.17 mmol) was added, and the resulting mixture stirred for 30 min at room temperature. 1-Benzhydryl-2-methylazetidin-3-yl methanesulfonate (0.286 g, 0.86 mmol) was added, and the resulting mixture stirred overnight at 50° C. The reaction mixture was cooled to room temperature and poured into water (30 mL). The aqueous phase was separated and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 25% ethyl acetate-petroleum ether) to afford (2S)-methyl 6-(1-(1-benzhydryl-2-methylazetidin-3-yl)-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.100 g, 21%) as yellow oil. MS (ESI, pos. ion) m/z 617 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[ClH:21].[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2Cl)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1ccccc1OC1CCNCC1
Yield: 198.7 %

Procedure:
To a stirred solution of 2-chlorophenol (20 g, 0.155 mole) in DMF (200 mL), was added cesium carbonate (101 g, 0.311 mole), followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (43.45 g, 0.155 mole). The reaction mixture was heated at 65° C. for 7 hours. The mixture was then filtered and concentrated under reduced. The resulting residue was diluted with ice cold water and the solid obtained was filtered and washed with water. The solid was dissolved in ether, washed with 2.5N aqueous NaOH solution, dried over sodium sulfate and concentrated under reduced pressure to afford 24.24 g (50%) of 4-(2-chloro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 312.13 (M+1)+, 98.35%. A solution of 4-(2-chloro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (24.2 g, 0.0776 mole) in dioxane.HCl (30 mL), was stirred at ambient temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was washed with hexane twice to afford 19.13 g (99.6%) of 4-(2-chloro-phenoxy)-piperidine hydrochloride. LCMS: 248.05 (M+1)+, 92.79%. 1H NMR (DMSO-d6): δ 9.3-8.9 (bs, 2H), 7.5-7.42 (d, 1H), 7.38-7.24 (m, 2H), 7.04-6.94 (t, 2H), 4.8-4.7 (m, 1H), 3.3-3.0 (bd, 4H), 2.2-2.05 (bs, 2H), 2.0-1.8 (bs, 2H).
Reaction SMILES: [C:1]([O:4][CH:5]=[CH:6][C@H:7]1[NH:10][C:9](=[O:11])[C@H:8]1[CH2:12][CH3:13])(=[O:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:4][CH2:5][CH2:6][C@H:7]1[NH:10][C:9](=[O:11])[C@H:8]1[CH2:12][CH3:13])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC[C@@H]1C(=O)N[C@@H]1C=COC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC[C@@H]1C(=O)N[C@@H]1CCOC(C)=O
Reaction time: 6 h
Yield: 99.1 %

Procedure:
Cis-(±)-4-[2-(acetoxy)ethenyl]-3-ethyl-2-azetidinone (20 g, 0.109 mole) is dissolved in ethyl acetate (150 ml) warming the mixture until complete solution. Then, 10% Palladium on carbon catalyst (1 g) is added and the starting compound is hydrogenated at room temperature and with a pressure of 3 atmosphere of hydrogen gas, in a Parr autoclave. After six hours the autoclave is discharged and the catalyst is filtered. The solvent is evaporated and the crude cis-(±)-4-[2-(acetoxy)ethyl]-3-ethyl-2-azetidinone (20 g) thus obtained is placed in a 250-ml flask equipped with a calcium chloride drying tube and a dry nitrogen inlet tube, charged with potassium carbonate (5 g, 3.6×10-2 mole) and anhydrous methanol (130 ml). The reaction mixture is stirred at room temperature for about one hour, then it is neutralized by the addition of citric acid (5.5 g, 2.9×10-2 mole), and filtered through a Buchner funnel. The solid on filter is washed with methanol (2×10 ml) and the filtrate plus the methanol washings are concentrated to dryness under reduced pressure. The residue thus obtained is dissolved in water (100 ml) and extracted with methylene chloride (3×20 ml). The combined methylene chloride extracts are washed with water (2×15 ml) and then discarded. The aqueous solutions are combined, saturated with ammonium sulfate and extracted with five 20-ml portions of ethyl acetate. The combined ethyl acetate extracts are dried over magnesium sulfate and the solvent is removed under reduced pressure to yield 10.4 g (67.3%) of cis-(±)-3-ethyl-4-(2-hydroxyethyl)-2-azetidinone II as a thick oil, sufficiently pure for the next step.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34][CH:35]([CH3:37])[CH3:36])[CH2:24][CH:23]2[OH:38])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(N(CC)CC)C.CS(C)=[O:48]>C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34]([CH:35]([CH3:36])[CH3:37])=[O:48])[CH2:24][C:23]2=[O:38])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: CS(C)=O
Reactant: CC(C)Sc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)S(=O)c1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(=O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(2-isopropylthiophenyl)piperidin-3-ol (60 mg) obtained in Step 1 in 5 ml of dimethyl sulfoxide (DMSO), was added 0.093 ml of triethylamine (0.66 mmol). The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (103 mg, 0.66 mmol) was added to the reaction mixture, which was then stirred for about 2 hours at room temperature. The reaction mixture was diluted with 100 ml of ethyl acetate, washed with brine. The resulting organic layer was dried on sodium sulfate. The resulting residue was purified with column chromatography to give 50 mg of the titled compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:25])=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:32][CH3:33].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:33][O:32][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:38]1[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]1)[N:13]=[CH:12][CH:11]=[C:10]2[O:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25]
Reactant: CN1CCNCC1
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCN1CCN(C)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
(2-{[7-(3-Chloropropoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (68 mg), 4-methylpiperazine (42 mg), and potassium carbonate (95 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (54 mg, yield 75%).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH2:29][CH2:30][OH:31])[N:17]=2)[CH2:9]1.[OH:33][C:34]1([C:41]2[S:42][C:43]([CH3:46])=[CH:44][N:45]=2)[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1>>[OH:31][CH2:30][CH2:29][N:18]1[C:19]2[C:24](=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[C:16]([NH:15][CH2:14][C:13]([NH:12][CH:10]2[CH2:11][N:8]([CH:37]3[CH2:36][CH2:35][C:34]([OH:33])([C:41]4[S:42][C:43]([CH3:46])=[CH:44][N:45]=4)[CH2:39][CH2:38]3)[CH2:9]2)=[O:32])=[N:17]1
Reactant: O=C(CNc1nn(CCO)c2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: Cc1cnc(C2(O)CCC(=O)CC2)s1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(C2(O)CCC(N3CC(NC(=O)CNc4nn(CCO)c5ccc(C(F)(F)F)cc45)C3)CC2)s1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-[1-(2-hydroxy-ethyl)-5-trifluoromethyl-1H-indazol-3-ylamino]-acetamide TFA salt (as prepared in Example 74, Step A) and 4-hydroxy-4-(5-methyl-thiazol-2-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[O:6][CH:7]=1.[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1.[I-].[K+].[OH-].[Na+]>CC(O)(CC)C>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[O:6][CH:7]=[C:3]([CH2:2][N:16]3[CH:20]=[CH:19][N:18]=[CH:17]3)[N:4]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(-c2nc(CCl)co2)cc1
Reactant: c1c[nH]cn1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCC(C)(C)O
Product: COc1ccc(-c2nc(Cn3ccnc3)co2)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 98.3 %

Procedure:
A suspension of 2.23 g (10 mmol) 4-chloromethyl-2-(4-methoxy-phenyl)-oxazole, 1.02 g (15 mmol) imidazole, 0.17 g (1 mmol) potassium iodide and 0.60 g (15 mmol) sodium hydroxide in 25 ml 2-methyl-2-butanol was stirred at 120° C. for 5 h. After evaporation, the residue was quenched with water and extracted with ethyl acetate. The extract was dried and concentrated to yield 2.51 g (98%) 1-[2-(4-methoxy-phenyl)-oxazol-4-ylmethyl]-imidazole as beige crystals.