Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([C:32]([OH:34])=[O:33])[CH2:28][CH2:27]1.C[O-].[Na+]>COCCO>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][C@H:26]2[CH2:31][CH2:30][C@H:29]([C:32]([OH:34])=[O:33])[CH2:28][CH2:27]2)=[O:4])[N:6]=1)#[N:24]
Reactant: N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: N#Cc1nc(C(=O)N[C@H]2CC[C@H](C(=O)O)CC2)c(O)c2ccc(Oc3ccccc3)cc12

Procedure:
To a mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (60 mg, 0.19 mmol) and trans-4-amino-cyclohexanecarboxylic acid (107 mg, 0.75 mmol) in 3 mL of 2-methoxyethanol was added NaOMe solid (30 mg, 0.56 mmol). The resultant mixture was microwaved at 140° C. for 1 h. Reaction mixture was concentrated and residue was dissolved in water (60 mL). It was acidified by 1 N HCl to pH=3-4. Precipitate was collected, and rinsed with water and MeOH. Solid was dried to provide the title compound 40 mg (0.093 mmol) in 49% yield. LC-MS ESI−: 430.00 (M−1)−.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31]C(CCCC(O)=O)=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]([C:48]([O:50]C(C)(C)C)=[O:49])[CH2:43][CH2:44][C:45](=[O:47])[NH2:46].Cl>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:21]([CH2:22][CH2:23][CH2:24][C:25]([NH:41][C@H:42]([C:48]([OH:50])=[O:49])[CH2:43][CH2:44][C:45](=[O:47])[NH2:46])=[O:26])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(N)=O
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)O)cc2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)N[C@@H](CCC(N)=O)C(=O)O)cc2)cc1

Procedure:
The product from Example 100 (56 mg, 0.1 mmole) and H-Gln-OtBu HCl (48 mg, 0.2 mmole) were processed as in Example 213A-B to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ11.53-13.22 (br.s, 1 H), 8.95 (s, 1 H), 8.06 (d, 1 H), 7.26 (m, 6 H), 7.18 (m, 3 H), 7.04 (m, 1 H), 6.96 (m, 2 H), 6.88 (m, 4 H), 6.73 (br.s, 2 H), 4.15 (m, 1 H), 4.06 (s, 2 H), 4.02 (s, 2 H), 2.91 (s, 3 H), 2.54 (t, 2 H), 2.39 (s, 3 H), 2.13 (m, 4 H), 1.93 (m, 1 H), 1.75 (m, 3 H); MS (APCI+) m/z 687 (M+H)+.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH3:19])=[N:11][N:12]([C:14]([CH3:18])([CH3:17])[CH2:15][CH3:16])[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=1>>[CH:1]1([CH:7]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=2)[C:9]2[C:10]([CH3:19])=[N:11][N:12]([C:14]([CH3:18])([CH3:17])[CH2:15][CH3:16])[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(C)(C)n1cc(C(O)C2CCCCC2)c(C)n1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: CCC(C)(C)n1cc(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)c(C)n1
Yield: 31.8 %

Procedure:
Using cyclohexyl[1-(1,1-dimethylpropyl)-3-methyl-1H-pyrazol-4-yl]methanol (1.0 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.67 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.41 g, 46%) was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH2:6][C:5]2=O.[C:19](=[N:25][Si](C)(C)C)=[N:20][Si](C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH2:6][C:5]2=[N:25][C:19]#[N:20]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: O=C1CC(c2ccccn2)Oc2ccc(Br)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1CC(c2ccccn2)Oc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a solution of 6-bromo-2-pyridin-2-yl-chroman-4-one (303 mg, 1 mmol) in DCM (10 mL) was added TiCl4 (4 mL, 1 M in CH2Cl2) dropwise within 15 minutes at room temperature. After stirring for 1 h, N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (0.5 mL, 2.2 mmol) was added dropwise. The mixture was stirred at room temperature overnight and poured into ice-water (50 g). The aqueous layer was extracted with CH2Cl2, which was combined with the organic layer. The organic layer was dried and concentrated to give crude 6-bromo-2-pyridin-2-yl-chroman-4-ylidene-cyanamide (300 mg, 92%).
Reaction SMILES: [OH:1][C@H:2]1[C:11](=[O:12])[C:10]2[CH:9]=[CH:8][N:7]3[C:13]([CH3:19])=[C:14]([CH2:16][O:17][CH3:18])[N:15]=[C:6]3[C:5]=2[NH:4][C@@H:3]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[OH:12][C@@H:11]1[C:10]2[CH:9]=[CH:8][N:7]3[C:13]([CH3:19])=[C:14]([CH2:16][O:17][CH3:18])[N:15]=[C:6]3[C:5]=2[NH:4][C@H:3]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C@H:2]1[OH:1]
Reactant: COCc1nc2c3c(ccn2c1C)C(=O)[C@H](O)[C@@H](c1ccccc1)N3
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COCc1nc2c3c(ccn2c1C)[C@@H](O)[C@H](O)[C@@H](c1ccccc1)N3
Yield: 77.9 %

Procedure:
6.0 g of (8R,9R)-8-hydroxy-2-methoxymethyl-3-methyl-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridin-7-one are suspended in 40 ml methanol and 0.6 g sodium borohydride are added in small portions over a period of 30 min. After 1 h at ambient temperature the reaction mixture is poured onto of 60 ml icewater and 2 g ammonium chloride. The organic layer is separated and the aqueous phase extracted three times with dichloromethane. The combined organic phases are dried over anhydrous sodium sulfate and the solvent removed in vacuo. The residue is purified by column chromatography on silica gel (eluent: dichloromethane/methanol 100:1). Crystallization from diethyl ether yields 4.7 g (78%) of the title compound as a light brown solid (BYK237362, m.p. 102-104° C.).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][C@@H:12]([CH3:16])[NH:13][C:14](=[O:15])[C:6]3=[CH:5][C:4]=2[CH:3]=1.[CH:17]([N:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1)([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>>[CH:17]([N:20]1[CH2:25][CH2:24][CH:23]([O:1][C:2]2[CH:10]=[CH:9][C:8]3[N:7]4[CH2:11][C@@H:12]([CH3:16])[NH:13][C:14](=[O:15])[C:6]4=[CH:5][C:4]=3[CH:3]=2)[CH2:22][CH2:21]1)([CH3:19])[CH3:18]
Reactant: C[C@@H]1Cn2c(cc3cc(O)ccc32)C(=O)N1
Reactant: CC(C)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3C[C@@H](C)NC2=O)CC1
Yield: 34 %

Procedure:
The title compound was synthesized in analogy to example 1, from (R)-8-hydroxy-3-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 1-isopropyl-piperidin-4-ol (commercially available), triphenylphosphine and di-tert-butyl-azodicarboxylate, to give the desired product as a light yellow solid (34%).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=1>>[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:34]2)=[CH:29][CH:28]=1
Reactant: NNc1ccc(F)cc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1ccc(F)cc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 4-fluoro-phenylhydrazine according to the method described for example 43. MS: M=417.1 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.[CH:25]1[CH:26]=CC2N(O)N=[N:31][C:29]=2[CH:30]=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.N1CCCC1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([N:31]4[CH2:26][CH2:25][CH2:30][CH2:29]4)=[O:24])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCNC1
Product: O=C(c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12)N1CCCC1
Reaction time: 0.25 h
Yield: 66.6 %

Procedure:
To a solution of (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I, 50 mg, 0.15 mmol) in anhydrous CH2Cl2 (2 mL) was added HOBt (41 mg, 0.31 mmol) followed by EDCI (88 mg, 0.46 mmol). The solution was stirred for 15 minutes, then treated with triethylamine (64 μL, 0.46 mmol) followed by pyrrolidine (38 μL, 0.46 mmol). After stirring at ambient temperature overnight, the reaction mixture was partitioned between saturated NH4Cl (20 mL) and CH2Cl2 (20 mL). The aqueous layer was extracted with CH2Cl2 (2×10 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4 and concentrated. The crude material was purified by silica chromatography (2 to 5% MeOH/CH2Cl2) to yield the final product as white solid (38 mg, 65%). LCMS (apci) m/z=381.1 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][CH:5]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[C:22]1(C)C=CC=C[CH:23]=1>C(Cl)(=O)C(Cl)=O>[CH3:21][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:22][CH3:23])=[O:17])=[CH:19][CH:20]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: CN(C)CCC(c1ccc(C(=O)O)cc1)c1ccccn1
Reactant: Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Product: CCOC(=O)c1ccc(C(CCN(C)C)c2ccccn2)cc1
Reaction time: 1 h

Procedure:
Acid 18a (927 mg, 3.26 mmol) was stirred in oxalyl chloride (5 mL) at room temperature for 2 minutes and dry toluene (4 mL) was added to facilitate stirring. After 1 h, the mixture was concentrated. Ethanol (10 mL) and triethylamine (1.35 mL) were added and the dark yellow mixture was stirred overnight. The mixture was then concentrated and partitioned between ethyl acetate (25 mL) and water (25 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layers were washed with water (20 mL) and the combined aqueous layers were extracted with ethyl acetate (20 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated to yield 18c as an oil. Purification by flash chromatography (4/1 CH2Cl2/MeOH) yielded 18c (136 mg) as a yellow oil. The structure was confirmed by 1H NMR and LC/MS. (Esters 18d, 18e, and 18f were similarly prepared.)
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:41]=[CH:40][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:31](=[O:39])[N:32]([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])=[C:20]([CH:30]=2)[O:21][C:22]([CH3:29])([CH3:28])[C:23]([O:25]CC)=[O:24])=[CH:7][CH:6]=1>Cl>[NH2:2][N:3]=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:31](=[O:39])[N:32]([CH:33]([CH3:34])[CH3:35])[CH:36]([CH3:38])[CH3:37])=[C:20]([CH:30]=2)[O:21][C:22]([CH3:29])([CH3:28])[C:23]([OH:25])=[O:24])=[CH:40][CH:41]=1
Reactant: CCOC(=O)C(C)(C)Oc1cc(OCCCCCOc2ccc(C=NN)cc2)ccc1C(=O)N(C(C)C)C(C)C
Agent: Cl
Product: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C=NN)cc2)cc1OC(C)(C)C(=O)O)C(C)C
Temperature: 25 °C

Procedure:
A mixture of 0.16 g (0.26 mmol) of ethyl 5-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetate monohydrochloride and 10 ml of 6N hydrochloric acid is heated to reflux for 16 hours. The mixture is cooled to room temperature and then concentrated under reduced pressure at 50° C. to afford 5-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetic acid as an oil; CHN calculated for C29H41N3O6.HCl.0.5H2O:
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[SH:41][C@@H:42]1[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]2[CH2:54][CH2:53][C@H:52]([CH2:55][N:56]([CH3:70])[C:57]([O:59][CH2:60][C:61]3[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=3)=[O:58])[CH2:51]2)=[O:49])[CH2:43]1.C(OCC)(=O)C>C(#N)C.C(N(CC)C(C)C)(C)C>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:8]([S:41][C@@H:42]3[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]4[CH2:54][CH2:53][C@H:52]([CH2:55][N:56]([CH3:70])[C:57]([O:59][CH2:60][C:61]5[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=5)=[O:58])[CH2:51]4)=[O:49])[CH2:43]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: CN(C[C@H]1CCN(C(=O)[C@@H]2C[C@H](S)CN2C)C1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](CN(C)C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C)C3)[C@H](C)[C@H]12
Yield: 47.6 %

Procedure:
To a solution of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (0.72 g) in anhydrous acetonitrile (5 ml), N,N-diisopropylethylamine (0.21 ml) and a solution of (2S,4S)-4-mercapto-1-methyl-2-[(3S)-3-(N-methyl-N-4-nitrobenzyloxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]pyrrolidine (0.54 g) in anhydrous acetonitrile (5 ml) were added while stirring in an ice bath. The resulting mixture was allowed to react overnight at 0° C. To the reaction mixture, ethyl acetate was added. The resulting mixture was washed with water and saturated saline solution, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column (ethyl acetate/methanol=6/4), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-1-methyl-2-[(3S)-3-(N-methyl-N-4-nitrobenzyloxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (0.46 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][CH:6]3[CH2:11][CH2:12][NH:13][CH2:14][CH:5]3[C:4]=2[CH:3]=1.[CH2:15](Br)[CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[OH:17][CH2:16][CH2:15][N:13]1[CH2:12][CH2:11][CH:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=3[CH:5]2[CH2:14]1
Reactant: Cc1ccc2c(c1)C1CNCCC1N2
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1ccc2c(c1)C1CN(CCO)CCC1N2
Reaction time: 16 h

Procedure:
A mixture of 8-methyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (10.0 g), ethylene bromohydrin (8.0 g) and potassium carbonate (14.6 g) in methyl ethyl ketone (80 ml) is refluxed with stirring for 16 hours. The insoluble materials are filtered off and the filtrate is concentrated under reduced pressure. The resulting residue is dissolved in a dilute hydrochloric acid. The dilute hydrochloric acid layer is separated, washed with benzene, made alkaline with aqueous sodium hydroxide and then extracted with benzene. The benzene layer is dried over anhydrous sodium sulfate and concentrated to give a crude product as an oily substance. The crude product is treated in the same manner as described in Example 1 (1) to give the dihydrochloride of the titled compound (7.8 g), m.p. 182° -185°C (recrystallized from aqueous ethanol).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28]([NH2:30])=[O:29])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21])C1C=CC=CC=1>C(O)C.O.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28]([NH2:30])=[O:29])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21]
Reactant: NC(=O)c1cccc(C=Cc2ccc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)c2)c1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: NC(=O)c1cccc(CCc2ccc(N3CC(=O)NS3(=O)=O)c(O)c2)c1

Procedure:
To a solution of 3-{2-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-vinyl}-benzamide in ethanol (2 mL) is added two equivalents of KHCO3. The mixture is diluted with 5 mL water and hydrogenated at 1 atm over 50 mg of 10% Pd/C for 18 h. The catalyst is filtered and the filtrate lyophilized. The resulting solid is purified by HPLC to give the title compound as an amorphous powder: m/z (M−1)−=374; 1H NMR (DMSO-d6) δ 7.95 (m, 1H), 7.81 (s, 1H), 7.72 (m, 1H), 7.35 (m, 4H), 6.75 (d, J=1.5 Hz 1H), 6.70 (m, 1H), 4.04 (s, 2H), 2.86 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[N:12]=[N:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:15][C:4]=2[N:3]=1.[O-2].[Mg+2]>COCCO.[Pd]>[C:16]1([C:14]2[N:13]=[N:12][C:5]3[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[CH2:2][NH:3][C:4]=3[CH:15]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Clc1nc2cc(-c3ccccc3)nnc2c2ccccc12
Agent: [Pd]
Agent: [Mg+2]
Agent: [O-2]
Solvent: COCCO
Product: c1ccc(-c2cc3c(nn2)-c2ccccc2CN3)cc1
Yield: 134.5 %

Procedure:
A solution of 12.5 g (0.043 mol) of 6-chloro-3-phenyl-pyridazino[4,3-c]isoquinoline (Example 1) in 1.5 L of 2-methoxyethanol is hydrogenated at room temperature and atmospheric pressure in the presence of 2.5 g of 10% palladium on carbon and 1.8 g (0.044 mol) of magnesium oxide. About 1700 ml of hydrogen are absorbed. The mixture is filtered, the solvent evaporated under reduced pressure and the residue recrystallized from isopropanol to give 15 g (74%) of 5,6-dihydro-3-phenyl-pyridazino[4,3-c]isoquinoline.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[P:18]([O:23]C)([O:21][CH3:22])[O:19][CH3:20]>>[CH2:1]([P:18](=[O:23])([O:21][CH3:22])[O:19][CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: COP(OC)OC
Reactant: CCCCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCCCCP(=O)(OC)OC
Temperature: 116 °C
Reaction time: 24 h

Procedure:
A mixture of n-hexadecyl bromide (4.89 g, 16 mmol) and freshly distilled trimethyl phosphite (2.48 g, 20 mmol) is stirred at 116° C. for 24 hours. The excess trimethyl phosphite is then removed by distillation in vacuo and the residue is stored over phosphorus pentoxide in vacuo for 24 hours. The corresponding dimethyl n-hexadecylphosphonate is isolated from the residue by extracting twice with 10 ml of methanol each time. The two methanol extracts are combined and concentrated in vacuo. The oily colorless residue thus obtained, which still contains n-hexadecyl bromide in addition to the methyl n-hexadecylphosphonate, is further reacted with trimethylsilyl chloride (1.02 g, 9.4 mmol) and sodium iodide (1.4 g, 9.4 mmol) in 4.7 ml of anhydrous acetonitrile. The reaction is carried out with stirring at room temperature and lasts 15 minutes.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]=2[F:25])[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[F:34]>C1COCC1.C(OCC)(=O)C.[Pd]>[CH3:35][C:2]([CH3:1])([CH3:36])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]=2[F:25])[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[F:34]
Reactant: CCOC(=O)/C=C/c1ncnc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ncnc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a solution of ethyl (2E)-3-(6-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-5-fluoropyrimidin-4-yl)acrylate (300 mg) in THF (2.0 mL) and ethyl acetate (2.0 mL) was added 10% palladium-activated carbon (30 mg) and, under a hydrogen atmosphere, the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (300 mg) as a pale-yellow solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([Cl:10])[C:4]#[C:5][Si](C)(C)C.ON=CC#[C:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](C)[CH:17]=1>>[OH:1][N:2]=[C:3]([Cl:10])[C:4]#[C:5][C:18]1[CH:17]=[C:16]([CH3:15])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cccc(C#CC=NO)c1
Reactant: C[Si](C)(C)C#CC(Cl)=NO
Product: Cc1cccc(C#CC(Cl)=NO)c1
Yield: 96.4 %

Procedure:
The title compound was prepared following the method herein described for Compound 3b, using Compound 91c instead of 3-trimethylsilylprop-2-ynal oxime. The residue was used in the next step without further purification. Yield: 96.4%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].CC(O)=O.C=O.[F:36][C:37]1[CH:45]=[C:44]2[C:40]([CH:41]=[CH:42][NH:43]2)=[CH:39][CH:38]=1>CO.O1CCOCC1>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:12][CH2:13][N:14]([CH2:17][C:41]3[C:40]4[C:44](=[CH:45][C:37]([F:36])=[CH:38][CH:39]=4)[NH:43][CH:42]=3)[CH2:15][CH2:16]1)[CH2:10][C:9]2=[O:28]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: Fc1ccc2cc[nH]c2c1
Agent: C=O
Solvent: CC(=O)O
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3c[nH]c4cc(F)ccc34)CC1)O2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.3 %

Procedure:
A mixture of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (170 mg, 0.564 mmol, Intermediate 1, free base), AcOH (0.051 ml, 0.90 mmol), and HCHO (35% in H2O, 0.07 ml, 0.847 mmol) in MeOH (12 ml) and dioxane (3 ml) was stirred at RT for 20 min and then treated with 6-fluoro-1H-indole (100 mg, 0.734 mmol). The resulting solution was stirred at 50° C. for 1 h. The solvent was then evaporated, the residue dissolved with DCM and washed with 5% aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4 and evaporated under vacuum. The crude mixture was purified by column chromatography (eluent:DCM/MeOH/NH4OH 97:3:0.3) to give (E)-3-{1′-(6-fluoro-1H-indol-3-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester as a brown solid (140 mg).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]Br)(=[O:3])[CH3:2].[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P:11]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:18])(=[O:3])[CH3:2]
Reactant: CCOP(OCC)OCC
Reactant: CC(=O)OCCCCCBr
Product: CCOP(=O)(CCCCCOC(C)=O)OCC

Procedure:
100.34 g (0.48 mol) of 5-bromopentyl acetate were heated at 150° C. for 8 hours with 79.8 g (0.048 mol) of triethyl phosphite while stirring and passing in nitrogen. The mixture was then fractionally distilled under reduced pressure.