Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9](OC)=[O:10])=[CH:7][C:6]=1[CH:15]([CH3:17])[CH3:16])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([C:5]1[CH:14]=[CH:13][C:8]([CH2:9][OH:10])=[CH:7][C:6]=1[CH:15]([CH3:17])[CH3:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(C)(C)C)c(C(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1cc(CO)ccc1C(C)(C)C
Reaction time: 0.08 h
Yield: 60.2 %

Procedure:
To the ester 26.3 (145 mg, 0.62 mmol) in anhydrous THF (5.0 mL) was added dropwise 1.0 M LiAlH4 in THF (1.2 mL, 1.20 mmol) at 0° C. The resulting mixture was stirred for 5 minutes. The reaction was slowly quenched with 1 N NaOH aqueous solution (3.00 mL). The mixture was extracted with EtOAc (10 mL), dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (0-10% EtOAc/hexane) to give 26.4 (77 mg, 60%) as a clear oil.
Reaction SMILES: [OH:1][C:2]([CH3:21])([CH3:20])[C@H:3]([CH3:19])/[CH:4]=[CH:5]/[C@H:6]([C@@H:8]1[C@:16]2([CH3:17])[C@H:11]([C@@H:12]([OH:18])[CH2:13][CH2:14][CH2:15]2)[CH2:10][CH2:9]1)[CH3:7]>C(O)(=O)C.[Pt]>[OH:1][C:2]([CH3:20])([CH3:21])[C@H:3]([CH3:19])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:16]2([CH3:17])[C@H:11]([C@@H:12]([OH:18])[CH2:13][CH2:14][CH2:15]2)[CH2:10][CH2:9]1)[CH3:7]
Reactant: C[C@H](/C=C/[C@@H](C)C(C)(C)O)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Agent: [Pt]
Solvent: CC(=O)O
Product: C[C@H](CC[C@@H](C)C(C)(C)O)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C

Procedure:
The compound of Example 15B (89 mg) was dissolved in acetic acid and hydrogenated over 10% platinum on carbon. After purging with nitrogen, the mixture was filtered through a pad of diatomaceous earth to remove catalyst and concentrated in vacuo to give material that was carried forward to the next step without further purification.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][C:19]([OH:21])=O)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C(N=C=NCCCN(C)C)C.O[C:35]1[C:43]2[N:42]=N[NH:40][C:39]=2[CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[CH:1]1[C:13]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][C:19]([NH:40][C:39]3[CH:38]=[CH:37][CH:36]=[CH:35][C:43]=3[NH2:42])=[O:21])=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)CNC(=O)C=C1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ccccc1NC(=O)CNC(=O)C=C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.9 %

Procedure:
2-(2-(9H-fluoren-9-ylidene)acetamido)acetic acid (279 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (295 mg, 80% yield) as a brown solid. LC-MS (m/z) 370 (M+1).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][C@@H:18]([CH3:22])[CH2:17]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[CH:25]1([CH2:28][NH:29][C:30](=[O:41])[NH:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=2)[CH2:27][CH2:26]1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[CH:25]1([CH2:28][NH:29][C:30]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([C:36]([N:19]3[CH2:20][CH2:21][N:16]([CH2:15][C:12]4[CH:11]=[CH:10][C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:23])([F:1])[F:24])=[CH:14][CH:13]=4)[CH2:17][C@@H:18]3[CH3:22])=[O:37])=[CH:39][CH:40]=2)=[O:41])[CH2:27][CH2:26]1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Reactant: C[C@H]1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1C(=O)c1ccc(NC(=O)NCC2CC2)cc1
Temperature: 25 °C
Yield: 6.5 %

Procedure:
(S)-1,1,1,3,3,3-Hexafluoro-2-(4-((3-methylpiperazin-1-yl)methyl)phenyl)propan-2-ol (0.854 mmol, 0.304 g), 4-(3-(cyclopropylmethyl)ureido)benzoic acid (0.854 mmol, 0.2 g) and triethylamine (2.56 mmol, 0.356 mL, 0.259 g) were combined in dichloromethane and stirred at room temperature. 1-Propanephosphonic acid cyclic anhydride (1.28 mmol, 0.762 mL, 0.815 g; 50% solution in ethyl acetate) was added and the reaction allowed to stir for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 5% methanol/dichloromethane) to afford the title compound (32 mg).
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:23])[C@H:6]([NH2:22])[C:7]([O:9][CH2:10][C@@H:11]([C:19]([OH:21])=[O:20])[NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[O:8])(=[O:3])[CH3:2].ClCC(O)=O.[N:29]([O-])=O.[Na+].C(O)(=O)C>O>[C:1]([O:4][C@H:5]([CH3:23])[C:6](=[N+:22]=[N-:29])[C:7]([O:9][CH2:10][C@@H:11]([C:19]([OH:21])=[O:20])[NH:12][C:13](=[O:18])[C:14]([F:15])([F:17])[F:16])=[O:8])(=[O:3])[CH3:2]
Reactant: O=N[O-]
Reactant: CC(=O)O[C@H](C)[C@H](N)C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)O
Agent: O=C(O)CCl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)O[C@H](C)C(=[N+]=[N-])C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3.9 %

Procedure:
To a mixture of O-[3(R)-acetoxy-2(S)-amino-1-oxobutyl]-N-trifluoroacetyl-L-serine (200 mg) and chloroacetic acid (0.015 ml) in water (2ml) was added sodium nitrite (80 mg) at room temperature. After stirring for 0.5 hour at room temperature, acetic acid was added and the mixture was extracted with ethyl acetate (3 times) and the ethyl acetate extracts were combined and washed with brine. After drying over sodium sulfate, the ethyl acetate extract was filtered and concentrated. The residue was chromatographed on preparative thin layer chromatography to give O-[3(R)-acetoxy-2-diazo-1-oxobutyl]-N-trifluoroacetyl-L-serine (8 mg).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][O:12][C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[S:23][CH2:22][CH2:21][C:20]3=[O:25])=[O:14])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>C(O)C>[CH2:1]([N:5]1[CH2:6][CH2:7][CH:8]([CH2:11][O:12][C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[S:23][CH2:22][CH2:21][CH:20]3[OH:25])=[O:14])[CH2:9][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCC(COC(=O)c2cccc3c2SCCC3=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCN1CCC(COC(=O)c2cccc3c2SCCC3O)CC1
Reaction time: 3 h

Procedure:
(1-Butylpiperidin-4-ylmethyl)thiochroman-4-one-8-carboxylate (0.064 g, 0.177 mmol)(Example 2-1) was dissolved in ethanol (5 ml) and treated with sodium borohydride (0.007 g, 0.186 mmol) with stirring. After 3 h, the reaction mixture was evaporated under reduced pressure and the residue partitioned between CH2Cl2 and water. The aqueous layer was then extracted with CH2Cl2 and the combined organic extracts were dried (Na2SO4) and evaporated under reduced pressure to give the title compound as a pale yellow oil which was dried in vacuo (0.060 g, 93%) and subsequently converted to the oxalate salt. m.pt 147°-148° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[CH2:21][C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:18]=[C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:19])[N:9]1[C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([CH3:8])[CH:5]=1)[O:1][CH2:21][C:22]#[N:23]
Reactant: Cc1cc(O)cc(N2C(=O)c3ccccc3C2=O)c1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCC#N)cc(N2C(=O)c3ccccc3C2=O)c1
Yield: 88.8 %

Procedure:
59 g (233 mmol) 2-(3-hydroxy-5-methyl-phenyl)-isoindole-1,3-dione, 44 ml (700 mmol) chloroacetonitrile and 96.7 g (700 mmol) potassium carbonate were heated for 4 h to 80° C. in 300 ml dry dimethyl-formamide. It was poured onto 2 l water, filtered and 60.5 g (89%) [3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-5-methyl-phenoxy]-acetonitrile of Fp 156°-157° C. was obtained.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:21])=[C:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[C:6]=1[C:7](O)=[O:8].[Cl-].[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([C@@H:33]([NH3+:35])[CH3:34])=[CH:29][CH:28]=1)=[O:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][C:2]1[S:3][C:4]([CH3:21])=[C:5]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)[C:6]=1[C:7]([NH:35][C@H:33]([C:30]1[CH:31]=[CH:32][C:27]([C:25]([O:24][CH3:23])=[O:26])=[CH:28][CH:29]=1)[CH3:34])=[O:8]
Reactant: Cc1sc(C)c(C(=O)O)c1Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc([C@H](C)[NH3+])cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2c(C)sc(C)c2Cc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 0.03 h

Procedure:
To a solution of 2,5-dimethyl-4-[4-(trifluoromethyl)benzyl]thiophene-3-carboxylic acid from Example 11, Step 4 (4.36 g, 1 eq.) and (1S)-1-[4-(methoxycarbonyl)phenyl]ethanaminium chloride from Example 1, Step 9 (3.29 g, 1.10 eq.) in dimethylformamide (50 mL) is added HATU (5.65 g, 1.07 eq.) in one portion. After stirring for 2 minutes, diisopropylethylamine (6.0 mL, 2.5 eq.) was added in one portion and the reaction stirred until consumption of the starting acid. The reaction was poured onto half-saturated sodium bicarbonate (400 mL) and the white suspension stirred vigorously for 30 minutes. The solids were collected by filtration, washed with water while onto the Buchner, dried and purified by chromatography on silica gel (2:98 to 10:90 EtOAc/CHCl3) to afford the desired product as a white solid. MS (+APCI): m/z 476 (M+1)+.
Reaction SMILES: Cl.Cl.COC1C=CC(N2CCNCC2)=CC=1.BrCCC1C=CC=CC=1.[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[C:32]([CH:35]=1)[C:33]#[N:34].CS(O[CH2:47][CH2:48][CH2:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1)(=O)=O>CN(C)C=O.O1CCCC1>[CH:50]1([CH2:49][CH2:48][CH2:47][N:39]2[CH2:40][CH2:41][N:36]([C:31]3[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[CH:35][C:32]=3[C:33]#[N:34])[CH2:37][CH2:38]2)[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1
Reactant: CS(=O)(=O)OCCCC1CCCCC1
Reactant: COc1ccc(N2CCNCC2)c(C#N)c1
Agent: BrCCc1ccccc1
Agent: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(CCCC3CCCCC3)CC2)c(C#N)c1
Yield: 46.6 %

Procedure:
Production Example 1 was repeated except that 1-(4-methoxyphenyl)piperazine dihydrochloride, (2-bromoethyl)benzene and tetrahydrofuran were replaced with 5-methoxy-2-(piperazin-1-yl)benzonitrile (599 mg), 3-cyclohexylpropyl methylsulfonate (608 mg) and N,N-dimethylformamide (6.8 mL), respectively, and the resulting crude product was purified on silica gel column chromatograpy (eluent, ethyl acetate: hexane=1:1) to provide 2-[4-(3-cyclohexylpropyl)piperazin-1-yl]-5-methoxybenzonitrile (439 mg).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([CH3:25])=[C:11]2[N:16]([CH:17]=1)[N:15]=[CH:14][N:13]=[C:12]2[O:18]C1C=CC=CC=1)(=[O:4])=[O:3].Cl>C(O)C>[CH3:1][S:2]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([CH3:25])=[C:11]2[N:16]([CH:17]=1)[N:15]=[CH:14][N:13]=[C:12]2[OH:18])(=[O:4])=[O:3]
Reactant: Cc1c(OCCCS(C)(=O)=O)cn2ncnc(Oc3ccccc3)c12
Agent: Cl
Solvent: CCO
Product: Cc1c(OCCCS(C)(=O)=O)cn2ncnc(O)c12
Temperature: 80 °C
Yield: 94.5 %

Procedure:
A mixture of 6-(3-methanesulfonyl-propoxy)-5-methyl-4-phenoxypyrrolo[2,1-f][1,2,4]triazine (1.1 g, 3.04 mmol), HCl (1N, 20 mL) and ethanol (20 mL) was heated at 80° C. for 3 h. The volatiles were removed in vacuo. The white solid was triturated with diethyl ether/hexane (2:1) to afford 6-(3-methanesulfonyl-propoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-ol (820 mg, 95%) as a white solid MS: (M+H)+=286.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:23])=[N:11][C:12]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])=[CH:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][O:36][CH3:37].[Li]C1C=CC=CC=1>C1COCC1.CCCCCC>[CH2:1]([O:8][C:9]1[C:10]([CH2:23][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][O:36][CH3:37])=[N:11][C:12]([N:16]2[C:17]([CH3:22])=[CH:18][CH:19]=[C:20]2[CH3:21])=[CH:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Reactant: COCOCCCCCCCCCBr
Agent: [Li]c1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOCCCCCCCCCCc1nc(-n2c(C)ccc2C)cc(C)c1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution at −78° C. containing 906 mg (2.95 mmol) of 3-(benzyloxy)-6-(2,5-dimethyl-1H-pyrrol-1-yl)-2,4-dimethylpyridine in 20 mL of anh. THF were added 789 mg (2.95 mmol) of 1-bromo-9-(methoxymethoxy)nonane followed by 1.99 mL (3.54 mmol) of a 1.80 M solution of PhLi in hexane. The reaction mixture was stirred at −78° C. for 30 min. then the reaction mixture was warmed to 23° C. slowly, and the reaction mixture was stirred 30 min. The reaction was quenched with satd aq ammonium chloride and then poured into 80 mL of water. The mixture was then extracted with two 80-mL portions of ethyl acetate. The combined organic layer was then washed with a 100-mL portion of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (15×5 cm). Elution with 4:1 hexanes-ethyl acetate afforded the expected product as a light yellow oil: yield 877 mg (60%); silica gel TLC Rf 0.3 (9:1 hexanes-ethyl acetate); 1H NMR (CDCl3) δ 1.18-1.22 (br m, 12H), 1.50 (quint, 2H, J=6.8 Hz), 1.65 (m, 2H), 2.06 (s, 6H), 2.26 (s, 3H), 2.75 (dd, 2H, J=7.6, 7.6 Hz), 3.28 (s, 3H), 3.43 (t, 2H, J=6.8 Hz), 4.53 (s, 2H), 4.82 (s, 2H), 5.78 (s, 2H), 6.79, (s, 1H) and 7.29-7.40 (m, 5H); 13C NMR (CDCl3) δ 13.30, 13.30, 16.35, 26.19, 28.92, 29.40, 29.48, 29.50, 29.55, 29.61, 29.73, 32.13, 55.05, 67.86, 75.24, 96.36, 106.40, 106.40, 121.68, 121.68, 127.73, 127.90, 127.90, 128.89, 128.89, 138.83, 141.97, 141.97, 146.80, 150.76 and 155.88; mass spectrum (APCI), m/z 493.3426 (M+H)+ (C31H45N2O3 requires 493.3430).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:31]#[N:32])=[C:6]([CH:30]=1)[O:7][C@@H:8]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1.C(=O)(O)[O-].[Na+]>Cl.O1CCOCC1>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:31]#[N:32])=[C:6]([O:7][C@@H:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CC[C@@H](Oc2cc(Cl)ccc2C#N)c2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1ccc(Cl)cc1O[C@H](CCN1CCNCC1)c1ccccc1

Procedure:
The product from step (a) (0.35 g) was stirred in 4M HCl in dioxane (10 ml) for 3 h, then poured into saturated sodium bicarbonate solution (100 ml) and extracted into ethyl acetate. The extract was evaporated to dryness and the residue triturated with 1N HCl in ether to give the product as a white solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[CH:7]=1)=[O:5].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Mg]Br)=[CH:30][CH:29]=1>C1COCC1>[Cl:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:31]2[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)=[CH:7]1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Cl)c2)c2ccccc2c1=O
Reactant: COc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Cl)c3)c3ccccc3c2=O)cc1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60, from 300 mg (0.84 mmol) of 1-(3-chloro-benzyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 3 mL THF and 3.7 mL 0.5M 4-methoxyphenylmagnesium bromide. Yield: 168 mg of a white solid. LC-MSD, m/z for C24H18ClNO3 [M+H]+=404.1, 406.0; HPLC retention time: 2.4 min.
Reaction SMILES: C[O:2][C:3]1([CH3:10])O[CH:8]2[CH:5]([CH2:6][CH2:7]2)[O:4]1.C([Cl:14])(=O)C>>[Cl:14][C@@H:8]1[CH2:7][CH2:6][C@H:5]1[O:4][C:3](=[O:2])[CH3:10]
Reactant: CC(=O)Cl
Reactant: COC1(C)OC2CCC2O1
Product: CC(=O)O[C@@H]1CC[C@H]1Cl
Yield: 83.5 %

Procedure:
28.9 g (0.2 mol) of 3-methoxy-3-methyl-2,4-dioxa-bicyclo[3,2,0]heptane (stereoisomer mixture) and 15.4 g (0.2 mol) of acetyl chloride are heated to the reflux for 5 hours. Distillation in vacuo gives 24.8 g (84%) of trans-1-chloro-2-acetoxy-cyclobutane. Boiling point19 79°, nD20 1.4473.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1Cl.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(OCCOCC)C>CCOC(C)=O.CCO>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: CCOCCOCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(N2CCOCC2)c(Cl)cc1[N+](=O)[O-]
Yield: 54 %

Procedure:
1,2-Dichloro-4-methyl-5-nitrobenzene (R.J. De Lang, et al. Tetrahedron (1998), 54(12), 2953-2966.) (1 g; 4.8 mmol), morpholine (1 ml) and 1,2-diethoxyethane (1 ml) were heated in a microwave oven at 160° C. for 2 h. The reaction mixture was poured on water/2N HCl 10/1 (50 ml) and extracted with TBME three times. The combined organic phases were dried over Na2SO4, evaporated and recrystallised from hot TBME to yield the title compound as yellow crystals (670 mg; 54%).
Reaction SMILES: [CH:1]1[CH:2]=[N:3][C:4]([NH:7][S:8]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[N:5][CH:6]=1.Cl[CH2:19][C:20]1[NH:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.C(O)(=O)C>[OH-].[Na+]>[NH:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=[C:20]1[CH2:19][NH:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([NH:7][C:4]2[N:5]=[CH:6][CH:1]=[CH:2][N:3]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: Nc1ccc(S(=O)(=O)Nc2ncccn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=S(=O)(Nc1ncccn1)c1ccc(NCc2nc3ccccc3[nH]2)cc1
Yield: 38 %

Procedure:
628 mg (3.8 mmol) sulfadiazine and 728 mg (3.0 mmol) 2-chloromethylbenzimidazole were dissolved in 10 ml 1 M NaOH. Solution was stirred and refluxed for four hours. Reaction mixture was neutralised with addition of 1 M acetic acid until product precipitated. Crystals were filtered and purified on silica using gradient elution (chloroform to 5% methanol in chloroform) to obtain the title compound as white crystals with 38% yield. 1H NMR (DMSO-d6, 500 MHz): 8.46 (2H, m), 7.70 (2H, m) 7.49 (2H, br, m), 7.14 (1H, t, 5.7 Hz) 7.13 (2H, m), 6.98 (1H, m), 6.72 (2H, m), 4.53 (2H, 5.7 Hz); MS (ESI+): m/z 381 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)[CH:6]=[CH:7][C:8]=1[S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])#[N:2].[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH:33][CH3:34])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][N:33]([CH3:34])[C:15]([NH:14][C:5]2[CH:6]=[CH:7][C:8]([S:9]([CH2:12][CH3:13])(=[O:10])=[O:11])=[C:3]([C:1]#[N:2])[CH:4]=2)=[O:23])=[CH:29][CH:30]=1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)Oc2ccccc2)cc1C#N
Reactant: CNCCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(NC(=O)N(C)CCc2ccc(Br)cc2)cc1C#N
Yield: 91.7 %

Procedure:
A solution of 25A (750 mg, 2.3 mmol) and 23B (486 mg, 4.5 mmol) with potassium carbonate (627 mg, 2.3 mmol) in DMF (6 mL) were heated at 50° C. for 15 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The organics were washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (0% to 100% EtOAc in hexanes) to yield give 25B (950 mg, 93%) as a colorless oil. MS (ESI) m/z 449.89/451.91 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[O:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=1>>[N+:37]([C:34]1[O:33][C:32]([CH2:31][O:1][C:2]2[CH:3]=[C:4]([C:8]3[C:17]4[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])[CH:5]=[CH:6][CH:7]=2)=[CH:36][CH:35]=1)([O-:39])=[O:38]
Reactant: O=[N+]([O-])c1ccc(CBr)o1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2ccc([N+](=O)[O-])o2)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 2-Bromomethyl-5-nitro-furan following the procedure of Example 478: MS (ES) m/z 517.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1/[CH:23]=[CH:24]/[C:25]1[S:29][C:28]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][C:26]=1[N+:34]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(OCC)(OCC)OCC.C(OCC)(=O)C>C1(C)C=C(C)C=C(C)C=1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23]1[NH:34][C:26]2[CH:27]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[S:29][C:25]=2[CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(/C=C/c2ccc(OCc3ccccc3)cc2OCc2ccccc2)s1
Agent: CCOP(OCC)OCC
Solvent: Cc1cc(C)cc(C)c1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3OCc3ccccc3)cc2s1
Temperature: 160 °C
Reaction time: 43 h
Yield: 47.2 %

Procedure:
To a solution of methyl (E)-5-[2-(2,4-bisbenzyloxyphenyl)vinyl]-4-nitrothiophene-2-carboxylate (3.08 g, 6.13 mmol) in mesitylene (15 ml) was added triethyl phosphite (3.15 ml, 18.4 mmol), and the mixture was stirred at 160° C. for 43 hr. The reaction mixture was allowed to cool to room temperature, and ethyl acetate (50 ml) was added. The organic layer was washed successively with 1N hydrochloric acid (30 ml), water (30 ml×2) and saturated brine (20 ml), and dried over sodium sulfate. After filtration and concentration, isopropyl alcohol (20 ml) was added to the obtained residue and the precipitated solid was collected by filtration. The solid was washed with isopropyl alcohol (10 ml×3) to give methyl 5-(2,4-bisbenzyloxyphenyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (1.36 g, yield 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7][OH:8].[CH3:13][S:14]([N:17]([CH2:36][CH2:37][Cl:38])[N:18]([S:32]([CH3:35])(=[O:34])=[O:33])[C:19](OCC1C=CC=CC=1[N+]([O-])=O)=[O:20])(=[O:16])=[O:15]>>[CH3:13][S:14]([N:17]([CH2:36][CH2:37][Cl:38])[N:18]([S:32]([CH3:35])(=[O:33])=[O:34])[C:19]([O:8][CH2:7][C:6]1[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])=[O:20])(=[O:15])=[O:16]
Reactant: CS(=O)(=O)N(CCCl)N(C(=O)OCc1ccccc1[N+](=O)[O-])S(C)(=O)=O
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CO
Product: CS(=O)(=O)N(CCCl)N(C(=O)OCc1cc(Cl)ccc1[N+](=O)[O-])S(C)(=O)=O

Procedure:
1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(5-chloro-2-nitrobenzyloxy)carbonyl]hydrazine (compound 13c) was prepared from 5-chloro-2-nitrobenzyl alcohol using a procedure similar to that described for compound 13a. The Mp was approximately 100-102° C., and the yield was approximately 14.6% by weight after recrystallization from ethanol. 1H NMR (acetone-d6): δ 8.2, 8.0 and 7.7 (3H, 2d, s, aromatic H), 5.8 (2H, d, ArCH2), 3.6-4.1 (4H, m, CH2CH2Cl), 3.5 and 3.2 (6H, 2s, 2 CH3SO2).