Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([NH2:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.[CH3:30][N:31]([CH3:36])[CH2:32][C:33](O)=[O:34].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:30][N:31]([CH3:36])[CH2:32][C:33]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([NH2:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1)=[O:34]
Reactant: NC(=O)c1cccc2oc(-c3cccc(N)c3)nc12
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)Nc1cccc(-c2nc3c(C(N)=O)cccc3o2)c1
Temperature: 30 °C
Reaction time: 18 h
Yield: 38.5 %

Procedure:
To a solution of 2-(3-aminophenyl)benzo[d]oxazole-4-carboxamide (60 mg, 0.23 mmol) in DMF (3 mL) was added HOBT (35 mg, 0.26 mmol), dimethylglycine (24 mg, 0.23 mmol), DIPEA (91 mg, 0.7 mmol) and EDCI (54 mg, 0.29 mmol). The mixture was stirred at 30° C. for 18 hr. The reaction mixture was purified by pre-HPLC to obtain 2-(3-(2-(dimethylamino)acetamido)phenyl)benzo[d]oxazole-4-carboxamide (30 mg, yield 37%). 1H-NMR (400 MHz, DMSO-d6) δ 2.29 (s, 6H), 3.12 (s, 2H), 7.54-7.58 (m, 2H), 7.95-8.06 (m, 5H), 8.46 (s, 1H), 8.69 (s, 1H), 10.11 (s, 1H); LC-MS (ESI) m/z 339 [M+1]−.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]2[S:31][C:30]3[N:32]4[C:23](=[CH:24][N:25]=[C:26]4[CH:27]=[CH:28][CH:29]=3)[CH:22]=2)=[O:20])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:33]>C(O)C>[ClH:33].[ClH:33].[ClH:33].[N:11]1([CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]2[S:31][C:30]3[N:32]4[C:23](=[CH:24][N:25]=[C:26]4[CH:27]=[CH:28][CH:29]=3)[CH:22]=2)=[O:20])[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(CCCNC(=O)C2=Cc3cnc4cccc(n34)S2)CC1
Agent: Cl
Solvent: CCO
Product: O=C(NCCCN1CCCNCC1)C1=Cc2cnc3cccc(n23)S1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4250 mg (9.29 mM) of N-[3-(4-tert-butoxycarbonyl-2,3,5,6-tetrahydro-7H-1,4-diazepin-1-yl)propan-1-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide in 100 ml of ethanol was added 3.8 ml (46.44 mM) of 12N-hydrochloric acid, and the mixture was stirred at room temperature for 1 hour. The resulting precipitate was recovered by filtration and rinsed with small amounts of ethanol and ether to provide the title compound. Yield 4020 mg (92.8%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:24])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([N:10]1[CH2:11][CH2:12][CH2:13][CH:8]([C:5]2[N:4]=[C:3]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:24])[CH:15]=3)[C:2]([NH2:1])=[N:7][CH:6]=2)[CH2:9]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1ccc(-c2nc(C3CCCNC3)cnc2N)cc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(-c2nc(C3CCCN(C(C)=O)C3)cnc2N)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of methyl 4-(3-amino-6-(piperidin-3-yl)pyrazin-2-yl)-2-fluorobenzoate (55 mg, 0.166 mmol) (for synthesis, see example 34, Step 7) in DCM (3 mL) in ice bath was added DIEA (0.116 mL, 0.666 mmol) followed by acetyl chloride (0.012 mL, 0.166 mmol). The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was partitioned between DCM and water. The DCM layer was separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was proceeded to next step without purification (50 mg, 81%). LCMS (m/z): 373.3 (MH+), 0.666 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:14][C:15]1[S:16][C:17]([CH:20]=O)=[CH:18][N:19]=1>ClCCl>[Cl:14][C:15]1[S:16][C:17]([CH:20]=[N:1][C:2]2[C:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:18][N:19]=1
Reactant: Nc1ncccc1-c1ccccc1
Reactant: O=Cc1cnc(Cl)s1
Solvent: ClCCl
Product: Clc1ncc(C=Nc2ncccc2-c2ccccc2)s1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
2-Amino-3-phenylpyridine (i.e. the product of Step A, 0.342 g, 2.01 mmol) was added to 2-chloro-1,3-thiazole-5-carbaldehyde (0.296 g, 2.01 mmol) in dichloromethane (10 mL) at room temperature. The suspension was stirred for 10 min and then concentrated to dryness under vacuum. The resulting residue was heated to 90° C. for 20 min on a rotory evaporator with a non-returning bump trap to facilitate water removal. The residual yellow solid was again dissolved in dichloromethane (10 mL) and heated to 90° C. on a rotory evaporator for an additional 20 min. At this time the yellow solid was checked by NMR to verify reaction completion. The title compound was obtained as a yellow solid and used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][CH3:13])[CH3:11])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([N:12]([CH3:13])[C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][NH:26]4)[CH3:11])[N:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[CH:20]=1
Reactant: CN[C@@H](C)c1nc2ccc(F)cc2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@@H](c1nc2ccc(F)cc2n1-c1ccccc1)N(C)c1ncnc2[nH]cnc12
Temperature: 90 °C
Yield: 83.6 %

Procedure:
A mixture of [(S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]methylamine (102 mg, 0.38 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (91 mg, 0.38 mmol) and DIPEA (0.33 mL, 1.9 mmol) in n-butanol (2 mL) was heated at 90° C. for 18 h in a sealed vial. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 181 (123 mg, 84%). LCMS (Method K): RT 3.39 min [M+H]+ 388.1. 1H NMR (DMSO-d6, 400 MHz, 80° C.): δ 7.99 (1H, s), 7.90 (1H, s), 7.75 (1H, dd, J=8.81, 4.87 Hz), 7.30-7.22 (2H, m), 7.17-6.95 (5H, m), 6.73 (1H, dd, J=8.93, 2.53 Hz), 3.12 (3H, br s), 1.71 (3H, d, J=6.76 Hz)
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:33](Cl)=[O:34])[CH:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:36]1([C:42](=[O:50])[CH2:43][N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:33]([N:47]3[CH2:48][CH2:49][N:44]([CH2:43][C:42]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[O:50])[CH2:45][CH2:46]3)=[O:34])[C@H:16]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)[C@H:17]([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1

Procedure:
cis-4-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 20) was reacted with 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) to give cis-2-{4-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C36H44N7O4Cl2 [(M+H)+] 708.2827, observed 708.2830.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:13][C:14]([O:16]CC)=[O:15])[C@H:8]3[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23][C@H:7]3[C:6]=2[C:5]=1[Cl:31].Cl>O.C1COCC1>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][C@@H:7]2[C@@H:8]([N:9]([CH2:13][C:14]([OH:16])=[O:15])[C:10]3[CH:11]=[CH:12][C:4]([Cl:3])=[C:5]([Cl:31])[C:6]=32)[CH2:19][CH2:20]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC(=O)CN1c2ccc(Cl)c(Cl)c2[C@@H]2CCN(C(=O)OC(C)(C)C)CC[C@@H]21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]2c3c(ccc(Cl)c3Cl)N(CC(=O)O)[C@H]2CC1
Temperature: 60 °C
Yield: 99.9 %

Procedure:
A solution of KOH (0.16 g, 2.8 mmol) in H2O (10 mL) was added to a solution of tert-butyl (5aS*,10bS*)-9,10-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,5a,6,10b-hexahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.96 g, 2.17 mmol) in THF (15 mL). The mixture was heated at 60° C. for 2 h. The reaction was then cooled to rt, acidified with 10% aqueous HCl, and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated to give crude white foam (0.90 g): 1H NMR (300 MHz, CDCl3) δ 7.14 (d, J=8.3 Hz, 1H), 6.21 (d, J=8.4 Hz, 1H), 4.08 (m, 1H), 3.93 (d, J=18.3 Hz, 1H), 3.76 (d, J=18.3 Hz, 1H), 3.47 (m, 5H), 2.04 (m, 4H), 1.44 (s, 9H); HRMS (FAB) calcd for Cl9H24CL2N2O4+H 415.1191, found 415.1198.
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([S:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][C:36]=2B(O)O)[CH:31]=[CH:30][CH:29]=1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([S:20][C:11]2[C:12]3[C:13]([C:36]4[CH:35]=[CH:34][CH:33]=[C:32]5[C:37]=4[N:28]=[CH:29][CH:30]=[CH:31]5)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[CH:22][CH:23]=1
Reactant: OB(O)c1cccc2cccnc12
Reactant: CC(C(=O)[O-])C1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Product: O=C(O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(-c3cccc4cccnc34)cc(F)cc12

Procedure:
Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate (Example 7, Step 9) and quinolin-8-ylboronic acid, the title compound was synthesized following the procedures described in Example 108.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([C@@H:25]([CH2:35]/[CH:36]=[CH:37]/[CH:38]=[O:39])[CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])(=[O:18])=[O:17])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CCOC(C)=O.C(O)C.[OH-].[OH-].[Pd+2]>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([C@@H:25]([CH2:35][CH2:36][CH2:37][CH:38]=[O:39])[CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])(=[O:17])=[O:18])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCCCCN([C@@H](C/C=C/C=O)CO[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCCN([C@@H](CCCC=O)CO[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 2 h
Yield: 55.4 %

Procedure:
A solution of the material from Step 4 (7.2 g, 12.04 mmol) in (1:1) EtOAc-ethanol (232 mL) was degassed with nitrogen, and 20% palladium hydroxide on carbon (0.72 g, 1.03 mmol) was added. The reaction mixture was stirred under hydrogen (1 atm) for 2 hours. The reaction mixture was filtered through celite and washed with dichloromethane. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using EtOAc-hexanes to afford 4 g of the title compound. 1H NMR (DMSO-d6): δ 9.60 (s, 1H), 7.79 (d, J=7.96 Hz, 2H), 7.50 (d, J=7.99 Hz, 2H), 4.79 (s, 2H), 3.68-3.60 (m, 1H), 3.45 (t, J=20.48 Hz, 2H), 3.23-3.09 (m, 1H), 3.08-2.98 (m, 1H), 2.37 (d, J=7.09 Hz, 2H), 1.62-1.06 (m, 10H), 0.91 (s, 9H), 0.84 (t, J=6.94 Hz, 3H), 0.80 (s, 9H), 0.09 (s, 6H), −0.06 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:12][C:13]([F:24])([F:23])[S:14]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)=[O:15]>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([S:14]([C:13]([F:24])([F:12])[F:23])=[O:15])=[CH:17][CH:18]=1)=[O:9]
Reactant: Nc1ccc(S(=O)C(F)(F)F)cc1
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(S(=O)C(F)(F)F)cc1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 169.2 using 5-bromo-6-chloro-nicotinic acid and 4-(trifluoromethylsulfinyl)aniline To afford an off-white crystalline solid. HPLC (Condition 4) tR=5.59 min, UPLC-MS (Condition 3) tR=1.10 min, m/z=425 [M−H]−.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:45])[N:14]([CH2:18][C:19]([NH:21][CH:22]([C:31](=[O:44])[CH2:32][O:33][C:34](=[O:43])[C:35]2[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:42])[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:20])[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:45])[N:14]([CH2:18][C:19]([NH:21][CH:22]([C:31](=[O:44])[CH2:32][O:33][C:34](=[O:43])[C:35]2[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:42])[CH2:23][C:24]([OH:26])=[O:25])=[O:20])[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CC(NC(=O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O)C(=O)COC(=O)c1c(Cl)cccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC(NC(=O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O)C(=O)COC(=O)c1c(Cl)cccc1Cl
Temperature: 20 °C
Yield: 75.3 %

Procedure:
The ester 56a (210 mg, 0.356 mmol) in dichloromethane (0.5 ml) was cooled to 0° C. and treated with trifluoroacetic acid (0.5 ml), stirred and warmed to 20° C. over 30 minutes. The solution was evaporated to dryness under reduced pressure, redissolved in dichloromethane and concentrated (×3). The residue was triturated with ethyl acetate and diluted with ether to afford the title compound 162 mg (85%) as a colorless solid: m.p. 165-8° C. (decomposition); [α]D23 −38.8° (c 0.1, CH3OH); IR (KBr) 3332, 3275, 1723, 1658, 1649, 1597, 1581, 1562, 1526, 1432, 1385, 1258, 1218, 1206; 1H NMR (d6-DMSO) δ8.96 (1H, d, J=7.3), 8.34 (1H, s), 7,85 (1H, dd, J=7.3), 7,58 (3H, m), 7.35 (5H, m), 6.29 (1H, t, J=7.3), 5,26 (2H, m), 5.15 (2H, s), 4.69 (3H, m), 2.75 (2H, m). Anal. Calcd. C27H23N3O9Cl2: C, 53.66; H, 3.84; N, 6.95. Found: C, 53.36; H, 3.90; N, 6.81. M.S. (+FAB); 604 (M++1), 285, 241, 195, 173, 149, 91.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23](=[O:31])OC4C=CC=CC=4)[CH:17]=3)=[CH:13][CH:12]=2)=[O:9])[C:4](=[O:34])[N:3]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[CH3:41][NH:42][CH2:43][CH2:44][OH:45]>CN1C(=O)CCC1>[OH:45][CH2:44][CH2:43][N:42]([CH3:41])[C:23](=[O:31])[NH:22][C:18]1[CH:17]=[C:16]([O:15][C:14]2[CH:32]=[CH:33][C:11]([NH:10][C:8]([C:5]3[C:4](=[O:34])[N:3]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:2]([CH3:1])[C:6]=3[CH3:7])=[O:9])=[CH:12][CH:13]=2)[CH:21]=[CH:20][N:19]=1
Reactant: CNCCO
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)cc2)c(=O)n(-c2ccccc2)n1C
Solvent: CN1CCCC1=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)N(C)CCO)c3)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 40 °C
Yield: 52 %

Procedure:
A mixture of phenyl (4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)phenoxy)pyridin-2-yl)carbamate (50 mg, 0.093 mmol), NMP (3 mL) and 2-(methylamino)ethanol (8.4 mg, 0.112 mmol) was heated at 40° C. for 2 hours. The solvent was evaporated under reduced pressure at 40° C., and then diluted with EtOAc (10 mL). The resulted mixture was washed with water (7 mL×3), followed by washing with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was washed with EtOAc (2 mL) to give the title compound as a white solid (25 mg, 52%).
Reaction SMILES: [NH2:1][C:2]([CH3:46])([CH3:45])[CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[CH2:20][C@H:19]([N:21]3[CH:25]=[C:24]([CH2:26][OH:27])[CH:23]=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:8]=1)=[O:6].[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].O[C@@H]1[C@H](O)[C@@H](N2C=C(C)C=N2)C[C@H]1N1C=NC2C1=NC(NC1CCC(N[C:99]([NH:101][CH:102]3[CH2:107][CH2:106][N:105]([C:108]4[CH:113]=[CH:112][CH:111]=[CH:110][N:109]=4)[CH2:104][CH2:103]3)=[O:100])CC1)=NC=2NCC(C1C=CC=CC=1)C1C=CC=CC=1>>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[CH3:45][C:2]([NH:1][C:99]([NH:101][CH:102]1[CH2:103][CH2:104][N:105]([C:108]2[CH:113]=[CH:112][CH:111]=[CH:110][N:109]=2)[CH2:106][CH2:107]1)=[O:100])([CH3:46])[CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[CH2:20][C@H:19]([N:21]3[CH:25]=[C:24]([CH2:26][OH:27])[CH:23]=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:8]=1)=[O:6]
Reactant: CC(C)(N)CNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1
Reactant: Cc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NC5CCC(NC(=O)NC6CCN(c7ccccn7)CC6)CC5)nc43)[C@H](O)[C@@H]2O)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1)NC(=O)NC1CCN(c2ccccn2)CC1

Procedure:
This compound is prepared from 9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (2-amino-2-methyl-propyl)-amide (first step a) using a procedure analogous to that of 1-{4-[9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-methyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-ylamino]-cyclohexyl}-3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-urea trifluoroacetate (Example 42). MS (ES+) m/e 829 (MH+)
Reaction SMILES: [NH2:1][CH:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([CH:9]([S:17][C:18]3[NH:22][N:21]=[N:20][N:19]=3)[CH2:10][CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:7][S:8][C@H:3]12.[CH3:28][CH2:29][C:30](Cl)=[S:31].[OH-].[Na+]>C(=O)(O)[O-].[Na+].CC(C)=O>[CH3:28][CH2:29][C:30]([NH:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([CH:9]([S:17][C:18]3[NH:19][N:20]=[N:21][N:22]=3)[CH2:10][CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:7][S:8][C@H:3]12)=[S:31]
Reactant: CCC(=S)Cl
Reactant: CS(=O)(=O)NCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCC(=S)N[C@@H]1C(=O)N2C(C(=O)O)=C(C(CCNS(C)(=O)=O)Sc3nnn[nH]3)CS[C@H]12
Reaction time: 0.33 h

Procedure:
To a stirred, cooled (-20°) solution of 11.32 g (0.026 mol) of 7-amino-3-[1-(2-methanesulfonamidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 220 ml of 3% sodium bicarbonate and 220 ml of acetone is added dropwise a solution of 3.66 g (0.029 mol) of methylthioacetyl chloride in 52 ml of acetone, during which time the pH of the reaction mixture is maintained at 8.0 by addition of 10% sodium hydroxide. After addition the reaction mixture is stirred an additional 20 minutes at -15°, then is warmed to 25° and extracted with ether. The remaining aqueous phase is cooled, 250 ml of ethyl acetate is added and the slurry is acidified with 3N hydrochloric acid. The layers are separated and the aqueous phase is extracted twice more with ethyl acetate. The combined extracts are dried (MgSO4) and evaporated to dryness to yield the title compound.
Reaction SMILES: [OH-:1].[Na+].Cl.Cl[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15]>O>[OH:1][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
To a 5-liter, 3-necked, round-bottom flask is added 532 g of NaOH in 3 liters of water and 520 g of 4-chloro-3-nitrobenzoic acid. The solution is heated to reflux (100° C.) under nitrogen and stirred for 10 hours. Upon completion, the reaction is cooled to room temperature and neutralized with concentrated hydrochloric acid. The product is isolated by filtration, washed with 3 liters of cold water and dried in a vacuum oven at 30° C. overnight at 3 mm Hg. The yield is 430 g (90 percent) of 4-hydroxy-3-nitrobenzoic acid with a melting point of 182° C.-183° C.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:35][C@H:36]([C:40]([N:42]2[CH2:59][CH2:58][CH2:57][C@H:43]2[C:44]([NH:46][CH:47]([CH:54]([CH3:56])[CH3:55])[C:48](=[O:53])[C:49]([F:52])([F:51])[F:50])=[O:45])=[O:41])[CH:37]([CH3:39])[CH3:38])=[O:34])=[CH:29][CH:28]=1)(O)=[O:25].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:12]([O:19][C:20]([CH2:21][NH:22][C:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:35][C@H:36]([C:40]([N:42]2[CH2:59][CH2:58][CH2:57][C@H:43]2[C:44]([NH:46][CH:47]([CH:54]([CH3:55])[CH3:56])[C:48](=[O:53])[C:49]([F:50])([F:51])[F:52])=[O:45])=[O:41])[CH:37]([CH3:39])[CH3:38])=[O:34])=[CH:29][CH:28]=1)=[O:25])=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)c1ccc(C(=O)O)cc1)C(C)C)C(=O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)c1ccc(C(=O)NCC(=O)OCc2ccccc2)cc1)C(C)C)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.2 %

Procedure:
To a mixture of glycine benzyl ester p-toluenesulfonate (66 mg) and 3(RS)-[(4-carboxyphenylcarbonyl)-L-valyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane (100 mg) in DMF (6 ml) were added HOBT (26 mg) and WSCD (30 mg) under ice-bath cooling. After being stirred at room temperature for 4 hours, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 ml) and washed with 5% aqueous citric acid (20 ml), water (20 ml), 5% aqueous sodium bicarbonate (20 ml) and brine (20 ml). The solution was dried over magnesium sulfate and evaporated under reduced pressure to give 3(RS)-[[4-[(benzyloxycarbonyl)methylaminocarbonyl]phenylcarbonyl]-L-valyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane (125 mg).
Reaction SMILES: N12CCN(CC1)CC2.[CH3:9][N:10]([CH3:14])[C:11](Cl)=[S:12].[Cl:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:26])[C:17]=1[OH:27]>CN(C)C=O>[Cl:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:26])[C:17]=1[O:27][C:11]([N:10]([CH3:14])[CH3:9])=[S:12]
Reactant: CN(C)C(=S)Cl
Reactant: COC(=O)c1ccc(Cl)c(O)c1C
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)c(OC(=S)N(C)C)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under an atmosphere of nitrogen, 12.3 g (109.7 mmol) of 1,4-diazabicyclo[2.2.2]octane and then 13.6 g (109.7 mmol) of dimethylaminothiocarbonyl chloride were added to 11.0 g (54.8 mmol) of methyl 4-chloro-3-hydroxy-2-methylbenzoate in 200 ml of N,N-dimethylformamide. The mixture was stirred at room temperature (RT) for 16 h and, for work-up, poured on ice-water. The product precipitated out and was removed by filtration. The residue was washed with 1M HCl. This gave 14.7 g of clean product.