Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=1)(=[O:4])=[O:3].C(OC(NCC1C=CC=CC=1CC(O)=O)=O)(C)(C)C.[ClH:36].Cl.[CH3:38][NH:39][C@@H:40]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:41][N:42]1[CH2:46][CH2:45][C@H:44]([OH:47])[CH2:43]1.CN[C@@H](C1C=CC=CC=1)CN1CCCC1.C(N(C(C)C)CC)(C)C.Cl>ClCCl.CCOCC>[ClH:36].[OH:47][C@H:44]1[CH2:45][CH2:46][N:42]([CH2:41][C@@H:40]([N:39]([CH3:38])[C:14](=[O:16])[CH2:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:12][CH:11]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:43]1
Reactant: CS(=O)(=O)NCc1ccc(CC(=O)O)cc1
Reactant: CN[C@H](CN1CC[C@H](O)C1)c1ccccc1
Agent: CC(C)(C)OC(=O)NCc1ccccc1CC(=O)O
Agent: CN[C@H](CN1CCCC1)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: CN(C(=O)Cc1ccc(CNS(C)(=O)=O)cc1)[C@H](CN1CC[C@H](O)C1)c1ccccc1

Procedure:
Compound 13a was prepared by following the procedure of Example 1, Step f, except 12a was substituted for 6a, 1-[2-methylamino-2-(S)-phenyl-ethyl]-pyrrolidin-3-(S)-ol dihydrochloride was substituted for methyl-[1-(S)-phenyl-2-pyrrolidin-1-yl-ethyl]-amine and diisopropylethylamine (3.3 eq) was substituted for diisopropylethylamine (2.2 eq). The resulting oil was dissolved in dichloromethane (0.1 M) and a solution of hydrochloric acid (5.5 eq) in ether (2.0 M) was added slowly at 0° C. The solvent was removed under reduced pressure. The resulting solid was triturated with ether then filtered off to afford the product as the hydrochloric acid salt. (55%) 1H NMR (400 MHz, DMSO-d6) δ 10.22-10.72 (m, 1H), 7.55 (m, 1H), 7.18-7.42 (m, 9H), 6.17 (m, 1H), 5.42-5.62 (m, 1H), 4.44 (m, 1H), 4.13 (m, 3H), 3.84 (m, 2H), 3.40-3.72 (m, 3H), 3.17 (m, 1H), 2.83 (s, 3H), 2.76 (m, 3H), 2.09-2.35 (m, 1H), 1.89 (m, 1H). Mass Spectral Analysis m/z=446.4 (M+H)+ tR=3.45 min (98%)
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]([O:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH2:20])([CH3:16])([CH3:15])[CH3:14]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:20][C@@H:19]([CH3:21])[C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:22])=[O:10])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of para-nitrobenzoic acid in tetrahydrofuran, 1.2 equivalents of 1,1′-carbonyldiumidazole are added and the mixture is stirred for 30 minutes. Then, 1.1 equivalents of the (S)-L-alanine tert-butyl ester are added and the mixture is stirred for 24 hours at room temperature. The solvent is removed under reduced pressure and the crude is diluted in chloroform and brine. The organic layer is washed with water and dried over MgSO4. The filtrate is concentrated under vacuum and the residue is purified by column chromatography to give the desired compound.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[C:11]([O:12]C)=[CH:10][CH:9]=[C:8]([CH:14]=[O:15])[N:7]=1>Br>[CH:14]([C:8]1[N:7]=[C:6]([CH2:5][CH2:4][C:3]([OH:16])=[O:2])[C:11]([OH:12])=[CH:10][CH:9]=1)=[O:15]
Reactant: COC(=O)CCc1nc(C=O)ccc1OC
Agent: Br
Product: O=Cc1ccc(O)c(CCC(=O)O)n1
Yield: 61.1 %

Procedure:
Under the conditions of example 16K, 8.8 g of 3-(6-formyl-3-methoxy-2-pyridyl)-propionic acid methyl ester in 114 ml of 48% hydrobromic acid is reacted and worked up. 4.7 g of 3-(6-formyl-3-hydroxy-2-pyridyl)-propionic acid is obtained as crude product, which is dissolved in 350 ml of methanol for further reaction and is stirred in the presence of 14.4 g of Amberlyst 15 for 16 hours at room temperature. The methanol is removed in a vacuum, the residue is absorptively precipitated with concentrated ammonia solution, filtered on diatomaceous earth and the filter residue is washed with concentrated ammonia solution. The filtrate is neutralized with concentrated hydrochloric acid, adjusted to pH 5 with diluted hydrochloric acid, shaken out with ethyl acetate, the organic phase is dried on sodium sulfate and concentrated by evaporation. The crude product is chromatographed on silica gel with hexane/0-20% ethyl acetate. 2.5 g of 3-(6-formyl-3-hydroxy-2-pyridyl)-propionic acid methyl ester of melting point 92°-95° C. is obtained.
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([CH3:13])[C:5]2[N:6]=[C:7]([NH2:10])[N:8]=[N:9][C:4]=2[CH:3]=1.[N+:14]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)([O-:16])=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:13][C:11]1[C:5]2[N:6]=[C:7]([NH2:10])[N:8]=[N:9][C:4]=2[CH:3]=[C:2]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:14]([O-:16])=[O:15])[CH:22]=2)[CH:12]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Cc1cc(Br)cc2nnc(N)nc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(-c2cccc([N+](=O)[O-])c2)cc2nnc(N)nc12
Temperature: 25 °C
Yield: 71.3 %

Procedure:
An oven dried 25 mL round bottom flask was charged with 7-bromo-5-methyl-benzo[1,2,4]triazin-3-ylamine (1.05 g, 4.49 mmol, 1 equiv), 3-Nitro phenyl boronic acid (1.05 g, 6.29 mmol, 1.4 equiv), sodium carbonate (1.9 g, 18 mmol, 4 equiv) and tetrakis(triphenylphosphine) palladium(0) (0.519 g, 0.449 mmol, 0.1 equiv). The reactants were flushed with argon and diluted with ethylene glycol dimethyl ether (6 mL), ethanol (1 mL) and DI water (1 mL). The reaction vessel was outfitted with condenser and refluxed for 2.5 hours. The reaction was cooled to ambient temperature and diluted with water. The resulting precipitate was filtered off, washed thoroughly with water and dried. Brown solids (0.9 g, 73% yield). MS (ESI+): m/z=282.4, LC retention time: 2.77 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[N:23]1([CH:29]2[CH2:35][CH2:34][C:33]3[CH:36]=[C:37]([NH2:40])[CH:38]=[CH:39][C:32]=3[CH2:31][CH2:30]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH3:14][NH:13][C:11](=[O:12])[C:10]1[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=1[NH:8][C:6]1[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=[C:2]([NH:40][C:37]2[CH:38]=[CH:39][C:32]3[CH2:31][CH2:30][CH:29]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH2:35][CH2:34][C:33]=3[CH:36]=2)[N:7]=1
Reactant: Nc1ccc2c(c1)CCC(N1CCOCC1)CC2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCC(N2CCOCC2)CC3)ncc1C(F)(F)F

Procedure:
The title compound was prepared from 2-(2-chloro-5-trifluoromethyl-pyrimidin-4-ylamino)-N-methyl-benzamide and 7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine in an analogous manner to Example 195 (microwave: 120° C., 60 minutes) to afford an off-white solid (35 mg, 86%). Mp: 158-62° C. LCMS (m/e) 541 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 10.85 (s, 1H), 8.45 (d, J=9 Hz, 1H), 8.36 (s, 1H), 7.50 (d, J=7 Hz, 1H), 7.47-7.37 (m, 2H), 7.30 (m, 1H), 7.25 (m, 2H), 7.10 (m, 1H), 6.27 (br s, 1H), 3.90-3.70 (m, 4H), 3.04 (s, 3H), 2.90-2.50 (m, 7H), 2.17 (m, 2H), 1.80-1.35 (m, 4H).
Reaction SMILES: CS[C:3]1[S:4][CH2:5][C:6](=[O:8])[N:7]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH:11]([CH2:15][OH:16])[CH2:10]1>>[OH:16][CH2:15][CH:11]1[O:12][CH2:13][CH2:14][N:9]([C:3]2[S:4][CH2:5][C:6](=[O:8])[N:7]=2)[CH2:10]1
Reactant: CSC1=NC(=O)CS1
Reactant: OCC1CNCCO1
Product: O=C1CSC(N2CCOC(CO)C2)=N1

Procedure:
2-(2-Hydroxymethyl-morpholin-4-yl)-thiazol-4-one was prepared from 2-Methylsulfanyl-thiazol-4-one and Morpholin-2-yl-methanol following general procedure E.
Reaction SMILES: [CH:1]1([O:7][C:8]([O:10][CH:11](I)[CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:14][CH2:15][CH2:16][O:17][CH2:18][C:19]1[N:20]=[CH:21][S:22][C:23]=1/[CH:24]=[CH:25]\[S:26][C:27]1[C@H:28]([CH3:41])[C@@H:29]2[C@@H:36]([C@H:37]([OH:39])[CH3:38])[C:35](=[O:40])[N:30]2[C:31]=1[C:32]([O-:34])=[O:33].[Na+]>CCCCCC.CN(C)C(=O)C>[OH:14][CH2:15][CH2:16][O:17][CH2:18][C:19]1[N:20]=[CH:21][S:22][C:23]=1/[CH:24]=[CH:25]\[S:26][C:27]1[C@H:28]([CH3:41])[C@@H:29]2[C@@H:36]([C@H:37]([OH:39])[CH3:38])[C:35](=[O:40])[N:30]2[C:31]=1[C:32]([O:34][CH:11]([O:10][C:8]([O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9])[CH3:12])=[O:33]
Reactant: CC(I)OC(=O)OC1CCCCC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3COCCO)[C@H](C)[C@H]12
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(=O)N(C)C
Product: CC(OC(=O)OC1CCCCC1)OC(=O)C1=C(S/C=C\c2scnc2COCCO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 1 h
Yield: 20969.6 %

Procedure:
A solution (2 ml) of 0.147 mg of 1-(cyclohexyloxycarbonyloxy)ethyl iodide in hexane was added to a solution of 51.8 mg of sodium (1R,5S,6S)-2-[[(Z)-2-[4-(2-hydroxyethoxy)methylthiazol-5-yl]ethen-1-yl]thio]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate in 2 ml of N,N-dimethylacetamide under an argon atmosphere at −10° C. The mixture was stirred at the same temperature for one hr, and 2 ml of hexane was then added to the reaction solution, followed by separation into an upper layer and a lower layer. Brine was added to the lower layer, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, were washed twice with brine, were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (chloroform:methanol=20:1) to give 61.7 mg of the title compound.
Reaction SMILES: Cl.[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3].[CH3:17][C:18]1([CH3:25])[CH2:21][CH:20]([C:22](Cl)=[O:23])[CH2:19]1.[Cl-]>>[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:22]([CH:20]2[CH2:21][C:18]([CH3:25])([CH3:17])[CH2:19]2)=[O:23])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3]
Reactant: CC1(C)CC(C(=O)Cl)C1
Reactant: CC(C)NCC(=O)c1ccc(O)c(O)c1
Agent: Cl
Agent: [Cl-]
Product: CC(C)NCC(=O)c1ccc(OC(=O)C2CC(C)(C)C2)c(O)c1

Procedure:
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and 3,3-dimethylcyclobutanecarbonyl chloride instead of isovalery chloride, there is obtained 3-hydroxy-4-(3,3-dimethylcyclobutanecarbonyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(3,3-dimethylcyclobutanecarbonyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Cl[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:6]=1
Reactant: Ic1cn[nH]c1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(Cn2cc(I)cn2)cc1
Temperature: 60 °C
Yield: 88.2 %

Procedure:
According to Scheme 9 Step 1: A suspension of 4-iodo-1H-pyrazole (26.3 mmol, 5.11 g), 1-(chloromethyl)-4-methoxybenzene (29.0 mmol, 3.95 mL) and K2CO3 (39.5 mmol, 5.46 g) in acetonitrile (150 mL) was heated at 60° C. overnight. The reaction mixture was cooled to room temperature and was filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel using DCM as eluent to afford 4-iodo-1-(4-methoxybenzyl)-1H-pyrazole (23.2 mmol, 7.3 g, 88%) as a yellow solid.
Reaction SMILES: COCC1CCCCN1C1N=CN=C(NC2C=C(CS(N)(=O)=O)C=CC=2)N=1.Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]2[CH:37]=[C:38]([CH2:42][S:43]([NH2:46])(=[O:45])=[O:44])[CH:39]=[CH:40][CH:41]=2)[N:30]=1.[C:47]1([NH:53][CH2:54][C@H:55]2[CH2:59][CH2:58][CH2:57][NH:56]2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[C:47]1([NH:53][CH2:54][C@H:55]2[CH2:59][CH2:58][CH2:57][N:56]2[C:29]2[N:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]3[CH:37]=[C:38]([CH2:42][S:43]([NH2:46])(=[O:45])=[O:44])[CH:39]=[CH:40][CH:41]=3)[N:30]=2)[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: c1ccc(NC[C@H]2CCCN2)cc1
Agent: COCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCC[C@@H]3CNc3ccccc3)n2)c1

Procedure:
B29 was prepared following the procedure reported for B4 using A1 and (R)-2-(phenylamino-methyl)pyrrolidine. It was obtained as a white crystalline solid; yield: 245 mg (62%). MS (ES) C21H25N7O2S requires: 439. found: 440 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[O:30])[CH:24]=[CH:25][C:26]=1[CH3:27]>>[CH3:20][C:21]1[CH:22]=[C:23]([NH:28][C:29](=[O:30])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Reactant: Cc1ccc(N=C=O)cc1C
Product: Cc1ccc(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4ncccc34)cc2)cc1C

Procedure:
45.2 mg of solid white 3-{4-[3-(3,4-dimethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 3,4-dimethylphenyl isocyanate.
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=[O:4].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>CCO>[CH2:12]([O:11][C:8]1[CH:7]=[CH:6][C:5]([C:3](=[O:4])[CH2:2][CH3:1])=[CH:10][CH:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCc1ccccc1
Reactant: CCC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCC(=O)c1ccc(OCc2ccccc2)cc1
Yield: 94 %

Procedure:
A mixture of 4-hydroxypropiophenone (20 g), benzyl chloride (16.1 ml), K2CO3 (12.9 g) and KI (2.21 g) in EtOH (80 ml) and H2O (1 ml) was stirred under reflux condition for 4 hours. The reaction mixture was cooled and filtered. Appeared crystal was dissovled with EtOAc and water. Organic layer was separated and washed with water and brine, dried over MgSO4 and filtered. Filtrate was evaporated under reduced pressure to give 30.0 g (94%) of 1-[4-(benzyloxy)phenyl]-1-propanone as a crystal.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]2[C:19](=[C:20]([NH:22][C:23]([C@@H:25]3[CH2:30][O:29][C:28]([CH3:32])([CH3:31])[CH2:27][N:26]3[CH2:33][C@@H:34]([NH2:36])[CH3:35])=[O:24])[CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][CH:14]=[CH:13][C:12]2=1.[CH3:37][C:38]1[C:43]([C:44](O)=[O:45])=[CH:42][N:41]=[CH:40][CH:39]=1>>[Cl:8][C:9]1[CH:10]=[C:11]2[C:19](=[C:20]([NH:22][C:23]([C@@H:25]3[CH2:30][O:29][C:28]([CH3:31])([CH3:32])[CH2:27][N:26]3[CH2:33][C@@H:34]([NH:36][C:44]([C:43]3[CH:42]=[N:41][CH:40]=[CH:39][C:38]=3[CH3:37])=[O:45])[CH3:35])=[O:24])[CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][CH:14]=[CH:13][C:12]2=1
Reactant: Cc1ccncc1C(=O)O
Reactant: C[C@H](N)CN1CC(C)(C)OC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccncc1C(=O)N[C@@H](C)CN1CC(C)(C)OC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Yield: 79 %

Procedure:
The desired compound was prepared according to Method E from (S)-4-((S)-2-Amino-propyl)-6,6-dimethyl-morpholine-3-carboxylic acid (6-chloro-9H-beta-carbolin-8-yl)-amide trifluoroacetate salt and 4-methyl-nicotinic acid in 79% yield.
Reaction SMILES: C(O[C:4](=[O:17])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=1[NH:13][CH:14]1[CH2:16][CH2:15]1)C.ClS[N:20]=[C:21]=[O:22]>ClCCl>[CH:14]1([N:13]2[C:6]3[C:5](=[CH:10][C:9]([F:11])=[C:8]([F:12])[CH:7]=3)[C:4](=[O:17])[NH:20][C:21]2=[O:22])[CH2:15][CH2:16]1
Reactant: CCOC(=O)c1cc(F)c(F)cc1NC1CC1
Reactant: O=C=NSCl
Solvent: ClCCl
Product: O=c1[nH]c(=O)n(C2CC2)c2cc(F)c(F)cc12
Temperature: -20 °C
Yield: 38.2 %

Procedure:
To a solution of 2-cyclopropylamino-4,5-difluorobenzoic acid ethyl ester (Example 22) (5.0 g, 22.0 mmol) in dry dichloromethane (120 mL) under a N2 atmosphere is added chlorosulfanyl isocyanate (3.11 g, 22 mmol). The solution is reacted at room temperature for 4 hours, and the solvent is removed under reduced pressure. The residue is cooled to −20° C., and a cold brine solution (100 mL) buffered with NaHCO3 is added. The solution is warmed to room temperature for 1 hour. The volume is reduced by half with a stream of air, and the solid is collected by filtration. The dry solid is added to a solution of triethylamine (5 mL) in THF (250 mL) and refluxed overnight. The reaction is cooled, the solvent removed under reduced pressure, dissolved in water (100 mL), and acidified to pH 1-2 with 1.0 M hydrochloric acid. The resulting precipitate is collected via filtration to afford 2.0 g of the title compound. MS CI: m/z 239 (MH+).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:24]([NH:26][C@@H:27]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH3:28])=[O:25])[CH2:10][CH2:11][CH2:12][NH:13]C(OCC1C=CC=CC=1)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H][H]>CO.[Pd]>[C:1]([NH:8][C@@H:9]([C:24]([NH:26][C@@H:27]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH3:28])=[O:25])[CH2:10][CH2:11][CH2:12][NH2:13])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: C[C@@H](NC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccc(O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@@H](NC(=O)[C@@H](CCCN)NC(=O)OC(C)(C)C)c1ccc(O)cc1
Yield: 88.5 %

Procedure:
To a solution of (R)-N2 -(Boc)-N5 -(Cbz)-(R)-N-[1-(4-hydroxyphenyl)-ethyl]ornithine amide (66.26 g; 139 mmol; see Example 4(b) above) in methanol (400 mL) was added 10% Pd/C (w/w; 3.53 g). After stirring for 18 h under 1 atmosphere of hydrogen the reaction was filtered through Celite to remove the catalyst and the filtrate was concentrated under reduced pressure to afford the sub-title compound as a white foam (43.2 g, 123 mmol).
Reaction SMILES: [CH3:1][C:2]1[S:18][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=O)=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:19].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[S:18][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]#[N:17])=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:19]
Reactant: Cc1sc2nc3ccc(C(N)=O)cn3c(=O)c2c1C
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1sc2nc3ccc(C#N)cn3c(=O)c2c1C
Yield: 94.2 %

Procedure:
From 1.0 g (0.0037 mol) of 2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide (Example 36), 50 ml of phosphorus oxychloride and 50 ml of chloroform and refluxing on a steam bath for eighteen hours, following the procedure of Example 27, there is obtained 0.89 g of 2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile; mp 306°-307° C. after recrystallization from glacial acetic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:5]2[C:6]([C@@H:10]3[CH2:12][C@H:11]3[C:13](OCC)=[O:14])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.[OH-].[Na+]>O1CCCC1.O>[CH3:1][C:2]1[CH:18]=[C:5]2[C:6]([C@@H:10]3[CH2:12][C@H:11]3[CH2:13][OH:14])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1cccn2nc(C)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc2c([C@@H]3C[C@H]3CO)cccn2n1
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
Under nitrogen atmosphere, to a solution of trans-ethyl 2-(2-methylpyrazolo[1,5-a]pyridin-4-yl)cyclopropanecarboxylate (5.40 g, 22.1 mmol) in tetrahydrofuran (150 mL) was added lithium aluminum hydride (0.750 g, 22.1 mmol) at 0° C., and the mixture was stirred for 30 min. To the reaction mixture were added ethyl acetate, water and 10% aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was washed with 2 N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by recrystallization (ethyl acetate/hexane) to give the title compound (4.30 g, yield 96%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:27][OH:28])[N:13]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH:27]=[O:28])[N:13]([C:15]2[CH:16]=[C:17]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:18]=[CH:19][CH:20]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(CO)n(-c2cccc(-c3ccccc3)c2)cc1OCc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1cc(=O)c(OCc2ccccc2)cn1-c1cccc(-c2ccccc2)c1

Procedure:
5-(Benzyloxy)-1-(biphenyl-3-yl)-2-(hydroxymethyl)pyridin-4(1H)-one (1 12 g, 292 mmol) was dissolved in 2.2 L of anhydrous THF and active manganese dioxide (407 g, 4.68 mol) was added. The reaction mixture was heated under reflux for 3 hours. The insoluble part was filtered off and the filtrate was concentrated to give crude 5-(benzyloxy)-1-(biphenyl-3-yl)-4-oxo-1,4-dihydropyridine-2-carbaldehyde, which was used in next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17].[OH-].[K+]>O1CCOCC1>[N+:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[O:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)([O-:18])=[O:17]
Reactant: OCC1CCNCC1
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccccc1OCC1CCNCC1
Temperature: 70 °C
Yield: 22.2 %

Procedure:
A mixture of 23.0 g (0.2 mole) of 4-hydroxymethylpiperidine, 31.5 g (0.2 mole) of 2-chloronitrobenzene, 11.8 g (0.21 mole) of potassium hydroxide and 200 ml of dioxane is heated to 70° C. for 3 days. The reaction mixture is then evaporated in a vacuum and the residue is taken up in diethyl ether, washed with water, extracted with dilute hydrochloric acid, rendered alkaline and the aqueous mixture extracted with diethyl ether. After evaporation of the solvent, there are obtained 10.5 g of 4-(2-nitrophenoxymethyl)-piperidine (22% of theory); b.p. 130°-132° C./0.01 mm. Hg.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10]CC(Cl)(Cl)Cl)=[O:9])[N:5]2[C:16](=[O:27])[CH:17]([NH:18][C:19](=[O:26])[CH2:20][N:21]3[CH:25]=[N:24][N:23]=[N:22]3)[C@H:4]2[S:3]1.CN(C)C=O>[Zn].C(O)(=O)C>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:16](=[O:27])[CH:17]([NH:18][C:19](=[O:26])[CH2:20][N:21]3[CH:25]=[N:24][N:23]=[N:22]3)[C@H:4]2[S:3]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cn3cnnn3)[C@H]2S1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)Cn3cnnn3)[C@H]2S1
Reaction time: 1.5 h
Yield: 68.1 %

Procedure:
Zinc powder (2.4 g) was added under ice-cooling and stirring to a solution of 2,2,2-trichloroethyl 2-methyl-7-[2-(1H-tetrazol-1-yl)acetamido]-3-cephem-4-carboxylate (2.0 g) in a mixture of anhydrous dimethylformamide (10 ml) and acetic acid (3 ml), and the mixture was stirred for 1.5 hours at the same temperature. After the reaction, zinc powder was filtered off, and the filtrate was extracted by pouring into a matrix of ethyl acetate (50 ml), ice-water and 10% hydrochloric acid (5 ml). The aqueous layer was further extracted with ethyl acetate (10 ml) and the ethyl acetate extract was combined, washed twice with water and dried over magnesium sulfate. After the solvent was distilled off, the residue was crystallized by adding a small amount of ether to give colorless crystals of 2-methyl-7-[2-(1H-tetrazol-1-yl)acetamido]-3-cephem-4-carboxylic acid (0.97 g), mp 202° to 203° C. (dec.).