Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH:9]([O:12][C:13]1[CH:18]=[C:17]([O:19][CH:20]([CH3:22])[CH3:21])[N:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[C:14]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28])([CH3:11])[CH3:10].Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34].O>COCCOC>[CH:20]([O:19][C:17]1[C:18]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:13]([O:12][CH:9]([CH3:10])[CH3:11])[C:14]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:15]([C:23]([F:24])([F:26])[F:25])[N:16]=1)([CH3:22])[CH3:21]
Reactant: CCOC(=O)c1c(OC(C)C)cc(OC(C)C)nc1C(F)(F)F
Reactant: CCOC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1c(OC(C)C)nc(C(F)(F)F)c(C(=O)OCC)c1OC(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.2 %

Procedure:
To a -78° C. solution of 0.021 mol of LDA in DME (30 ml) was added a solution of 4.65 g (0.014 mol) of product of Example 6 in 20 ml of DME. The resulting solution was stirred for 10 minutes and treated with 2.7 ml (0.035 mol) of ethyl chloroformate. After stirring at -78° C. for 30 minutes the reaction mixture was warmed to room temperature in 30 minutes and poured into 50 ml of water. The mixture was extracted with ether. The ether extract was washed with 10% K2CO3, dried over CaSO4 and concentrated. The residue was first kugelrohr distilled at 0.15 torr (pot temperature 55° C.) to remove low boiling material (1.08 g), then distilled at 164°-173° C. (0.15 torr) to give 1.95 g (34.5%) of product as an oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH2:11][C:12]3[CH:13]=[C:14]([NH:18][C:19]([C:21]4[N:22]([CH3:27])[N:23]=[C:24]([CH3:26])[CH:25]=4)=[O:20])[CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=2)[NH:3]1.[CH:28](OCC)=[O:29].[O-]CC.[Na+].Cl>C(O)C>[OH:29][CH:28]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([CH2:11][C:12]3[CH:13]=[C:14]([NH:18][C:19]([C:21]4[N:22]([CH3:27])[N:23]=[C:24]([CH3:26])[CH:25]=4)=[O:20])[CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: Cc1cc(C(=O)Nc2cccc(Cc3ccc4c(c3)NC(=O)C4)c2)n(C)n1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(=O)Nc2cccc(Cc3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Temperature: 78 °C
Yield: 66.9 %

Procedure:
2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indol-6-ylmethyl)-phenyl]-amide (0.100 g, 0.278 mmol) and ethyl formate (0.068 mL, 0.834 mmol) were dissolved in anhydrous ethanol (0.55 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (0.519 mL, 1.39 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a brown precipitate. The suspension was filtered yielding an light brown solid as the pure 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indol-6-ylmethyl)-phenyl]-amide (0.072 g, 0.186 mmol, 67%).
Reaction SMILES: [CH:1](=[C:8](/[CH2:12][C:13]([N:15]1[CH2:23][C@H:22]2[C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:16]1)=[O:14])\[C:9]([OH:11])=[O:10])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:26])=[N-]>C(OCC)C>[CH:1](=[C:8](/[CH2:12][C:13]([N:15]1[CH2:16][C@H:17]2[C@H:22]([CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:23]1)=[O:14])\[C:9]([O:11][CH3:26])=[O:10])/[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)/C(=C/c1ccccc1)CC(=O)N1C[C@H]2CCCC[C@H]2C1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)/C(=C/c1ccccc1)CC(=O)N1C[C@H]2CCCC[C@H]2C1

Procedure:
To a solution of (E)-2-benzylidene-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid (50 mg) in diethyl ether was added a solution of diazomethane in diethyl ether with stirring and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure to give 52 mg of methyl (E)-2-benzylidene-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate as a colorless viscous oil.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].Br[CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O.CCOC(C)=O>[Cl:17][C:15]1[CH:16]=[C:11]([CH:12]=[C:13]([Cl:18])[CH:14]=1)[CH2:10][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: Clc1cc(Cl)cc(CBr)c1
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1nccn1Cc1cc(Cl)cc(Cl)c1
Temperature: 60 °C
Yield: 91 %

Procedure:
To a solution of 2-nitroimidazole and 1-bromomethyl-3,5-dichloro-benzene in anhydrous DMSO was added Na2CO3. The reaction mixture was heated to 60° C. for 6 h. The reaction mixture was then diluted with EtOAc and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 98:2 CH2Cl2:MeOH to afford 1-(3,5-dichloro-benzyl)-2-nitro-1H-imidazole (0.66 g, 91%).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13](=O)[CH2:14][CH3:15])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:27][O:28][CH3:29].Cl.N1C=CC=CC=1>CCO>[CH3:29][O:28][N:27]=[C:13]([C:11]1[CH:10]=[CH:9][C:8]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:12]=1)[CH2:14][CH3:15]
Reactant: CON
Reactant: CCC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCC(=NOC)c1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure P, 1-[6-phenyl-5-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-propan-1-one (Compound 78), (24 mg, 0.07 mmol), NH2OMe—HCl (23 mg, 0.25 mmol) and pyridine (21 mg, 0.28 mmol) in EtOH (2 ml) were reacted to give title compound as a white solid.
Reaction SMILES: [N:1]1[C:6]2[CH:7]3[CH2:12][NH:11][CH2:10][CH2:9][N:8]3[C:13](=[O:14])[C:5]=2[CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[Br:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[Br:24][C:25]1[CH:30]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:28]=[CH:27][C:26]=1[S:35]([N:11]1[CH2:10][CH2:9][N:8]2[C:13](=[O:14])[C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:6]=3[CH:7]2[CH2:12]1)(=[O:37])=[O:36]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Br
Reactant: O=C1c2cccnc2C2CNCCN12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1c2cccnc2C2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3Br)CCN12
Temperature: 0 °C

Procedure:
To a solution of 8,9,10,10a-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-a]pyrazin-5(7H)-one (may be prepared as in Intermediate 7, 130 mg) in DCM (5 mL) was added DIPEA (0.360 mL, 2.061 mmol). The mixture was cooled to 0° C. and 2-bromo-4-(trifluoromethyl)benzenesulfonyl chloride (233 mg) was added.
Reaction SMILES: [CH3:1][N:2]([C@@H:22]([C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([CH3:34])[CH:25]=1)[CH3:23])[C:3]([N:5]1[CH2:10][CH2:9][N:8]2[C:11](=[O:14])[CH2:12][CH2:13][C@H:7]2[C@@H:6]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])=[O:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:45](Cl)(=[O:48])[O:46][CH3:47]>C1COCC1>[CH3:1][N:2]([C@@H:22]([C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([CH3:34])[CH:25]=1)[CH3:23])[C:3]([N:5]1[CH2:10][CH2:9][N:8]2[C:11](=[O:14])[C:12]([C:45]([O:46][CH3:47])=[O:48])([C:45]([O:46][CH3:47])=[O:48])[CH2:13][C@H:7]2[C@@H:6]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])=[O:4]
Reactant: COC(=O)Cl
Reactant: Cc1cc([C@@H](C)N(C)C(=O)N2CCN3C(=O)CC[C@H]3[C@@H]2c2ccccc2C)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(C(=O)OC)C[C@H]2[C@H](c3ccccc3C)N(C(=O)N(C)[C@H](C)c3cc(C)cc(C(F)(F)F)c3)CCN2C1=O
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
To a solution of (1S,8aS)-N-methyl-N-((R)-1-(3-methyl-5-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-o-tolylhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide (350 mg, 0.74 mmol) in anhydrous THF (20 mL) under N2 atmosphere was added LHMDS (4.43 mL, 1 M in THF, 4.43 mmol) at −60° C. The reaction was stirred for 30 min followed by addition of methyl carbonochloridate (174 mg, 1.85 mmol). After stirring for another 3 h at room temperature. The reaction was quenched with water at 0° C. and then extracted with EtOAc (2×30 mL). The combined organic layers were dried over anhydrous Na2SO4 and then concentrated in high vacuum. The residue was purified by silica gel chromatography (DCM/MeOH=20/1 to 10/1) to give the title compound (200 mg, yield: 46%); m/z (ES+): 590 [M+H]+.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][C:34](O)=[O:35])[C:28]2=[O:37])=[CH:23][CH:22]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:34](=[O:35])[CH2:33][N:29]2[CH2:30][CH2:31][CH2:32][C:27]([C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)[C:28]2=[O:37])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzhydrylpiperazine (0.227 g, 0.90 mmol) in dichloromethane (15 mL) under nitrogen was added the product of Example 90D (0.31 g, 0.90 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.344 g, 1.80 mmol) and N,N-dimethylpyridin-4-amine (0.011 g, 0.09 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:3) gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.38-7.42 (m, 4H), 7.15-7.32 (m, 10H), 6.93-7.00 (m, 4H), 4.23 (s, 1H), 4.16 (s, 2H), 3.62-3.66 (m, 2H), 3.47 (t, J=6.4 Hz, 2H), 3.40-3.45 (m, 2H), 2.55-2.65 (m, 2H), 2.36-2.43 (m, 4H), 1.77-1.86 (m, 2H); MS (DCI+) m/z 580 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=3[N:17]=[C:16]2[C:25]2[C:33]([F:34])=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][C:26]=2[F:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][N+:37]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].CN.C(O)C>CN(C=O)C>[F:34][C:33]1[CH:32]=[C:28]([C:29](=[O:31])[NH:37][CH3:36])[CH:27]=[C:26]([F:35])[C:25]=1[C:16]1[N:15]([CH2:14][C@H:10]2[O:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9]2)[C:19]2[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=2[N:17]=1
Reactant: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Reactant: Cc1ccc2c(c1)nc(-c1c(F)cc(C(=O)O)cc1F)n2C[C@@H]1CN(C(=O)OC(C)(C)C)CCO1
Agent: CN
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCO
Product: CNC(=O)c1cc(F)c(-c2nc3cc(C)ccc3n2C[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)c(F)c1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
(R)-4-(1-((4-(tert-butoxycarbonyl)morpholin-2-yl)methyl)-5-methyl-1H-benzo[d]imidazol-2-yl)-3,5-difluorobenzoic acid (750 mg, 1.54 mmol) was added to DMT-MM (408 mg, 1.69 mmol) in DMF (30.00 mL) under N2. The resulting suspension was stirred for 30 min. Afterward, methylamine 33% (by weight) solution in absolute ethanol (0.458 mL, 1.69 mmol) was added, and the mixture was stirred for 3 hr. The mixture was then concentrated under reduced pressure, and the resulting residue was dissolved in EtOAc and washed sequentially with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified on preparative HPLC MS using the short high pH shallow gradient method (mobile phase: 30-50% B; A: H2O with 10 mM NH4CO3 and 0.375% NH4OH v/v; B: CH3CN; 10 min run; XBridge Prep C18 OBD, Waters reverse phase column; column size: 30×50 mm; and particle size 5 μm). This produced (S)-tert-butyl 2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-5-methyl-1H-benzo[d]imidazol-1-yl)methyl)morpholine-4-carboxylate as an oil, which was used without further purification (1.4 g, >100% yield) in the next step. The oil was analyzed on analytical HPLC MS using the high pH gradient method (mobile phase: 5-95% B; A: H2O with 10 mM NH4CO3 and 0.375% NH4OH v/v; B: CH3CN; 2.25 min run; X-Bridge C18; column size: 2.1×30 mm, particle size: 5 μm). MS m/z 501.4 [M+H]+ (ESI), Rt 1.85 min.
Reaction SMILES: Cl.CCOC(C)=O.C(OC([NH:15][C@@H:16]([CH2:41][OH:42])[C:17]([NH:19][C@@H:20]([C@H:31]([OH:40])[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:18])=O)(C)(C)C>C(Cl)Cl>[NH2:15][C@@H:16]([CH2:41][OH:42])[C:17]([NH:19][C@@H:20]([C@H:31]([OH:40])[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:18]
Reactant: COc1ccc([C@@H](O)[C@H](NC(=O)[C@H](CO)NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H](O)[C@H](NC(=O)[C@@H](N)CO)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To HCl-EtOAc (5 N, 10 mL) was added a solution of (2S,3R)-benzyl 2-((S)-2-((tert-butoxycarbonyl)amino)-3-hydroxypropanamido)-3-hydroxy-3-(4-methoxyphenyl)propanoate (646 mg, 1.32 mmol) in DCM (10 mL). The mixture was stirred at ambient temperature for 30 min and then concentrated. The residue was washed with diethyl ether (5 mL) to afford (2S,3R)-benzyl 2-((S)-2-amino-3-hydroxypropanamido)-3-hydroxy-3-(4-methoxyphenyl)propanoate (HCl salt, 474 mg, 85% yield) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[C:4]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1.[I-].[K+].[C-:19]#[N:20].[K+].O>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:19]#[N:20])=[C:4]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1
Reactant: [C-]#N
Reactant: ClCc1ccc(Br)cc1OC1CCCCC1
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc(Br)cc1OC1CCCCC1
Temperature: 70 °C
Reaction time: 1.33 h
Yield: 27.9 %

Procedure:
To a solution of 4-bromo-1-chloromethyl-2-cyclohexyloxybenzene (5.58 g) in ethanol (55.8 ml) were added potassium iodide (3.36 g) and potassium cyanide (1.56 g) at room temperature under nitrogen, and the mixture was stirred at 70° C. for 80 minutes. The resulting mixture was poured into water and the aqueous layer was extracted with toluene. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/toluene=2:1 to 1:1) to give (4-bromo-2-cyclohexyloxyphenyl)acetonitrile (1.51 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:4](=[O:15])[CH2:3]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:23][S:24]([O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[C:4](=[O:15])[CH2:3]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 65981.7 %

Procedure:
A 100-mL round-bottom flask was charged with a solution of tert-butyl 4-hydroxy-2-oxopiperidine-1-carboxylate (1.00 g, 4.65 mmol) in dichloromethane (30 mL). Triethylamine (1.03 mL, 7.42 mmol) and 4-dimethylaminopyridine (0.057 g, 0.47 mmol) were added, and the mixture was cooled to 0° C. Methanesulfonyl chloride (0.47 mL, 6.05 mmol) was added dropwise and the resulting solution stirred for 1 h at room temperature. The reaction mixture was washed with water (2×10 mL) and 0.1 M aqueous HCl solution (2×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford tert-butyl 4-(methylsulfonyloxy)-2-oxopiperidine-1-carboxylate (0. 900 g, 66%) as a brown solid. MS (ESI, pos. ion) m/z 294 [M+H]+.
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]([O:13]CC)(=[O:12])[CH:10]=[CH2:11].[OH-].[K+]>C(O)C>[C:1]1(=[N:7][O:8][CH2:11][CH2:10][C:9]([OH:13])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ON=C1CCCCC1
Reactant: C=CC(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCON=C1CCCCC1
Temperature: 60 °C
Reaction time: 96 h
Yield: 24503 %

Procedure:
A mixture of 32.8 g (0.29 mol) of cyclohexanone oxime, 26 g (0.26 mmol) of ethyl acrylate, 26 ml (0.052 mol) of a 2N solution of KOH in ethanol and 150 ml of ethanol is stirred for 96 hours at 60° C. and afterwards concentrated on a vacuum rotary evaporator. The residue (an orange oil) is dissolved in 175 g (0.31 tool) of a 10% solution of KOH in ethanol and the solution is heated for 1 hour to 60° C. The solvent is distilled off and the solid residue is taken up in water. After acidification with c. 15 ml of conc. hydrochloric acid and extraction with ethyl acetate, the organic phase is washed with water, dried over Na2SO4 and concentrated on a vacuum rotary evaporator. Distillation of the residue yields 11.8 g (25%) of the desired acid as an orange liquid. The boiling point is 135° C./0.05 mbar.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1.[C:15]([C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][C:25](Cl)=[O:26])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>N1C=CC=CC=1>[C:15]([C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][C:25]([NH:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:8][CH:9]=2)=[O:26])=[CH:21][CH:20]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1ccc(OCC(=O)Cl)cc1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(OCC(=O)NCc2ccc(NS(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
To a stirred pyridine (15 ml) suspension of N-[4-(aminomethyl)-phenyl]methane sulfonamide hydrochloride (376 mg, 1.59 mmol) was added (4-tert-butylphenoxy)acetic acid chloride (300 mg, 1.3 mmol) at 0° C. and the mixture was stirred for 1 hour at ambient temperature. The reaction was then partitioned with ethylacetate and 2M aqueous solution of hydrogen chloride and the organic layer was separated, washed with brine, dried over magnesium sulfate. Then, filtration to remove magnesium sulfate, evaporation under reduced pressure gave the residue, which was applied to a silica gel chromatography column and eluted with a volume mixture of hexane/ethylacetate (1/1 to 1/2) to furnish 240 mg (62% yield) of title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:6](=[S:13])[NH:5][C:4](=[O:14])[C:3]=1[N:15]=O.N.O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(=O)C>[NH2:15][C:3]1[C:4](=[O:14])[NH:5][C:6](=[S:13])[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:2]=1[NH2:1]
Reactant: CCCCCn1c(N)c(N=O)c(=O)[nH]c1=S
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCn1c(N)c(N)c(=O)[nH]c1=S
Temperature: 75 °C
Reaction time: 0.08 h
Yield: 74.7 %

Procedure:
To a mixture of 6-amino-1-pentyl-5-nitroso-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (6.4 g, 0.0264 mol), aqueous ammonia (60 mL, 0.60 mol) and water (60 mL) at 75° C. was added sodium dithionite (9.0 g, 0.050 mol) in small portions. After the addition was complete, the color of the solution changed from red to pale yellow. After stirring at 75° C. for another 5 mins, a precipitate was formed. Stirring was continued at room temperature for 1.5 h. The solution was then neutralized with 10% acetic acid (150 mL). The solid was filtered and washed with water to yield the product (4.5 g, 86.1%). LCMS calculated for C9H17N4OS: (M+H) 229.1. found 229.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:14][CH:15]([OH:30])[CH2:16][N:17]1[C:21](=[O:22])[C:20]([CH3:23])=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:18]1>C(O)C>[OH:30][CH:15]([CH2:14][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[CH2:16][N:17]1[C:21](=[O:22])[C:20]([CH3:23])=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:18]1
Reactant: C1COCCN1
Reactant: Cc1c(-c2ccccc2)on(CC(O)CCl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1c(-c2ccccc2)on(CC(O)CN2CCOCC2)c1=O
Yield: 88.7 %

Procedure:
1.55 g (17.9 mmoles) of morpholine and 2.46 g (17.9 mmoles) of anhydrous potassium carbonate powder were added to a solution of 4.00 g (14.9 mmoles) of 2-(3-chloro-2-hydroxypropyl)-4-methyl-5-phenyl-3-isoxazolone in 50 ml of ethanol, and the mixture was heated under reflux for 4 hours. At the end of this time, the reaction mixture was cooled by allowing it to stand, and then insoluble materials were removed by filtration. The filtrate was then concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, using ethyl acetate containing 5% by volume methanol as the eluent, to give 4.21 g (yield 83.5%) of the title compound as a colorless syrupy substance.
Reaction SMILES: [C:1]1([C:7]2[C:8]([O:10][C:11](=[O:13])[CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.S(Cl)([Cl:22])=O>>[Cl:22][C:12]1[C:11](=[O:13])[O:10][C:8](=[O:9])[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C1OC(=O)C(c2ccccc2)=C1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of phenylmaleic anhydride (5.74 mmol, 1.0 g) in thionyl chloride (6.0 mL) was added drop wise pyridine (11.4 mmol, 0.9 g). The reaction mixture was stirred for 60 min at 0° C., followed by heating to 75° C. for 20 min. The reaction mixture was cooled to room temperature and the thionyl chloride was removed in vacuo. The crude residue was suspended in toluene (10 mL), refluxed for 10 min., followed by filtration of the hot mixture. The filtrate was concentrated to give 1.15 g (96%) of the title. 1H NMR (400 MHz, CDCl3) δ 8.05-8.00 (m, 2H), 7.59-7.51 (m, 3H).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH2:30]([O:29][C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:12]1[CH:13]=[CH:14][C:15]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[CH:16][CH:17]=1)=[O:28])[CH3:31]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)CCCCCCCCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)CCCCCCCCCc1ccc(C(=O)c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.2 %

Procedure:
At 0°-3° C., 9.6 g of phthalic anhydride are added to a solution of 18 g of ethyl 10-phenyldecanoate in 100 ml of 1,2-dichloroethane, after which 26 g of aluminium chloride are added in portions over a period of 1 hour. After stirring for 20 hours at room temperature, the mixture is poured onto ice/2N hydrochloric acid and extracted with methylene chloride. Washing of the organic phase with saturated sodium chloride solution, drying and evaporation gives 25.1 g of 2-[4'-(9"-ethoxycarbonylnonyl)benzoyl]benzoic acid as a waxy solid which can be used for the next step without purification.