Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24])[C:4](N1[C@@H](CC2C=CC=CC=2)COC1=O)=[O:5].C1C[O:28]CC1.OO.[Li+].[OH-]>O>[OH:1][CH2:2][C@@H:3]([CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24])[C:4]([OH:5])=[O:28]
Reactant: C=CCCCC[C@H](CO)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: C1CCOC1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: C=CCCCC[C@H](CO)C(=O)O
Temperature: 25 °C

Procedure:
A 0.05 M solution of (4S)-3-[(2R)-2-(hydroxymethyl)-7-octenoyl]-4-benzyl-1,3-oxazolidin-2-one (2.55 g, 7.70 mmol) in a 4:1 mixture of THF and H2O was treated with 30% H2O2 (4.0 mL, 30.82 mmol), followed by LiOH (0.70 g, 15.41 mmol) at 0° C. The resulting mixture was stirred and allowed to warm to room temperature overnight. THF was then removed under vacuum. The residue was washed with dichloromethane (50 mL×2) to remove (S)-4-benzyl-oxazolidin-2-one. The desired product was isolated by EtOAc extraction of the acidified (pH 1˜2) aqueous phase. No further purification was required. Standing under high vacuum yielded the title compound. MH+173.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:16][CH:15]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:29]([O:31][CH3:32])=[O:30]>N1C=CC=CC=1>[C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([CH2:13][NH:12][C:3]2[C:2]([NH:1][C:29]([O:31][CH3:32])=[O:30])=[CH:11][CH:10]=[CH:9][C:4]=2[C:5]([O:7][CH3:8])=[O:6])=[CH:15][CH:16]=1)#[N:27]
Reactant: COC(=O)Cl
Reactant: COC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1
Solvent: c1ccncc1
Product: COC(=O)Nc1cccc(C(=O)OC)c1NCc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a stirred solution of methyl 3-amino-2-[(2'-cyanobiphenyl-4-yl)methylamino]benzoate (10 g) in pyridine (50 ml) was added dropwise methyl chloroformate (9.0 ml) under ice-cooling. The mixture was stirred at room temperature for 3 hours and concentrated. The residue was extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was recrystallized from ethyl acetate-hexane to afford pale yellow needles (10.5 g, 90%), m.p. 113°-115° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[CH2:9]([N:11]([CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:12]1[C:17]([NH:18][CH2:19][CH3:20])=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:10]>>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:25]1[CH2:24][CH2:23][CH:22]([CH2:21][N:11]([CH2:9][CH3:10])[C:12]2[C:17]([NH:18][CH2:19][CH3:20])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:27][CH2:26]1)=[O:8]
Reactant: CCNc1cccnc1N(CC)CC1CCNCC1
Reactant: O=C(O)c1ccc[nH]1
Product: CCNc1cccnc1N(CC)CC1CCN(C(=O)c2ccc[nH]2)CC1

Procedure:
Following the general procedure of EXAMPLE 149 and making non-critical variations, but using pyrrole-2-carboxylic acid (823 mg, 7.40 mmol) and 4-[N-ethyl-N-(3-ethylamino-2-pyridinyl)aminomethyl]piperidine (970 mg, 3.70 mmol), a crude product is obtained. Chromatography [with 40-100% ethyl acetate/hexane], followed by crystallization from ether/hexane gives the title compound, mp=109°-110°.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[N:29]([O-])=O.[Na+]>CC(O)=O.O>[NH2:29][C:19]1[C:18]2[C:22](=[CH:23][CH:24]=[C:16]([NH:15][C:13]([C:10]3([C:8]4[CH:7]=[CH:6][C:5]5[O:1][CH2:2][O:3][C:4]=5[CH:9]=4)[CH2:12][CH2:11]3)=[O:14])[CH:17]=2)[NH:21][C:20]=1[C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: O=N[O-]
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1[nH]c2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc2c1N
Temperature: 45 °C

Procedure:
A solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-yl)cyclopropane carboxamide (50 mg, 0.13 mmol) was dissolved in AcOH (2 mL) and warmed to 45° C. To the mixture was added a solution of NaNO2 (9 mg) in H2O (0.03 mL). The mixture was allowed to stir for 30 mm at 45° C. before the precipitate was collected and washed with Et2O. This material was used in the next step without further purification. To the crude material, 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-nitroso-1H-indol-5-yl)cyclopropanecarboxamide, was added AcOH (2 mL) and Zn dust (5 mg). The mixture was allowed to stir for 1 h at ambient temperature. EtOAc and H2O were added to the mixture. The layers were separated and the organic layer was washed with sat. aq. NaHCO3, dried over MgSO4, and concentrated in vacuo. The residue was taken up in DMF (1 mL) and was purified using prep-HPLC. LCMS: m/z 392.3; retention time of 2.18 min.
Reaction SMILES: [C:1](O)(=O)CCCCCCCC(O)=O.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]>>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:1])=[O:23]
Reactant: O=C(O)CCCCCCCC(=O)O
Reactant: O=C(O)CCCCCCCBr
Product: COC(=O)CCCCCCCBr

Procedure:
Methyl 8-bromooctanoate was prepared from azelaic acid essentially as described in U.S. Pat. No. 3,852,419, or by direct esterification of 8-bromooctanoic acid as follows:
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>C(#N)C>[CH:16]1([NH:19][CH:6]2[CH2:7][CH2:8][C:3]([CH2:2][OH:1])([C:10]3[N:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[CH2:4][CH2:5]2)[CH2:18][CH2:17]1
Reactant: O=C1CCC(CO)(c2ncccn2)CC1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC#N
Product: OCC1(c2ncccn2)CCC(NC2CC2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 4-(hydroxymethyl)-4-(pyrimidin-2-yl)cyclohexanone (238 mg, 1.15 μmol), cyclopropylamine (106 μl, 1.50 mmol), and acetic acid (87 μl, 1.50 mmol) in acetonitrile (6 mL) was treated at 0° C. with NaBH(OAc)3 (367 mg, 1.73 mmol). After being stirred at 25° C. for 20 h, the reaction was then basified (1 M aqueous NaOH, pH˜12), extracted (5×10% MeOH/DCM), and washed (1× brine). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to provide (4-(cyclopropylamino)-1-(pyrimidin-2-yl)cyclohexyl)methanol (281 mg, 1.14 mmol, quantitatively) as a pale yellow film.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:9]([C:23]([F:26])([F:25])[F:24])[N:8]=2)[CH:6]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[Sn:34](Cl)([CH2:43][CH2:44][CH2:45][CH3:46])([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38]>C1COCC1>[CH2:43]([Sn:34]([CH2:35][CH2:36][CH2:37][CH3:38])([CH2:39][CH2:40][CH2:41][CH3:42])[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:9]([C:23]([F:26])([F:25])[F:24])[N:8]=2)[CH:6]=1)[CH2:44][CH2:45][CH3:46]
Reactant: FC(F)(F)c1ccc(-c2cc(-n3cnc(I)c3)nc(C(F)(F)F)c2)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(-c3ccc(C(F)(F)F)cc3)cc(C(F)(F)F)n2)cn1
Temperature: 23 °C
Reaction time: 48 h

Procedure:
To a solution of 2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-4-(4-trifluoromethylphenyl)-pyridine (example E.93) (1.2 g, 2.48 mmol) in THF (15 mL) at 0° C. was quickly added added i-PrMgCl.LiCl (1 M in THF, 3.0 mL, 3.0 mmol) and the mixture was stirred at 0° C. for 15 min. Then Bu3SnCl (0.94 mL, 3.48 mmol) was added, the cooling bath was removed and the mixture was stirred at 23° C. for 48 h. Poured into sat. NH4Cl-sol., extracted with EtOAc, washed with brine and dried over Na2SO4. Removal of the solvent in vacuum left a brown oil, which was purified by alox (neutral) column chromatography with heptane/methylene chloride gave a yellow oil (1.7 g, 106%, ca. 90% pure). MS (ISP) 648.3 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[N:10]([S:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:22])=[O:21])[CH:9]=[CH:8]2
Reactant: COc1cccc2cc[nH]c12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2ccn(S(=O)(=O)c3ccccc3)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.3 %

Procedure:
To a cooled (ice water bath) solution of 7-(methyloxy)-1H-indole (3 g, 20.38 mmol) in DMF (100 mL) was added sodium hydride (0.618 g, 24.46 mmol) portionwise. After 15 minutes a solution of benzenesulfonyl chloride (3.94 mL, 30.6 mmol) in 20 ml of DMF was added dropwise. The reaction mixture was stirred at RT for 24 h, at which time it was concentrated. The residue was dissolved in DCM (100 ml) and washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (Biotage; 0% to 100% DCM:Hex; 50 g-HP-silica gel column) to give 3.65 g of the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.65 (s, 3H), 6.60-6.75 (m, 2H), 7.08-7.22 (m, 2H), 7.40-7.62 (m, 3H), 7.77-7.92 (m, 3H). MS (ES) [M+H]+ 288.0.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:24]=[CH:23][C:22]3[C:21]4[C:16](=[CH:17][C:18]([C:25](=[O:35])[CH2:26][CH2:27][CH2:28][N:29]5[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)=[CH:19][CH:20]=4)[CH2:15][C:14]=3[CH:13]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].O>CO>[N:1]1([CH2:7][CH2:8][CH2:9][CH:10]([C:12]2[CH:24]=[CH:23][C:22]3[C:21]4[C:16](=[CH:17][C:18]([CH:25]([CH2:26][CH2:27][CH2:28][N:29]5[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]5)[OH:35])=[CH:19][CH:20]=4)[CH2:15][C:14]=3[CH:13]=2)[OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(CCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCN3CCCCC3)ccc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC(CCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(O)CCCN3CCCCC3)ccc1-2
Temperature: -10 °C
Reaction time: 16 h

Procedure:
A solution of 24.5 g (0.052 mole) of 2,7-bis(4-piperidinobutyryl)fluorene dissolved in 400 ml of methanol is cooled to -10°C. and 3.8 g (0.1 mole) of sodium borohydride is slowly added wih stirring. The reaction mixture is gradually permitted to come to room temperature and stirring continued for an additional 16 hours. The contents of the reaction mixture are poured into approximately 1 liter of water, and the resulting solid which forms is filtered, washed with water and recrystallized from a solution of benzene. Recrystallization from a benzene-ether mixture results in the preparation of α, α'-bis(3-piperidinopropyl)-2,7-fluorenedimethanol having a m.p. of 181.5°-4.0°C, λmaxEtOH 273, and E 1cm1% 592.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[C:15]([CH2:19]Cl)[CH2:16][S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:39]1[C:43]([SH:44])=[N:42][N:41]=[N:40]1.CN(C)C=O.Cl>C(N(CC)CC)C>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[C:15]([CH2:19][S:44][C:43]4[NH:42][N:41]=[N:40][N:39]=4)[CH2:16][S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1nnn[nH]1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nnn[nH]3)CS(=O)[C@H]12
Temperature: 0 °C
Yield: 100.5 %

Procedure:
A mixture of benzhydryl 7-(2-phenylacetamido)-3-chloromethyl-3-cephem-4-carboxylate-1-oxide (70.0 g), 1H-tetrazole-5-thiol (15.6 g) and N,N-dimethylformamide (700 ml) was stirred to give a homogeneous solution and thereto was added triethylamine (32.1 g), keeping the temperature at 20° to 30° C. The resulting solution was stirred for 40 minutes at room temperature. After the reaction mixture was added to ice water (2.8 l), the mixture was adjusted to pH 2.0 with 10% hydrochloric acid and then filtered. The filter cake was washed with water and dried over phosphorus pentoxide under reduced pressure to give benzhydryl 7-(2-phenylacetamido)-3-(1H-tetrazole-5-yl)thiomethyl-3-cephem-4-carboxylate-1-oxide (78.8 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(CC)CC.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:19][CH2:20]2)[C:34](=[O:37])[CH2:35][CH3:36])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CCNCCN2CCN(c3ccccc3)CC2)cc1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)N(CCc1ccc([N+](=O)[O-])cc1)CCN1CCN(c2ccccc2)CC1
Reaction time: 2 h
Yield: 89 %

Procedure:
To a stirred solution of [2-(4-nitro-phenyl)-ethyl]-[2-(4-phenyl-piperazin-1-yl)-ethyl]-amine 27a (0.375 g, 1.05 mmol), Et3N (0.267 g, 2.64 mmol) in 25 mL of dry CH2Cl2 under nitrogen at 0° C. was added a solution of propionyl chloride (0.137 g, 1.48 mmol). The temperature was allowed to rise to room temperature, the mixture stirred for 2 h, and then washed with water. The aqueous layer was extracted with dichloromethane. The combined organic phase was dried (Na2SO4) and concentrated. The crude product was purified by column chromatography over silica gel (EtOAc/Hex=9/1) to give 28a as a colorless oil: 0.39 g (89% yield). 1H NMR (CDCl3, 400 MHz): δ 1.16 (3H, t, J=7.2, CH3), 2.38 (2H, q, J=7.2, CH2), 2.51 (2H, t, J=7.2 Hz, CH2Ar), 2.62 (4H, t, J=4.8, (CH2)2N), 2.99 (2H, t, J=7.2, CH2—CH2NCO), 3.15-3.20 (4H, m, (CH2)2NHPh, 3.32 (2H, t, J=7.2, CH2—CH2Ar), 3.58 (2H, t, J=7.2, CH2NCO), 6.83-6.93 (3H, m, ArH), 7.23-7.28 (2H, m, ArH), 7.34 (1H, d, J=8.0, ArH), 7.38 (1H, d, J=8.8, ArH, 8.15 (1H, d, J=8.8, ArH), 8.18 (1H, d, J=8.4, ArH).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:11][C@H:12]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:13]([CH3:16])([OH:15])[CH3:14])[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[OH:24]O.N>C(O)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:11][C@H:12]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[C:13]([CH3:16])([OH:15])[CH3:14])[C:5]2[S:10](=[O:24])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: OO
Reactant: CC(C)(O)[C@H](Nc1nc(Cl)nc2c1SCC2)c1ccc(F)cc1
Agent: N
Solvent: CC(=O)O
Product: CC(C)(O)[C@H](Nc1nc(Cl)nc2c1S(=O)CC2)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
300 mg (R)-1-(2-chloro-6,7-dihydro-thieno[3,2-d]pyrimidin-4-ylamino)-1-(4-fluoro-phenyl)-2-methyl-propan-2-ol are placed in 2.0 ml acetic acid. The reaction mixture is cooled to +10° C. 127 μl hydrogen peroxide (35%) are added dropwise. The reaction mixture is stirred for 1 hour at +10° C. and then stirred into ice water. It is then made basic with an ammonia solution. The precipitate formed is suction filtered and purified by chromatography (silica gel, petroleum ether/ethyl acetate 50/50 to 0/100 then ethyl acetate/methanol 50/50). 70 mg of the product are obtained as an oil. Analytical HPLC-MS (method D): RT=1.17 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:16][C@H:12]2[CH2:13][NH:14][CH2:15][C@@:11]2([C:17]([O:19][CH3:20])=[O:18])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:16][C@H:12]2[CH2:13][N:14]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:15][C@@:11]2([C:17]([O:19][CH3:20])=[O:18])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@]12CNC[C@@H]1C[C@@H](NC(=O)OC(C)(C)C)C2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: COC(=O)[C@]12C[C@H](NC(=O)OC(C)(C)C)C[C@H]1CN(C(=O)OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the product from Step D (21.5 g, 75.6 mmol) in DCM (400 mL) was added TEA (31.6 mL, 226.8 mmol) and benzyl chloroformate (14.5 mL, 95%, 98.3 mmol) at 0° C. under Ar. The mixture was stirred at rt for 3 h and quenched by the addition of aqueous NaHCO3 solution. The aqueous phase was extracted with DCM (3×) and the combined organic phases were dried over Na2SO4. Evaporation and purification by column chromatography (eluent: 20% EtOAc in hexanes to 30%) gave the product as a colorless gel. 1H-NMR (400 MHz, CDCl3): δ 1.43 (s, 9H), 1.89 (br. s., 2H), 2.13 (br. s., 2H), 2.99 (d, J=1.0 Hz, 1H), 3.22-3.57 (m, 2H), 3.59-3.83 (m, 4H), 3.99 (d, J=11.6 Hz, 1H), 4.23 (d, J=5.8 Hz, 1H), 4.85 (br. s., 1H), 5.12 (d, J=3.0 Hz, 2H), 7.28-7.42 (m, 5H). LC/MS: C22H30N2O6: m/z 441.2 (M+Na).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH3:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([NH:21][NH2:22])=[O:20])=[CH:17][CH:16]=1>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[N:22][NH:21][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1
Reactant: COc1ccc(C(=O)NN)cc1
Reactant: O=Cc1ccc2ccccc2n1
Solvent: CCO
Product: COc1ccc(C(=O)NN=Cc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Yield: 49.1 %

Procedure:
A mixture of 3.14 gm (0.02 mole) of 2-quinolinecarboxaldehyde, 3.32 gm (0.02 mole) of 4-methoxybenzhydrazide and 100 ml of ethanol is refluxed for 9 hrs. The hot solution is filtered and cooled slowly to room temperature. The mixture is chilled. The crystals which separate are collected. The crude mixture is crystallized from ethyl acetate and recrystallized from tetrahydrofuran to yield 3.0 gm (49%) of title compound, having a melting point of 220°-222° C.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:25]=[C:24]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=1[CH3:31]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:22]2[CH:23]=[C:24]([S:26]([CH2:29][CH3:30])(=[O:27])=[O:28])[CH:25]=[CH:20][C:21]=2[CH3:31])[CH:11]=1
Reactant: CCS(=O)(=O)c1ccc(C)c(Br)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: CCS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OCC(=O)O)c1

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-chloro-2-ethynyl phenoxy)acetate (Intermediate 3) and 2-bromo-4-(ethylsulfonyl)-1-methylbenzene (Intermediate 65), the title compound was obtained as a brown oil.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:14])[F:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=1>C(#N)C>[Br:1][C:2]1[C:7]([O:8][CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=2)=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:13])[F:14])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(CBr)cc1
Reactant: COc1c(OC(F)F)ccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c(OC(F)F)ccc(Br)c1OCc1ccc(C(N)=O)cc1
Temperature: 80 °C
Yield: 67 %

Procedure:
To a stirring solution of 6-bromo-3-(difluoromethoxy)-2-methoxyphenol (1.0 g, 3.71 mmol) in acetonitrile (10 mL) was added potassium carbonate (1.53 g, 11.08 mmol) and 4-(bromomethyl)benzamide (795 mg, 3.71 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure to afford 4-((6-bromo-3-(difluoromethoxy)-2-methoxyphenoxy)methyl)benzamide as a solid (1 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11](Cl)[N:10]=1.[NH2:19][CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([NH2:32])[N:24]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:32][C:25]1[N:24]=[C:23]([NH:22][CH2:21][CH2:20][NH:19][C:11]2[CH:12]=[CH:13][C:14]([N+:15]([O-:17])=[O:16])=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=2)[CH:28]=[CH:27][C:26]=1[N+:29]([O-:31])=[O:30]
Reactant: NCCNc1ccc([N+](=O)[O-])c(N)n1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1-c1ccc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc(NCCNc2ccc([N+](=O)[O-])c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
1 mmol of 2-(2,4-dichlorophenyl)-6-chloro-3-nitropyridine was taken with 2 mmol of (2-aminoethyl)(6-amino-5-nitro(2-pyridyl))amine and 3 mmol of N,N-diisopropylethylamine in 2 ml of DMF at 80° C. for two hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate, and purified by column chromatography eluting with 5-10% methanol/methylene chloride to obtain {2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[6-(2,4-dichlorophenyl)-5-nitro(2-pyridyl)]amine.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[H][H]>C(O)C.O.[Pt]=O>[F:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C=Cc1ccccc1F
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCc1ccccc1F
Yield: 85.1 %

Procedure:
A mixture of ethyl 2-fluorocinnamate (29.25 g, 0.176 mol) and platinum oxide hydrate (0.25, EM Scientific) in 95% ethanol (150 mL) was placed on a Parr hydrogenation apparatus and shaken under 2-4 atm at hydrogen pressure. After the appropriate amount of hydrogen was consumed, the catalyst was removed by filtration, and the filtrate was concentrated in vacuo to give 29.39 g (99%) of crude ethyl 3-(2-fluorophenyl)propionate. This material was used without further purification.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC(S(N[C:11]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[C:26]4=[N:27][C:28]([CH3:32])=[CH:29][C:30]([CH3:31])=[C:25]4[N:24]=[C:23]3[CH2:33][CH3:34])=[CH:18][CH:17]=2)=[O:12])(=O)=O)=CC=1.[Cl:41][C:42]1[S:46][C:45]([S:47]([NH2:50])(=[O:49])=[O:48])=[CH:44][CH:43]=1>>[Cl:41][C:42]1[S:46][C:45]([S:47]([NH:50][C:11]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[C:26]4=[N:27][C:28]([CH3:32])=[CH:29][C:30]([CH3:31])=[C:25]4[N:24]=[C:23]3[CH2:33][CH3:34])=[CH:18][CH:17]=2)=[O:12])(=[O:49])=[O:48])=[CH:44][CH:43]=1
Reactant: NS(=O)(=O)c1ccc(Cl)s1
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(-c3ccccc3)cc2)cc1
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(Cl)s2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example 18) and 5-chloro-2-thiophenesulfonamide.