Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.Cl[CH2:12][CH2:13][C:14]([OH:16])=[O:15]>C(O)C.[OH-].[K+]>[N+:7]([C:6]1[CH:5]=[CH:4][C:3]([O:10][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:2][CH:1]=1)([O-:9])=[O:8]
Reactant: O=C(O)CCCl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCOc1ccc([N+](=O)[O-])cc1
Yield: 35.5 %

Procedure:
Dissolve p-nitrophenol (11 g, 100 mmol), 3-chloropropanoic acid (14 g, 100 mmol) in a mixture of ethanol (100 mL) and 20% aqueous KOH solution (100 mL). Heat to reflux for 2 hrs, then adjust pH=1-3, extract with EtOAc (300 mL×3), combine the organic layers and wash with brine (300 mL×2), dry over anhydrous Na2SO4. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:4) affords the title compound (7.5 g, 14.9%). MS: (M+1): 212.1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([OH:12])[CH:3]=1.[I:13]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([OH:12])[C:3]=1[I:13]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(=O)c1cc(Cl)c(Cl)cc1O
Solvent: CC(=O)O
Product: CC(=O)c1cc(Cl)c(Cl)c(I)c1O
Temperature: 90 °C
Reaction time: 18 h
Yield: 46.1 %

Procedure:
A solution of 1-(4,5-dichloro-2-hydroxyphenyl)ethanone (12 g, 59 mmol) in acetic acid (70 mL) was treated with N-iodosuccinimide (16 g, 71 mmol) and stirred at 90° C. for 18 hours. The reaction mixture was treated with additional N-iodosuccinimide (8 g, 36 mmol) and stirred at 90° C. for 4 hours. The reaction mixture was concentrated, diluted with EtOAc, and quenched with saturated sodium bicarbonate until the bubbling stopped. The organic layer was separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried and concentrated to give a brown solid. This material was recrystallized from methanol to give desired product (9.0 g, 46%) as a tan solid. LCMS for C8H6Cl2IO2 (M+H)+: m/z=330.9, 332.9. Found: 330.8, 332.9.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[CH:34]([CH3:35])[CH:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH:27](C(OC)=O)[C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45].O>N1C(C)=CC(C)=CC=1C>[CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[C@@H:34]([CH3:35])[C@H:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH2:27][C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45]
Reactant: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4C(=O)OC)C(CCC(=O)OC)C3C
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Product: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4)[C@@H](CCC(=O)OC)[C@@H]3C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.8 %

Procedure:
To a solution of methyl pheophorbide-a (100 mg, 0.17 mmol) in 2,4,6-collidine (25 mL, distilled) was added distilled water (6 μL, 0.33 mmol, 2 equiv.) and the mixture was refluxed under argon with stirring. The reaction was monitored by HPLC (hexaneacetone, 90:10-mobile phase, LiChrospherCN-column, detection at 425 and 410 nm). After 10 min the reaction was shown to have reached 100% completion by HPLC peak area. The solution was cooled to room temperature after 30 min of reflux and solvent removed under reduced pressure. The residue was precipitated from methylene chloride-methanol to give methyl pyropheophorbide-a (80 mg, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:27][C:28]([NH2:30])=[NH:29].C(N(CC)CC)C>CN(C)C=O.O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:27]=[C:28]([NH2:30])[NH2:29])=[O:13])=[CH:5]2
Reactant: N=C(N)N
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(N)=NC(=O)c1cc2cc(Cl)ccc2[nH]1
Yield: 132.8 %

Procedure:
The reaction was carried out in a manner similar to Example 84 except for using 2.00 g (10.2 mmol) of 5-chloro-2-indolecarboxylic acid, 1.82 g (11.3 mmol) of carbonyldiimidazole, 5.86 g (61.3 mmol) of guanidine hydrochloride, 6.20 g (61.3 mmol) of triethylamine, 50 ml of tetrahydrofuran and 50 ml of dimethylformamide. Thus 1.85 g (66.2%) of 5-chloro-2-indoloylguanidine hydrochloride was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.[NH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23]2[N:27]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:26]3[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=3[N:24]=2)[CH2:18][CH2:17]1>ClCCl>[F:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][N:27]2[C:26]3[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=3[N:24]=[C:23]2[NH:22][CH:19]2[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][NH:13][C:10]([C:2]3[NH:1][C:9]4[C:4]([CH:3]=3)=[CH:5][CH:6]=[CH:7][CH:8]=4)=[O:12])[CH2:17][CH2:18]2)=[CH:30][CH:31]=1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Solvent: ClCCl
Product: O=C(NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)c1cc2ccccc2[nH]1
Temperature: 25 °C
Yield: 19.5 %

Procedure:
A mixture of 1.6 parts of 1H-indole-2-carboxylic acid, 3.67 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine, 2.1 parts of N,N'-methanetetraylbis[cyclohexanamine] and 195 parts of dichloromethane was stirred over weekend at room temperature. The reaction mixture was filtered over Hyflo and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 1 parts (19.5%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-1H-indole-2-carboxamide; mp. 232.1° C. (compound 76).
Reaction SMILES: C(N)C1C=CC=CC=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[C:19]([NH2:28])=[N:20][C:21]([NH2:27])=[N:22]3)[CH2:11][CH2:10]1.[CH3:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1.[ClH:38].O1CCOCC1>>[ClH:38].[CH3:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[C:19]([NH2:28])=[N:20][C:21]([NH2:27])=[N:22]4)[CH2:11][CH2:10]2)=[CH:32][CH:31]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: NCc1ccccc1
Product: Cc1ccc(CN2CCC(COc3cccc4nc(N)nc(N)c34)CC2)cc1
Yield: 90 %

Procedure:
The benzylamine was obtained by reacting 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (75 mg; 0.27 mmol) and 4-methylbenzyl bromide (60 mg; 0.32 mmol) via Method BB to a solid, which was stirred in the presence of 4M HCl in dioxane (4 eq). Solids were filtered and rinsed once with ether to give title compound. (101 mg; 90% yield). 1HNMR (400 MHz, DMSO-d6) δ 12.8 (s, 1H), 11.0 (s, 1H), 8.82 (s, 1H), 8.23 (s, 1H), 7.69 (m, 2H), 7.5 (d, J=8.0 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 4.91 (br s, 2H), 4.17 (m, 4H), 3.36 (br d, J=11.6 Hz, 2H), 2.85 (m, 2H), 2.33 (s, 3H), 2.2 (m, 1H), 1.79 (m, 4H). MS m/z (ESI) 378 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH:8]=[CH2:9].[F:11][C:12]1[CH:13]=[C:14]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][C:40]([O:42][CH2:43][CH:44]=[CH2:45])=[O:41])=[CH:35][CH:34]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[C:22]([OH:30])[C:21]=1[CH:31]=[O:32].O>CN(C)C=O>[CH2:7]([O:30][C:22]1[C:21]([CH:31]=[O:32])=[C:20]([CH:25]=[CH:24][C:23]=1[C:26]([F:29])([F:27])[F:28])[CH2:19][O:18][C:17]1[CH:16]=[CH:15][C:14]([C:33]2[CH:34]=[CH:35][C:36]([CH2:39][C:40]([O:42][CH2:43][CH:44]=[CH2:45])=[O:41])=[CH:37][CH:38]=2)=[CH:13][C:12]=1[F:11])[CH:8]=[CH2:9]
Reactant: C=CCBr
Reactant: C=CCOC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C=O)c(F)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OCC=C)c3C=O)c(F)c2)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 23.7 %

Procedure:
Potassium carbonate (148 mg, 1.07 mmol) and allyl bromide (0.091 ml, 1.1 mmol) were successively added to a solution of allyl (3′-fluoro-4′-{[2-formyl-3-hydroxy-4-(trifluoromethyl)benzyl]oxy}-1,1′-biphenyl-4-yl)acetate (476 mg, 0.975 mmol) obtained in Example (12-4) in N,N-dimethylformamide (5 ml), and the mixture was stirred at 50° C. for 1.5 hours. After the reaction mixture was poured into water and the mixture was extracted with ethyl acetate, the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=3/1) to give allyl (4′-{[3-(allyloxy)-2-formyl-4-(trifluoromethyl)benzyl]oxy}-3′-fluoro-1,1′-biphenyl-4-yl)acetate (122 mg, yield: 24%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:5]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:6].C(=O)([O-])[O-].[K+].[K+].[C:25](Cl)(=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[CH2:25]([O:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:5]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:6])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)CCC(=O)c1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Reaction time: 8 h

Procedure:
A mixture of methyl 3-(3-hydroxy-4-nitrobenzoyl)propionate, potassium carbonate, benzoyl chloride, and dimethylformamide was stirred overnight and the solvent removed by evaporation under reduced pressure. The residue was distributed between water and ether, and the aqueous phase was extracted with ether. The combined ethereal solution was washed in turn with dilute sodium hydroxide solution and water. Evaporation of the dried solution gave methyl 3-(3-benzyloxy-4-nitrobenzoyl)propionate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([O:14][CH3:15])=[C:4]([C:16]2[CH:21]=[CH:20][C:19](CC(C)C)=[CH:18][CH:17]=2)[N:3]=1.[F-:26].[Cs+]>CS(C)=O.C(OC(=O)C)C>[F:26][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([O:14][CH3:15])=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([O:12][CH:8]([CH3:9])[CH3:7])=[CH:18][CH:17]=2)[N:3]=1
Reactant: [F-]
Reactant: COc1ccc2c(Cl)nc(-c3ccc(CC(C)C)cc3)c(OC)c2c1
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc2c(F)nc(-c3ccc(OC(C)C)cc3)c(OC)c2c1
Temperature: 140 °C
Yield: 175.8 %

Procedure:
To a solution of 1-chloro-3-(4-isobutylphenyl)-4,6-dimethoxyisoquinoline (142 mg, 0.4 mmol) in DMSO (2 mL), was added CsF (122 mg, 0.800 mmol) and the mixture was heated to 140° C. for 4 hrs. The reaction was diluted with ethylacteate and washed with water, and brine. The organic phase was collected, dried over sodium sulfate, and concentrated under vacuum to give the crude product which was purified by silica gel chromatography using a gradient of 5-25% EtOAc/Hexanes. The product fractions were collected and the solvent removed under vacuum to give 120 mg of the desired product as a white solid containing starting material. MS: MS m/z 342.1 (M++1).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][OH:19])[CH2:12][CH2:11]1.C([O:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[N:31][C:32](Cl)=[CH:33][CH:34]=2)[N:29]=1)C1C=CC=CC=1>C1COCC1>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:32]2[N:31]=[C:30]3[C:35]([CH:36]=[CH:37][C:28](=[O:27])[NH:29]3)=[CH:34][CH:33]=2)[CH2:14][CH2:15]1
Reactant: OCCCN1CCN(c2cccc(Cl)c2Cl)CC1
Reactant: Clc1ccc2ccc(OCc3ccccc3)nc2n1
Agent: Cl
Solvent: C1CCOC1
Product: O=c1ccc2ccc(OCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2[nH]1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 57 %

Procedure:
An intermediate compound, 2-Benzyloxy-7-{3-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-propoxy}-[1,8]naphthyridine, was produced as follows: To a suspension of 3-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-propan-1-ol hydrochloride (400 mg, 1.23 mmol) in THF (5 mL) cooled to −40° C. was added KOtBU (1 M in THF, 2.3 mL, 2.3 mmol, 1.9 equiv). The mixture became a cloudy solution. After stirring for 20 min at −40° C., 2-benzyloxy-7-chloro-[1,8]naphthyridine (333 mg, 1.23 mmol) was added as a solution in THF (8 mL) via cannula. The reaction was allowed to warm to 0° C. slowly over 1 h. The reaction was quenched with saturated NH4Cl and H2O and extracted with EtOAc. The organic layer was washed with saturated NaHCO3 and brine, dried over Na2SO4 and concentrated. Purification by liquid chromatography (CH2Cl2 to 2% MeOH/CH2Cl2) gave the title compound as a clear oil/foam (367 mg, 0.701 mmol, 57%). MS: APCI: M+1: 523.0 (Exact Mass: 522.16).
Reaction SMILES: [Cl:1][C:2]1[C:17]([Cl:18])=[C:16]([O:19]C)[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[CH3:13])=[O:5]>C1C=CC=CC=1>[Cl:1][C:2]1[C:17]([Cl:18])=[C:16]([OH:19])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[CH3:13])=[O:5]
Reactant: COc1ccc(C(=O)c2cccc(C)c2C)c(Cl)c1Cl
Solvent: c1ccccc1
Product: Cc1cccc(C(=O)c2ccc(O)c(Cl)c2Cl)c1C

Procedure:
The procedure of Example 24b is repeated with 39 g of 2,3-dichloro-4-methoxy-2',3'-dimethylbenzophenone in 300 ml of benzene. The resultant product is recrystallized from toluene to yield 2,3-dichloro-4-hydroxy-2',3'-dimethylbenzophenone.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C@@H:6]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][CH2:14][CH2:15][C:16]2([CH3:21])OCC[O:17]2)[C:8]1=[O:22])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][C@@H:6]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][CH2:14][CH2:15][C:16](=[O:17])[CH3:21])[C:8]1=[O:22])[CH3:2]
Reactant: CCOC(=O)C[C@@H](c1cccc(F)c1)N1CCCC(CCCC2(C)OCCO2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@@H](c1cccc(F)c1)N1CCCC(CCCC(C)=O)C1=O

Procedure:
A solution of 2-6 (500 mg, 1.10 mmol), p-TSA (10 mg) and acetone (50 mL) was heated at reflux for 4 h. The cooled reaction mixture was diluted with EtOAc and then washed with sat. NaHCO3 and brine, dried (MgSO4), and concentrated to afford 2-7 as a yellow oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:27]=[CH:28][C:29]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:21]([NH:23][CH:24]1[CH2:26][CH2:25]1)=[O:22].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[Cl:17][C:18]1[CH:19]=[C:20]([CH:27]=[CH:28][C:29]=1[N:30]1[CH2:31][CH2:32][N:33]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][C@H:8]4[C:7](=[O:16])[NH:6][C:5]=3[CH:4]=2)[CH2:34][CH2:35]1)[C:21]([NH:23][CH:24]1[CH2:26][CH2:25]1)=[O:22]
Reactant: O=C(NC1CC1)c1ccc(N2CCNCC2)c(Cl)c1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)c(Cl)c1
Temperature: 105 °C
Yield: 54.8 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), 3-chloro-N-cyclopropyl-4-(piperazin-1-yl)benzamide (128 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 25-95% ACN in water, basic). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-MeOH (2:1, 15 mL) and dried in vacuum to afford (S)-3-chloro-N-cyclopropyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (120.4 mg, 0.250 mmol, 54.9% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.50-0.60 (m, 2 H) 0.61-0.72 (m, 2 H) 1.84-2.01 (m, 3 H) 2.12-2.23 (m, 1 H) 2.51-2.57 (m, 4 H) 2.77-2.86 (m, 1 H) 3.02 (br. s., 4 H) 3.35-3.46 (m, 3 H) 3.54-3.64 (m, 1 H) 3.95-4.03 (m, 1 H) 6.98 (d, J=1.77 Hz, 1 H) 7.16 (d, J=8.34 Hz, 1 H) 7.63 (d, J=1.77 Hz, 1 H) 7.75 (dd, J=8.34, 2.02 Hz, 1 H) 7.85 (d, J=2.02 Hz, 1 H) 8.39 (d, J=4.04 Hz, 1 H) 10.45 (s, 1 H). [M+H] calc'd for C25H29ClN6O2, 481; found, 481.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1([CH3:23])[CH2:22][O:21]1.O>CCCCCC.O1CCCC1>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]([OH:21])([CH3:22])[CH2:23][C:9]1[S:8][C:7]([Cl:6])=[N:11][CH:10]=1
Reactant: CC1(c2ccc(Cl)cc2Cl)CO1
Reactant: Clc1nccs1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(O)(Cc1cnc(Cl)s1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
Butyl lithium (2.5 M, 12.5 ml) in hexane was added to a solution of 2-chlorothiazole (3.6 g, 30 mmol) in tetrahydrofuran (100 ml) at -78° C. under an atmosphere of nitrogen. After 10 minutes, a solution of 2-(2,4-dichlorophenyl)-2-methyloxirane (5.4 g, 26 mmol) in tetrahydrofuran (40 ml) was added and the mixture was slowly allowed to warm to room temperature and then stirred for a further 3 hours. Water was added and the tetrahydrofuran was then evaporated under reduced pressure. The residue was extracted with ethyl acetate (2×300 ml) and the combined organic extract was washed with saturated sodium chloride solution and then dried. Flash chromatography of the residue on a silica gel column using ethyl acetate-petroleum ether as eluant gave 2-(2,4-dichlorophenyl)-1-(2-chlorothiazol-5-yl)-propan-2-ol (6.4 g) as a white solid, m.pt. 164° C.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.CS(O[CH2:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=1)(=O)=O>>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([O:24][CH3:25])[CH:21]=1)[CH2:17][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: COc1cc(COS(C)(=O)=O)cc(OC)c1
Product: COc1cc(Cn2ccc3c(C=O)cccc32)cc(OC)c1

Procedure:
The same procedures used in Example 1 were repeated except for using 725 mg of indole-4-carbaldehyde and 3,5-dimethoxybenzyl methanesulfonate instead of the benzyl bromide used in Example 1 to give 1.29 g of 1-(3,5-dimethoxybenzyl)indole-4-carbaldehyde as a pale brown amorphous substance. The yield thereof was found to be 86%.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH:8](OCC)OCC)[N:5]=[CH:4][C:3]=1[C:15]#[N:16]>Cl>[C:15]([C:3]1[CH:4]=[N:5][N:6]2[CH:7]=[CH:8][NH:1][C:2]=12)#[N:16]
Reactant: CCOC(Cn1ncc(C#N)c1N)OCC
Agent: Cl
Product: N#Cc1cnn2cc[nH]c12
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
A solution of 5-amino-4-cyano-1-(2,2-diethoxyethyl)-pyrazole (23 g) in lN hydrochloric acid (205 ml) was heated at 60-70° C. The mixture was stirred for 0.5 hour at the same condition. The reaction mixture was cooled under ice-water and the resultant solid was collected by filtration, washed with ice-water and dried over phosphorus pentoxide in vacuo to the crude product. The product was crystallized from ethanol (400 ml) to give 7-cyano-1H-imidazo[1,2-b]pyrazole (12.4 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[N:12][O:13][C:14]([C:17](=[O:30])[NH:18][NH:19][C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([OH:28])[CH:22]=2)([CH3:16])[CH3:15])[C:9](O)=[O:10])[N:7]=1.[NH2:31][CH:32]1[C:69](=[O:70])[N:34]2[C:35]([C:53]([O:55]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:54])=[C:36]([CH2:39][S:40][C:41]3[N:46]4[N:47]=[C:48]([CH3:50])[N:49]=[C:45]4[N:44]=[C:43]([CH2:51][OH:52])[CH:42]=3)[CH2:37][S:38][C@H:33]12.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.C(=O)([O-])O.[Na+:115]>CN(C=O)C.O.CCOCC>[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[N:12][O:13][C:14]([C:17](=[O:30])[NH:18][NH:19][C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([OH:28])[CH:22]=2)([CH3:16])[CH3:15])[C:9]([NH:31][CH:32]2[C:69](=[O:70])[N:34]3[C:35]([C:53]([O-:55])=[O:54])=[C:36]([CH2:39][S:40][C:41]4[N:46]5[N:47]=[C:48]([CH3:50])[N:49]=[C:45]5[N:44]=[C:43]([CH2:51][OH:52])[CH:42]=4)[CH2:37][S:38][C@H:33]23)=[O:10])[N:7]=1.[Na+:115]
Reactant: CC(C)(ON=C(C(=O)O)c1csc(N)n1)C(=O)NNC(=O)c1ccc(O)c(O)c1
Reactant: Cc1nc2nc(CO)cc(SCC3=C(C(=O)OC(c4ccccc4)c4ccccc4)N4C(=O)C(N)[C@H]4SC3)n2n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2nc(CO)cc(SCC3=C(C(=O)[O-])N4C(=O)C(NC(=O)C(=NOC(C)(C)C(=O)NNC(=O)c5ccc(O)c(O)c5)c5csc(N)n5)[C@H]4SC3)n2n1
Reaction time: 0.25 h

Procedure:
In 30 ml of DMF were dissolved 3.22 g of 2-(2-amino-1,3-thiazol-4-yl)-2-{1-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxyimino}acetic acid.hydrochloride, 5.17 g of diphenylmethyl 7-amino-3-[(5-hydroxymethyl-2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylate obtained in Example 37 and 1.38 g of 1-hydroxybenzotriazole and ice-cooled. Then, 1.86 g of DCC was added thereto and the mixture was stirred for 15 minutes under ice-cooling, and further stirred at room temperature for 30 minutes. After the reaction mixture was filtered, 15 ml of chloroform was added thereto and the mixture was added dropwise into 4 liters of ether. precipitates were collected by filtration, washed with ether and then dried. Powder obtained was purified through silica gel column chromatography to obtain powder. A mixed solution of 30 ml of trifluoroacetic acid and 8 ml of anisole was ice-cooled and the powder previously obtained was added thereto, and the mixture was stirred for 30 minutes and added dropwise into 400 ml of ether, precipitates were collected by filtration, washed with ether and then dried to obtain powder. The powder was suspended in 200 ml of water and dissolved at pH 7 by adding a 5% sodium hydrogencarbonate solution. After the resulting solution was adsorbed to 200 ml of HP 20 column filled with water, it was washed with water Subsequently, the mixture was eluted with a 50% methanol-water After evaporation of methanol, the residue was freeze-dried to obtain 3.75 g of the title compound.