Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.Cl.[CH2:4]([N:11]([CH2:25]/[CH:26]=[CH:27]/[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH2:33])=[NH:32])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[C:38](=[NH:43])(OCC)[CH3:39].C(N(CC)CC)C.Cl>CO.O1CCOCC1>[ClH:1].[ClH:1].[ClH:1].[C:38]([N:22]1[CH2:21][CH2:20][CH:19]([O:18][C:15]2[CH:14]=[CH:13][C:12]([N:11]([CH2:25]/[CH:26]=[CH:27]/[C:28]3[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=3)[C:31]([NH2:33])=[NH:32])[CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:17][CH:16]=2)[CH2:24][CH2:23]1)(=[NH:43])[CH3:39]
Reactant: CCOC(C)=N
Reactant: N=C(N)c1cccc(/C=C/CN(Cc2ccccc2)c2ccc(OC3CCNCC3)cc2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=N)N1CCC(Oc2ccc(N(C/C=C/c3cccc(C(=N)N)c3)Cc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 210 %

Procedure:
To a solution of 3-[3-[N-benzyl-N-[4-(piperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzamidine trihydrochloride (335 mg) in methanol (20 ml) were added ethyl acetimidate hydrochloride (230 mg) and triethylamine (0.51 ml) at room temperature. The resulting mixture was stirred at room temperature for 12 hours. To the reaction mixture was added a 4M solution of hydrogen chloride in dioxane (1 ml) and the solution was concentrated in vacuo. The residue was purified by preparative HPLC (YMC-Pack ODS YMC) using 30% aqueous acetonitrile as an eluant to afford an amorphous solid. To a solution of the solid in methanol (10 ml) was added a 4M solution of hydrogen chloride in dioxane (0.5 ml) and the mixture was concentrated to dryness in vacuo. A solution of the residual solid in water (about 10 ml) was lyophilized to give the title compound (252 mg, yield 70%) as a colorless amorphous solid.
Reaction SMILES: Cl[C:2]1[N:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][C:7]([F:11])=[CH:6]2.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=1>CN1CCCC1=O>[Cl:19][C:20]1[CH:21]=[C:22]([NH:26][C:2]2[N:3]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[N:4]=[C:5]3[C:10]=2[CH:9]=[CH:8][C:7]([F:11])=[CH:6]3)[CH:23]=[CH:24][CH:25]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Fc1ccc2c(Cl)n(-c3ccc(Cl)cc3)nc2c1
Solvent: CN1CCCC1=O
Product: Fc1ccc2c(Nc3cccc(Cl)c3)n(-c3ccc(Cl)cc3)nc2c1

Procedure:
In analogy to the procedure described in example 4.1, 3-chloro-2-(4-chloro-phenyl)-6-fluoro-2H-indazole (example 40.2) was reacted with 3-chloro-phenylamine ([108-42-9]) in N-methyl 2-pyrrolidone for 72 h at 175° C. in a sealed tube to give the title compound as colorless crystals. MS: m/e=372.1 [M+H+].
Reaction SMILES: CS([N:5]1[CH2:9][C@@H:8]([P:10]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:7][C@H:6]1[CH2:24][P:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26])(=O)=O.[OH-].[Na+]>C1(O)C=CC=CC=1.Br>[CH:18]1([P:10]([CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)([C@@H:8]2[CH2:9][NH:5][C@H:6]([CH2:24][P:25]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:26])[CH2:7]2)=[O:11])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CS(=O)(=O)N1C[C@@H](P(=O)(C2CCCCC2)C2CCCCC2)C[C@H]1CP(=O)(c1ccccc1)c1ccccc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: Oc1ccccc1
Product: O=P(C[C@@H]1C[C@H](P(=O)(C2CCCCC2)C2CCCCC2)CN1)(c1ccccc1)c1ccccc1
Yield: 65 %

Procedure:
(2S,4S)-N-methanesulfonyl-4-dicyclohexylphosphinyl-2 -diphenylphosphinylmethylpyrrolidine [IX] in an amount of 350 mg was mixed with and dissolved in 700 mg of phenol and 5.3 ml of 48% hydrobromic acid, and the solution was refluxed in nitrogen atmosphere for 8-10 hours. After completion of the reaction, the solution was made alkaline with a 30% aqueous solution of caustic soda and was then extracted three times with 20 ml of ethyl acetate in each case. The extract was washed with 20 ml of water and then with 20 ml of a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by way of column chromatography on silica gel whereby 196 mg (yield: 65%) of the title compound was obtained as crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.[CH:13]1([CH2:16][NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].C(I)C.C(O)C.[O-]CC.[Na+].Cl>O1CCCC1.O>[CH:13]1([CH2:16][N:17]2[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:6]([OH:8])[C:5]3[C:4](=[CH:3][C:2]([F:1])=[CH:12][CH:11]=3)[C:9]2=[O:10])[CH2:14][CH2:15]1
Reactant: O=C1OC(=O)c2cc(F)ccc21
Reactant: CCOC(=O)CNCC1CC1
Agent: CC[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: CCI
Product: CCOC(=O)c1c(O)c2ccc(F)cc2c(=O)n1CC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.6 %

Procedure:
A solution of 4-fluorophthalic anhydride (24.99 g, 150 mmol) and ethyl 2-(cyclopropylmethylamino)acetate (23.58 g, 150 mmol) in tetrahydrofuran (200 mL) was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved, in N,N-dimethylformamide (200 mL) and potassium carbonate (20.73 g, 150 mmol) and ethyl iodide (14.4 mL, 180 mmol) were added. The mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (300 mL) and a solution of 20% sodium ethoxide ethanol solution (102 g, 300 mmol) was added thereto. The mixture was stirred at room temperature for 1 h. The reaction mixture was poured into 1N hydrochloric acid (300 mL) and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the component eluted earlier was concentrated to give ethyl 2-cyclopropylmethyl-7-fluoro-4-hydroxy-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (13.11 g, 28.6%) as crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:2]1=2.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:15]1([S:21]([N:1]2[CH2:6][CH2:5][O:4][C:3]3[N:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:2]2=3)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)c1cnc2c(c1)NCCO2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc2c(c1)N(S(=O)(=O)c1ccccc1)CCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.3 %

Procedure:
To a solution of methyl 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate (278.9 mg, 1.436 mmol) in DCM (20 mL) was added benzenesulfonyl chloride (278 μL, 2.156 mmol), DIPEA (753 μL, 4.31 mmol) and DMAP (88 mg, 0.719 mmol). The reaction was stirred at room temperature for 16 hours. LCMS analysis indicated a predominance of product in the reaction mixture. The solvent was removed under reduced pressure and the resulting oil was purified by flash column chromatography using a gradient elution of hexanes with 25-70% EtOAc to provide methyl 1-(phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate (280 mg, 0.837 mmol, 58.3% yield) as a yellow glass. LCMS (+ESI) m/z=334.8 [M+H]+.
Reaction SMILES: [CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:32]12[N:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:36]([CH2:37][CH2:38]1)[CH2:35][NH:34][CH2:33]2>>[CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([N:34]5[CH2:33][CH:32]6[N:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:36]([CH2:37][CH2:38]6)[CH2:35]5)=[O:24])=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCCCC1
Yield: 73 %

Procedure:
Following amide formation method 1, 6-(7-Cycloheptyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (75 mg, 0.178 mmol, 1.0 eq) was combined with tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (37.7 mg, 0.18 mmol, 1.0 eq) to give tert-butyl 3-(6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid (80 mg, 0.130 mmol, 73% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 8.76 (s, 1H) 8.68 (d, J=8.59 Hz, 1H) 8.42-8.57 (m, 1H) 8.40 (d, J=2.02 Hz, 1H) 7.83 (dd, J=8.59, 2.02 Hz, 1H) 6.49 (s, 1H) 4.46-4.62 (m, 2H) 4.29 (br s, 2H) 3.19 (s, 6H) 2.56-2.73 (m, 2H) 1.84-2.12 (m, 8H) 1.65-1.84 (m, 6H) 1.54-1.65 (m, 3H) 1.52 (s, 9H); MS (m/z, MH+): 617.7.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:21]([N:23]1[CH2:62][CH2:61][CH2:60][C@H:24]1[C:25]([NH:27][C@H:28]([C:30]([NH:32][C@H:33]([C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]1[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=1[Cl:45])=[O:40])=[O:31])[CH3:29])=[O:26])=[O:22])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:20])[NH:9][S:10]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[NH:63]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[C@H:64]([C:69](OC1C=CC([N+]([O-])=O)=CC=1)=[O:70])[CH2:65][C:66](=[O:68])[NH2:67].C(Cl)(Cl)Cl.CO>O1CCCC1>[NH:63]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[C@H:64]([C:69]([NH:2][C@H:3]([C:21]([N:23]1[CH2:62][CH2:61][CH2:60][C@H:24]1[C:25]([NH:27][C@H:28]([C:30]([NH:32][C@H:33]([C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]1[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=1[Cl:45])=[O:40])=[O:31])[CH3:29])=[O:26])=[O:22])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:20])[NH:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:17])=[CH:18][CH:19]=1)(=[O:11])=[O:12])=[O:70])[CH2:65][C:66](=[O:68])[NH2:67]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 57 %

Procedure:
At 0° C. the solution of 1160 mg (1.26 mmol) of HCl.Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 12) in 50 ml of anhydrous tetrahydrofuran was adjusted to pH 9, to which the pre-cold solution of 500 mg (1.41 mmol) of Boc-Asn-ONp in 10 ml of anhydrous tetrahydrofuran was added. The reaction mixture was stirred at room temperature for 96 h and TLC (chloroform/methanol, 9:1) indicated complete disappearance of HCl.Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 12). The reaction mixture was evaporated to dryness and the residue was purified on sinica gel chromatography (CHCl3/CH3OH, 10:1) to provide 800 mg (57%) of the title compound as a glassy mass. Mp 86–88° C., FAB-MS (m/e) 1097[M+H]+.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([C:12]1[CH:25]=[CH:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]=2[CH:13]=1)(=[O:11])[CH3:10]>>[CH:13]1[C:14]2[CH:15]=[CH:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]=2[CH:24]=[CH:25][C:12]=1[C:9](=[O:11])[CH:10]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc2c(ccc3ccccc32)c1
Reactant: O=Cc1ccccc1
Product: O=C(C=Cc1ccccc1)c1ccc2c(ccc3ccccc32)c1

Procedure:
By a procedure similar to that of example 1.59.1, starting from benzaldehyde and commercial 2-acetylphenanthrene, 1-(2-phenanthrenyl)-3-phenylprop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:23])=[CH:4][C:5]([F:22])=[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]3[CH:19]=[CH:20][N:21]=[C:9]23)[CH:7]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].N1C=CC=CC=1.C(Cl)Cl>O>[Br:23][C:3]1[C:2]([NH:1][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:7][C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]3[CH:19]=[CH:20][N:21]=[C:9]23)=[C:5]([F:22])[CH:4]=1
Reactant: Nc1cc(-n2c(=O)cc(C(F)(F)F)n3ccnc23)c(F)cc1Br
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n3ccnc23)c(F)cc1Br
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 8-(5-amino-4-bromo-2-fluorophenyl)-7,8-dihydro-5-trifluoromethylimidazo[1,2-a]pyrimidin-7-one (5.0 g), methanesulfonyl chloride (1.21 g), pyridine (2.02 g) and methylene chloride (30 ml) was stirred for 5 days at room temperature. The reaction solution was poured into water and extracted with ethyl acetate. The extract layer was washed with water and dried on anhydrous magnesium sulfate followed by distilling off the solvent under reduced pressure. The residual solid was washed with ether to give the compound of interest (4.8 g) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:22]3[NH:21][C:20](=[O:23])[N:19]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)C.[ClH:34]>C(OCC)(=O)C>[ClH:34].[CH2:24]([N:19]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:22]=2[NH:21][C:20]1=[O:23])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2[nH]c(=O)n3Cc2ccccc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=c1[nH]c2c(N3CCNCC3)cccc2n1Cc1ccccc1

Procedure:
To a solution of 0.112 g of 4-(1-benzyl-2-oxo-2,3-dihydro-1H-benzoimidazol-4-yl)-piperazine-1-carboxylic acid tert-butyl ester in 15 mL ethyl acetate with 5 mL ethanol is added 3 mL of 2M ethanolic hydrogen chloride. The resulting solution is refluxed for one hour, and on cooling, a solid precipates. The solid is filtered and dried over night under vacuum to give 82 mg of 1-benzyl-4-piperazin-1-yl-1,3-dihydro-benzoimidazol-2-one hydrochloride. MS: 309 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[ClH:15].[CH2:16](O)[CH3:17]>>[ClH:15].[NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[CH2:3][C:4]([O:6][CH2:16][CH3:17])=[O:5]
Reactant: CCO
Reactant: COc1cccc(C(N)CC(=O)O)c1
Agent: Cl
Product: CCOC(=O)CC(N)c1cccc(OC)c1

Procedure:
Corresponding to Example 1b, 60 g of (8a) were treated with hydrochloric acid in ethanol. A white, crystalline product was obtained (yield: 75 g).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36]C)=[O:35])=[CH:29][CH:28]=3)[CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:38]([F:41])([F:40])[F:39])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].C(O)(=O)C>C1COCC1.CO.O>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([NH:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([CH2:33][C:34]([OH:36])=[O:35])=[CH:31][CH:32]=3)[CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:38]([F:39])([F:40])[F:41])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)Cc1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a stirred solution of methyl {4-[({3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amino)methyl]phenyl}acetate (0.06 g, 0.11 mmol) in THF/methanol/water (2:1:1, 10 mL) was added lithium hydroxide monohydrate (0.06 g, 1.4 mmol). The reaction was stirred at 40° C. for 1 h. The reaction mixture was made acidic (pH 6) with glacial acetic acid, and the solid was collected and dried over P2O5 to give the title compound as an orange solid (0.05 g, 93%): MS (EI) m/z 541.3 (M+H)+; 1H NMR (DMSO-d6): δ 3.53 (s, 2H), 4.12 (d, J=5.8 Hz, 2H), 6.35-6.55 (m, 4H), 6.97 (t, J=7.4 Hz, 1H), 7.15-7.22 (m, 4H), 7.36 (t, J=7.8 Hz, 2H), 7.55 (t, J=7.4 Hz, 1H), 7.61 (d, J=8.2 Hz, 2H), 7.72 (t, J=8.0 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 8.29 (d, J=7.1 Hz, 1H), 9.08 (s, 1H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[N:13]1[CH:18]=[C:17]([C:19]([OH:21])=O)[CH:16]=[N:15][CH:14]=1.Cl.[CH3:23][NH:24][O:25][CH3:26]>C(Cl)Cl.[NH4+].[Cl-].O>[CH3:26][O:25][N:24]([CH3:23])[C:19]([C:17]1[CH:16]=[N:15][CH:14]=[N:13][CH:18]=1)=[O:21]
Reactant: O=C(O)c1cncnc1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1cncnc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
1,1′-carbonyldiimidazole (1.23 g, 7.57 mmol) was added to a suspension of pyrimidine-5-carboxylic acid (783 mg, 6.31 mmol) in DCM (20 mL) and the mixture was stirred at room temperature for 15 min before addition of N,O-dimethylhydroxylamine hydrochloride (739 mg, 7.57 mmol). The mixture was stirred at room temperature for 5 d, then was diluted with saturated aqueous NH4Cl and water and extracted with DCM. The organic phase was washed with water, and the aqueous phases were back-extracted with DCM. The organic phase was dried (Na2SO4), filtered, and concentrated, affording the crude title compound as a light yellow oil which was used without further purification in the next reaction.
Reaction SMILES: Br[C:2]1[CH:16]=[N:15][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[Cl-].[Li+].CCN(C(C)C)C(C)C.C([Sn](CCCC)(CCCC)[C:33]1[O:34][CH:35]=[CH:36][N:37]=1)CCC.[F-].[K+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:34]1[CH:35]=[CH:36][N:37]=[C:33]1[C:2]1[CH:16]=[N:15][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: N#Cc1cc2c(cn1)[nH]c1ncc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc2c(cn1)[nH]c1ncc(-c3ncco3)cc12
Temperature: 165 °C
Yield: 45.1 %

Procedure:
A solution of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (101 mg, 0.369 mmol) and lithium chloride (46.9 mg, 1.11 mmol) in DMF (0.63 mL) was treated with DIPEA (161 μL, 0.922 mmol) and 2-(tri-n-butylstannyl)oxazole (232 μL, 1.11 mmol), and then degassed by the bubbling of nitrogen for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (21.3 mg, 18.4 μmol, 5.0 mol %) was added and the mixture heated at 165° C. for 15 hours. The mixture was allowed to cool and treated with saturated aqueous potassium fluoride solution at ambient temperature. The resulting solids were removed by filtration and washed with 20% methanol in DCM and water. The filtrate was filtered through a pad of celite, washing with 20% methanol in DCM. The layers were separated, the aqueous phase extracted into 20% methanol in DCM, and the combined organic phases concentrated in vacuo. The residue was dissolved in AcOH with sonication and heating, filtered hot, and allowed to cool. The resulting suspension was treated with water and then filtered to collect the tan-gray solid, which was redissolved in DMF and purified by preparative HPLC [2-60% MeCN/water modified with 0.1% ammonium hydroxide] to afford a tan solid (43.5 mg, 45%). 1H NMR (400 MHz, DMSO-D6): 9.29 (d, J=2.2 Hz, 1H), 9.26 (d, J=2.2 Hz, 1H), 9.03 (m, 1H), 8.97 (m, 1H), 8.28 (m, 1H), 7.43 (m, 1H). LCMS (Method D): RT=8.29 min, M+H+=262.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:23](=[O:24])[N:6]2[C:7]([C:20]([OH:22])=[O:21])=[C:8]([C:11]3[S:15][C:14]4=[CH:16][N:17]=[C:18]([CH3:19])[N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].O.C(=O)([O-])O.[Na+].[C:31]([O:37][CH2:38]I)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>CN(C=O)C.C(OCC)(=O)C>[OH:1][C@@H:2]([C@H:4]1[C:23](=[O:24])[N:6]2[C:7]([C:20]([O:22][CH2:38][O:37][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[O:21])=[C:8]([C:11]3[S:15][C:14]4=[CH:16][N:17]=[C:18]([CH3:19])[N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CC(C)(C)C(=O)OCI
Reactant: Cc1ncc2sc(C3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)cn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ncc2sc(C3=C(C(=O)OCOC(=O)C(C)(C)C)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)cn12
Reaction time: 1.5 h

Procedure:
To a solution of 46.8 mg of (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(5-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylic acid 5 ml of water was added 134 ml of a 0.1 N aqueous sodium hydrogen carbonate solution. The mixture was lyophilized, dissolved in 1 ml of DMF, added with 0.034 ml of pivaloyloxymethyl iodide under the atmosphere of argon at −30° C., and stirred at the same temperature for 1.5 hours. The reaction mixture was diluted with 50 ml of ethyl acetate, and washed with 50 ml of semi-saturated aqueous saline. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to a volume of 1 ml. The residue thus obtained was purified by column chromatography on silica gel (dichloromethane:methanol=20:1) and on Sephadex LH-20(chloroform:methanol=1:1) in this sequence to give 44.5 mg of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]([O:24][S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])(=[O:27])=[O:26])[CH:20]=[C:21]([CH3:23])[CH:22]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]([O:24][S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])(=[O:27])=[O:26])[CH:20]=[C:21]([CH3:23])[CH:22]=2)[CH2:12][CH2:13]1
Reactant: Cc1cc(OCCN2CCN(C(=O)OC(C)(C)C)CC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(OCCN2CCNCC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Yield: 84.6 %

Procedure:
2-Chlorobenzenesulfonic acid 3-[[N-(tert-butoxycarbonyl)-piperazin-4-yl]ethoxy]-5-methylphenyl ester (1.02 g, 2.0 mmol), as prepared in the preceding step, was treated with 40 mL of 4N HCl in 1,4-dioxane at room temperature for 2 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography (10% methanol in methylene chloride saturated with NH3) to give the title compound as a pale-yellow liquid (695 mg, 84%). 1 H-NMR (300 MHz, CDCl3): δ 1.92 (bs, 2H), 2.24 (s, 3H), 2.53 (d, 3 H), 2.73 (t, 2H), 2.92 (t, 4H), 3.98 (t, 2H), 6.50 (t, 1H), 6.54 (t, 1H), 6.61 (t, 1H) 7.38 (dt, 1H), 7.62 (m, 2H), 7.97 (dd, 1H).