Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH3:9])[CH3:2].[CH2:10](Br)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH2:1][CH3:2])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCc1cnccc1C
Reactant: BrCCc1ccccc1
Product: CCc1cnccc1CCCc1ccccc1
Yield: 92.6 %

Procedure:
1.13 g (9.35 mmol) of 3-ethyl-4-methylpyridine and 1.73 g (9.35 mmol) of phenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 1.95 g of the desired compound (yield: 92.8%). The resulting compound was identified as 1-phenyl-3-(3-ethyl-4-pyridyl)-propane (hereinafter referred to as compound by the following analytical results.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH:9]([CH3:22])[CH2:10][C:11]1[CH:21]=[CH:20][C:14]2[O:15][CH:16]([CH2:18][NH2:19])[O:17][C:13]=2[CH:12]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:23])[N:7]([CH:9]([CH3:22])[CH2:10][C:11]1[CH:21]=[CH:20][C:14]2[O:15][CH:16]([CH2:18][NH:19][C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])[O:17][C:13]=2[CH:12]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(Cc1ccc2c(c1)OC(CN)O2)N(C)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(Cc1ccc2c(c1)OC(CNC(=O)OCc1ccccc1)O2)N(C)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of 0.31 g (0.96 mmol) of 1F in 5 mL of dichloromethane was added 0.2 mL (1.14 mmol) of N,N-diisopropylethylamine and 10 mg (0.08 mmol) of 4-dimethylaminopyridine (4-DMAP) followed by 0.15 mL of benzyl chloroformate (1.04 mmol) at room temperature. The mixture was allowed to stir for 1 hours and concentrated to dryness under reduced pressure. The residue was purified by silica gel flash column chromatography using 40% ethyl acetate in hexane to give 0.41 g (0.89 mmol, 94%) of 1G as a thick colorless gum (M+Na, 479).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:16])[CH:12]([CH3:15])[CH2:13][CH3:14].[Br:17]Br>C(O)(=O)C>[Br:17][C:12]([CH3:15])([CH2:13][CH3:14])[C:11]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[C:7]([Cl:8])[C:2]=1[Cl:1])=[O:16]
Reactant: CCC(C)C(=O)c1ccc(OC)c(Cl)c1Cl
Reactant: BrBr
Solvent: CC(=O)O
Product: CCC(C)(Br)C(=O)c1ccc(OC)c(Cl)c1Cl

Procedure:
By following the procedure described in Example 5, Step B, using as the reactants 2',3'-dichloro-4'-methoxy-2-methylbutyrophenone (26 g., 0.10 mole), acetic acid (75 ml.) and bromine (16 g., 0.10 mole), there is obtained 2-bromo-2-methyl-2',3'-dichloro-4'-methoxybutyrophenone.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][N:6]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)(=[O:14])=[O:13])[CH2:5][CH:4]1[OH:21].[NH:22]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:23]([C:28](O)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:34]([O:33][C:31](=[O:32])[NH:22][C@H:23]([C:28](=[O:29])[NH:2][CH:3]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][N:6]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)(=[O:14])=[O:13])[CH2:5][CH:4]1[OH:21])[CH2:24][CH:25]([CH3:26])[CH3:27])([CH3:35])([CH3:37])[CH3:36]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1(C)CC(N)C(O)CN(S(=O)(=O)c2ccccn2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1CC(C)(C)CN(S(=O)(=O)c2ccccn2)CC1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
4-Amino-6,6-dimethyl-1-(pyridine-2-sulfonyl)-azepan-3-ol HCl salt from Example 92g (0.22 g, 0.6 mmol) was dissolved in 5 ml DMF. To this solution, was added Boc-Leu-OH (0.22 g, 0.9 mmol) and HBTU (0.34 g, 0.9 mmol) and then NMM (0.24 g, 2.4 mmol). The mixture was stirred at r.t. overnight. DMF was removed under high vacuum. The residue was diluted with EtOAc and washed with H2O, 10% NaHCO3 and brine. Purification by column chromatography gave 0.22 g of the title compound (72% yield); MS (M+H+): 512.9; 1H-NMR (400 MHz, CDCl3): •8.68-8.67(d, 1H), 7.97-7.88(m, 2H), 7.69-7.64(m, 1H), 6.62-6.53(m, 1H), 5.06-5.00(m, 1H), 4.03-3.18(m, 7H), 1.80-1.42(m, 15H), 1.04-0.92(m, 12H).
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].[NH2:6][C:7](=[S:12])[C:8]([O:10][CH3:11])=[O:9].[CH3:13]CO>>[CH3:2][C:3]1[N:6]=[C:7]([C:8]([O:10][CH2:11][CH3:13])=[O:9])[S:12][CH:4]=1
Reactant: CC(=O)CCl
Reactant: CCO
Reactant: COC(=O)C(N)=S
Product: CCOC(=O)c1nc(C)cs1
Temperature: 80 °C
Yield: 33.8 %

Procedure:
1-Chloropropan-2-one (0.334 mL, 4.20 mmol) and methyl 2-amino-2-thioxoacetate (500 mg, 4.20 mmol) was dissolved in EtOH. The reaction solution was heated to 80° C. for overnight, cooled to RT, concentrated and purified with a silica gel column by ISCO CombiFlash® chromatography eluting with 10%-35% EtOAc/Haptane to give the title compound as a yellowish oil (243 mg, 33.8%) as the ethyl ester. A methyl ester product was isolated as a yellow solid (104 mg, 15.8%).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][C:22]1[CH2:23][S:24][C@@H:25]2[C@H:45]([NH:46][CH:47]=[O:48])[C:44](=[O:49])[N:26]2[C:27]=1[C:28]([O:30][CH:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>C(OCC)(=O)C>[Br-:20].[C:38]1([CH:31]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[O:30][C:28]([C:27]2[N:26]3[C:44](=[O:49])[C@@H:45]([NH:46][CH:47]=[O:48])[C@H:25]3[S:24][CH2:23][C:22]=2[CH2:21][P+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:29])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=CN[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CBr)CS[C@H]12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: O=CN[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Product: [Br-]
Reaction time: 8 h
Yield: 86.3 %

Procedure:
A solution of triphenylphosphine (1.47 g, 1.5 equiv.) in ethyl acetate (10 ml) was added to a stirred solution of diphenylmethyl 3-bromomethyl-7β-formamidoceph-3-em-4-carboxylate (1.82 g, 3.725 mmole) in ethyl acetate (50 ml). The mixture was stirred overnight at ca. 20° out of direct light, and the precipitated solid was filtered off, washed with ethyl acetate and dried to give the title phosphonium salt (2.41 g, 86%), λmax. (EtOH) 268.5 nm (ε 8,700) and 275.5 nm (ε 8,150), νmax. (CHBr3) 3440 (NH), (1788 azetidin-2-one), 1710 (CO2R), 1680 and 1500 (CONH) and 1443 cm-1 (P+ --C6H5), τ (CDCl3) 1.45 (1H,d, J 9 Hz; NH), 1.73 (1H, s; CHO), 3.57 (1H, s; (C6H5)2CH), 4.32 (1H,dd, J 9 and 5 Hz; C7 --H), 4.62 and 4.78 (2H, centres of 2 AB-quartets, JP-H 16 Hz, JH-H 15 Hz; C3 --CH2P+), 5.12 (1H,d, J 5 Hz; C6 -H), 6.06 and 6.60 (2H, broadened AB-q, J 18 Hz; C2 -H2).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].CO.O>CCOCC>[N:7]1([CH2:6][CH2:5][CH2:4][OH:3])[CH:11]=[N:10][CH:9]=[N:8]1
Reactant: CCOC(=O)CCn1cncn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: OCCCn1cncn1

Procedure:
To a solution of Ethyl-3-(1H-1,2,4-triazol-1-yl)propanoate (2.95 g, 17.5 mmol) in ether (90 ml), LiAlH4 (0.66 g, 17.5 mmol) was added. After heating to reflux for 60 h, 10 ml of 50%-methanol-water was added. The reaction mixture was filtered and the filter washed with 100 ml of methanol and twice with 100 ml of hot water. After evaporation the title product was obtained after purification using preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][CH3:8])=[N:5][N:6]=1.[Br:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]#[N:24])=[CH:13][CH:12]=1>C(O)(C)C>[BrH:9].[CH2:7]([C:4]1[S:3][C:2](=[NH:1])[N:6]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:15][CH:16]=2)[N:5]=1)[CH3:8]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCc1nnc(N)s1
Solvent: CC(C)O
Product: Br
Product: CCc1nn(Cc2ccc(-c3ccccc3C#N)cc2)c(=N)s1
Yield: 132 %

Procedure:
To 15 ml of isopropyl alcohol, 2.7 g of 2-amino-5-ethyl-1,3,4-thiadiazole and 1.3 g of 4'-bromomethyl-2-cyanobiphenyl were added, followed by heating under reflux for 3 hours. After the reaction mixture was cooled, crystals so precipitated were collected by filtration, washed successively with isopropyl alcohol and diethyl ether and then dried, whereby 2.53 g of the title compound was obtained.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][C@H]4CCCN(C(OC(C)(C)C)=O)C4)[N:16]=3)[C:12]([Cl:36])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[C:37](=[O:54])(ON1C(=O)CCC1=O)[O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.Cl.O1[CH2:61][CH2:60]OCC1>C(OCC)(=O)C.C(Cl)Cl>[Cl:36][C:12]1[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([C@H:61]3[CH2:60][CH2:4][CH2:5][NH:8][CH2:9]3)[CH3:22])[N:16]=2)=[CH:14][C:9]([NH:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([NH:1][C:37](=[O:54])[O:38][CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:3][CH2:4]2)=[N:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CNc2cccc(-c3cc(N[C@H]4CC[C@H](N)CC4)ncc3Cl)n2)C1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: C1COCCO1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(c1cccc(-c2cc(N[C@H]3CC[C@H](NC(=O)OCc4ccccc4)CC3)ncc2Cl)n1)[C@H]1CCCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (R)-tert-butyl 3-((2′-(trans-4-aminocyclohexylamino)-5′-chloro-2,4′-bipyridin-6-yl-amino)methyl)piperidine-1-carboxylate (36 mg, 0.070 mmol), DCM (1.2 ml), TEA (0.019 ml, 0.140 mmol) and benzyl 2,5-dioxopyrrolidin-1-yl carbonate (26.1 mg, 0.105 mmol) was stirred at ambient temperature for 2 hours and the reaction progress was followed by LCMS. To this crude reaction mixture was added 25 ml of ethyl acetate, washed with 2M sodium carbonate, water (2×) and saturated salt solution (1×), dried with sodium sulfate, filtered, concentrated to crude intermediate. To the crude intermediate was added 4M HCl in Dioxane (2 ml, 8.00 mmol) and stirred at ambient temperature for 1 hour. The crude reaction mixture was concentrated to constant mass, dissolved in 1 ml of DMSO and purified by prep LC. After lyophilization, 15 mg of the title compound, was obtained as a TFA salt. LCMS (m/z): 549.4 (MH+), retention time=0.67 min.
Reaction SMILES: [N:1]1(CCOC2C=C(CC#N)C=CC=2)CCOCC1.[C:19]1([N:25]([C:28]2[CH:33]=[CH:32]C=CC=2)C=N)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C(C)=CC=CC=1.CCCCCC>[C:19]1([NH:25][CH:28]=[CH:33][C:32]#[N:1])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N#CCc1cccc(OCCN2CCOCC2)c1
Reactant: N=CN(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Product: N#CC=CNc1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 170.8 %

Procedure:
A mixture of 2-[3-(2-morpholin-4-ylethoxy)phenyl]acetonitrile (5.0 g) and N,N-diphenylformamidine (5.0 g, 25.5 mmol) in xylene (150 ml). was heated at 100° C. under a nitrogen atmosphere. After 3 h, the reaction mixture was cooled to room temperature and diluted with hexane to give 2-|3-(2-morpholin-4-ylethoxy)benzoyl[-3-phenylaminoacrylonitrile (5.0 g) as a solid.
Reaction SMILES: C(OCC1C2C(=CN=C(C([NH:21][OH:22])=O)C=2)N(CC2C=CC(F)=CC=2F)C=1)C1C=CC=CC=1.[Cl:32][C:33]1[CH:56]=[C:55]([F:57])[CH:54]=[CH:53][C:34]=1[O:35][CH2:36][C:37]1[C:41]2[CH:42]=[N:43][C:44]([C:46]([O:48]CC)=O)=[CH:45][C:40]=2[N:39]([CH2:51][CH3:52])[CH:38]=1.ClC1C(O)=C(C=C(F)C=1)CC1C2C=NC(C(OCC)=O)=CC=2N(CC)C=1>>[Cl:32][C:33]1[CH:56]=[C:55]([F:57])[CH:54]=[CH:53][C:34]=1[O:35][CH2:36][C:37]1[C:41]2[CH:42]=[N:43][C:44]([C:46]([NH:21][OH:22])=[O:48])=[CH:45][C:40]=2[N:39]([CH2:51][CH3:52])[CH:38]=1
Reactant: CCOC(=O)c1cc2c(cn1)c(COc1ccc(F)cc1Cl)cn2CC
Reactant: O=C(NO)c1cc2c(COCc3ccccc3)cn(Cc3ccc(F)cc3F)c2cn1
Agent: CCOC(=O)c1cc2c(cn1)c(Cc1cc(F)cc(Cl)c1O)cn2CC
Product: CCn1cc(COc2ccc(F)cc2Cl)c2cnc(C(=O)NO)cc21

Procedure:
Ethyl 3-(2-chloro-4-fluoro-phenoxymethyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate and ethyl 3-(3-chloro-5-fluoro-2-hydroxy-benzyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate. The title compound can be prepared from ethyl 3-hydroxymethyl-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate and 2-chloro-4-fluorophenol using methods similar to step (e) of Example 54. (b) 3-(2-Chloro-4-fluoro-phenoxymethyl)-1-ethyl-N-hydroxy-1H-pyrrolo[3,2-c]pyridine-6-carboxamide. The title compound can be prepared from a mixture of ethyl 3-(2-chloro-4-fluoro-phenoxymethyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate and ethyl 3-(3-chloro-5-fluoro-2-hydroxy-benzyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate in a manner similar to step (e) of Example 11. Purification by HPLC can provide the pure title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4](=[O:35])[CH:5]([CH:24](O)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]C(OC)=O)[CH:6]([CH:8]=[CH:9][CH:10]([O:16][Si](C(C)(C)C)(C)C)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1.[C:36]([OH:39])(=[O:38])C.O1CCC[CH2:41]1.O>C1(C)C=CC=CC=1>[CH3:1][S:2][C:3]1[C:4](=[O:35])[CH:5]([CH:24]([C:36]([O:39][CH3:41])=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:6]([CH:8]=[CH:9][CH:10]([OH:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1
Reactant: C1CCOC1
Reactant: CCCCCC(C=CC1C=C(SC)C(=O)C1C(O)CCCCCC(=O)OC)O[Si](C)(C)C(C)(C)C
Reactant: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC(O)C=CC1C=C(SC)C(=O)C1C(CCCCC)C(=O)OC
Reaction time: 24 h
Yield: 65 %

Procedure:
To 350 mg of 2-methylthio-5-(1-hydroxy-6-methoxycarbonylhexyl)-4-(3-t-butyldimethylsilyloxy-1-octenyl)-2-cyclopentenone obtained in Example 6 was added a solvent mixture of 10 ml of acetic acid, 5 ml of tetrahydrofuran, and 5 ml of water, and the mixture was stirred for 24 hours. Toluene was then added, and after concentration, the concentrate was diluted with saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. Subsequently, the extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated, followed by silica gel chromatography to give 178 mg (yield 65%) of 2-methylthio-5-(1-methoxycarbonylhexyl)-4-(3-hydroxy-1-octenyl)-2-cyclopentenone.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].C[C:22]1[NH:26][C:25]2[CH:27]=[CH:28][C:29]([C:31]([OH:33])=O)=[CH:30][C:24]=2[N:23]=1.CN1CCO[CH2:37][CH2:36]1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>ClCCl.CN(C)C=O>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:31]([C:29]1[CH:28]=[CH:27][C:25]2[N:26]([CH2:36][CH3:37])[CH:22]=[N:23][C:24]=2[CH:30]=1)=[O:33]
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Reactant: CN1CCOCC1
Reactant: Cc1nc2cc(C(=O)O)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCn1cnc2cc(C(=O)Nc3ccc(N4CCC(CN5CCCC5C)C4)cc3C)ccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 56.1 %

Procedure:
2-Methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine (27 mg, 0.1 mmol) and 2-methyl-1H-benzoimidazole-5-carboxylic acid (17.6 mg, 0.1 mmol) were dissolved in a mixture of 3 ml of dichloromethane and 1 ml of dimethylformamide. To this solution was then added N-methylmorpholine (33 μl, 0.3 mmol), 1-hydroxybenzotriazole (17.6 mg, 0.13 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (22 mg, 0.123 mmol). The reaction was stirred at room temperature for 20 h. Evaporation and RP-HPLC gave 25 mg of the title compound with trifluoro-acetic acid as a salt (46%). MS: 432.5 (M+H)
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]1([CH:12]([O:19][C:20]([C:22]2[N:27]3[C:28](=[O:51])[CH:29]([NH:30][C:31](=[O:50])[CH:32]([C:42]4[N:43]=[C:44]([NH:47]C=O)[S:45][CH:46]=4)[NH:33][C:34]([C:36](=[O:41])[NH:37][NH:38]C=O)=[O:35])[C@H:26]3[S:25][CH2:24][C:23]=2[CH2:52][S:53][C:54]2[S:55][CH:56]=[N:57][N:58]=2)=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO>[ClH:3].[ClH:3].[C:6]1([CH:12]([O:19][C:20]([C:22]2[N:27]3[C:28](=[O:51])[CH:29]([NH:30][C:31](=[O:50])[CH:32]([C:42]4[N:43]=[C:44]([NH2:47])[S:45][CH:46]=4)[NH:33][C:34]([C:36](=[O:41])[NH:37][NH2:38])=[O:35])[C@H:26]3[S:25][CH2:24][C:23]=2[CH2:52][S:53][C:54]2[S:55][CH:56]=[N:57][N:58]=2)=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=CNNC(=O)C(=O)NC(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nncs3)CS[C@H]12)c1csc(NC=O)n1
Solvent: CO
Product: Cl
Product: NNC(=O)C(=O)NC(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nncs3)CS[C@H]12)c1csc(N)n1

Procedure:
Methanol (100 ml) was ice-cooled and 2.15 g of phosphorus oxychloride was added dropwise under stirring. To this mixture was added 5.49 g (6.91 mmole) of 7-[2-(2-formylamino-1,3-thiazol-4-yl)-2-(3-formylcarbazoyl)carbonylaminoacetamido]-3-[(1,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester obtained in Reference example 57, and the mixture was stirred for 3 hours under ice-cooling.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[F:55][C:56]([F:68])([F:67])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[S:63](Cl)(=[O:65])=[O:64]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:63]([C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=2[C:56]([F:55])([F:67])[F:68])(=[O:65])=[O:64])[CH2:49][CH2:48]1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(S(=O)(=O)c2ccccc2C(F)(F)F)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 14 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-(trifluoromethyl)benzenesulfonyl chloride as starting materials in 14% yield. LCMS for C31H30ClF3N7O3S (M+H)+: m/z=672.2.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[S:11][CH2:12][CH3:13].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]=[C:21]=[O:22])[CH:15]=1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:21](=[O:22])[NH:20][C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[S:11][CH2:12][CH3:13]
Reactant: CCSc1cc2c(cc1Br)NCC2
Reactant: O=C=Nc1cccnc1
Product: CCSc1cc2c(cc1Br)N(C(=O)Nc1cccnc1)CC2
Yield: 70 %

Procedure:
6-Bromo-5-ethylthioindoline (D84) (0.28 g, 1.09 mmol) was treated with 3-pyridylisocyanate as in the procedure described in Example 1. The product was recrystallised from ethanol/diethyl ether to yield the title compound (0.29 g, 70%) as an off-white crystalline solid m.p. 226°-227° C.
Reaction SMILES: O[CH2:2][CH:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])[CH2:4][NH:5][C:6](=[O:12])[O:7]C(C)(C)C.[Cl:23]S([N:27]=C=O)(=O)=O.O.C(=O)(O)[O-].[Na+]>C(#N)C>[ClH:23].[NH2:27][CH2:2][CH:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])[CH2:4][NH:5][C:6](=[O:12])[OH:7]
Reactant: CC(C)(C)OC(=O)NCC(CO)c1ccccc1C(F)(F)F
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cl
Product: NCC(CNC(=O)O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 387 mg (1.21 mmol) of the compound of Example 12A in 19.3 ml of acetonitrile was cooled to −15° C., and 148 μl (1.70 mmol) of chlorosulphonyl isocyanate were added. After 5 min, 10 ml of water were added and stirring of the reaction mixture was continued at 60° C. overnight. After cooling to RT, 10 ml of a saturated aqueous sodium bicarbonate solution were added. The mixture was extracted four times with ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator. 5 ml of a 4 N solution of hydrogen chloride in dioxane were added to the residue and the mixture was stirred for 5 min Once more, the volatile components were then removed on a rotary evaporator. The residue (300 mg, about 90% pure) corresponded to the title compound and was reacted further without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([N+:22]([O-])=O)[CH:15]=3)[N:9]=[C:10]([CH:11]([CH3:13])[CH3:12])[C:3]=12.[Cl-].[NH4+].C1C[O:30]CC1>CO.O.[Fe]>[NH2:22][C:16]1[CH:15]=[C:14]([N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([Cl:1])=[C:3]3[C:10]([CH:11]([CH3:13])[CH3:12])=[N:9]2)[CH:21]=[CH:20][C:17]=1[C:18]([NH2:19])=[O:30]
Reactant: CC(C)c1nn(-c2ccc(C#N)c([N+](=O)[O-])c2)c2nccc(Cl)c12
Reactant: C1CCOC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CC(C)c1nn(-c2ccc(C(N)=O)c(N)c2)c2nccc(Cl)c12
Temperature: 70 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Compound (6b) (0.335 g) was dissolved in DMF (8.6 mL), and sodium hydride (0.097 g, a 55% dispersion in paraffin liquid) was added to the resulting solution at 0° C., followed by stirring for 30 min. Then, 4-fluoro-2-nitrobenzonitrile was added to the reaction solution, followed by stirring at 60° C. for 30 min. Water was added to the reaction solution, and the precipitate was collected by filtration and washed by sprinkling water to obtain 4-{4-chloro-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-nitrobenzonitrile (0.5 g, 85%). 4-{4-Chloro-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-nitrobenzonitrile (0.35 g) and ammonium chloride (0.35 g) were dissolved in a solvent mixture of THF (3 mL), methanol (3 mL), and water (3 mL). Iron (0.57 g) was added to the resulting solution, followed by stirring at 70° C. for 1 hr. Insoluble matters were filtered by celite, and the solvent was distilled away. The precipitate was washed with water and was collected by filtration to obtain compound (106a) (0.32 g, 95%) as a white solid.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.C(OC(=O)[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])C.[CH2:27]([O:29][C:30](C1ON=C(C2C=CC([N+]([O-])=O)=CC=2)C=1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:19]1[C:3]([C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)=[N:2][O:1][C:18]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:31])[CH3:28]
Reactant: O=[N+]([O-])c1ccc(C(Cl)=NO)cc1
Reactant: CCOC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)no1
Reactant: CCOC(=O)C(C)c1ccccc1
Product: CCOC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)noc1-c1ccccc1
Temperature: 80 °C

Procedure:
The title compound was prepared from N-hydroxy-4-nitro-benzimidoyl chloride and phenyl propionic acid ethyl ester by the same procedure as described for the synthesis of 3-(4-nitro-phenyl)-isoxazol-5-carboxylic acid ethyl ester in Example 1. The reaction mixture was refluxed for 16 hours instead of heating at 80° C. for 2.5 hours. The crude product was purified by flash chromatography over silica gel with 10-30% EtOAc in light petroleum to give the title compound in 40% yield. 1H NMR (DMSO-d6) δ: 0.98 (t, 3H), 4.11 (q, 2H), 7.53-7.61 (m, 3H), 7.87-7.93 (m, 4H), 8.32 (d, 2H); Mass (ES+), 339 (M++1).