Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12]1[C:13](=O)[O:14][C:15](O)([CH3:24])[C:16]=1[C:17]1[CH:18]=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=1.COC(C)(C)C>C(O)CCC>[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12]1[C:13](=[O:14])[NH:2][N:3]=[C:15]([CH3:24])[C:16]=1[C:17]1[CH:18]=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=1
Reactant: CC1(O)OC(=O)C(c2c(F)cccc2Cl)=C1c1ccc(Cl)nc1
Reactant: NN
Solvent: O
Solvent: CCCCO
Solvent: COC(C)(C)C
Product: Cc1n[nH]c(=O)c(-c2c(F)cccc2Cl)c1-c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Hydrazine hydrate (12 g) is added to a solution of 3-(2-chloro-6-fluoro-phenyl)-4-(6-chloro-pyridin-3-yl)-5-hydroxy-5-methyl-5H-furan-2-one (Compound No. II.a.1, 80 g) in 400 ml of 1-butanol and this mixture is heated for 7 h to 120° C. Subsequently, the mixture is poured into 400 ml of tert-butyl methyl ether. The resulting mixture is stirred for 30 min, then cooled to 0° C. and filtered. The solid remainder is washed with tert-butyl methyl ether to deliver 4-(2-chloro-6-fluoro-phenyl)-5-(6-chloro-pyridin-3-yl)-6-methyl-2H-pyridazin-3-one (Compound No. I.a.01) as colourless solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]#[C:10][CH2:11][N:12]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:37])[C@@H:19]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[C:28]([Cl:36])[CH:27]=2)[CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:13]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)(=O)C>[NH2:7][CH2:8][C:9]#[C:10][CH2:11][N:12]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:37])[C@@H:19]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[C:28]([Cl:36])[CH:27]=2)[CH2:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)=[N:13]1
Reactant: CC(C)(C)OC(=O)NCC#CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC#CCN)n2)cc1Cl
Yield: 64.3 %

Procedure:
(4-{3-[2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-but-2-ynyl)-carbamic acid tert-butyl ester (240 mg, 0.43 mmol) was dissolved in methylene chloride (10 mL) and trifluoroacetic acid (2 mL) was added while stirring. The reaction continued to stir for 45 min. The reaction was concentrated in vacuo at 0° C. to give a yellow oil. The reaction was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium bicarbonate (2×50 mL), saturated aqueous brine solution (50 mL), dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% methanol/ethyl acetate to 10% methanol/ethyl acetate) afforded N-[1-(4-amino-but-2-ynyl)-1H-pyrazol-3-yl]-2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (128 mg, 69%) as a thick, faintly yellow oil: ESI-LRMS m/e calcd for C22H27ClN4O3S [M+] 462.2, found 463.2 [M+H+]; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.21 (m, 2H, CH2), 1.38-1.82 (m, 8H, 4×CH2), 1.98 (brs, 2H, NH2), 2.05-2.24 (m, 1H, CH), 3.29 (t, J=2.0 Hz, 2H, NCH2), 3.33 (s, 3H, SO2CH3), 3.86-3.95 (m, 1H, CH), 4.87 (t, J=2.0 Hz, 2H, NCH2), 6.44 (d, Jo=2.3 Hz, 1H, Ar), 7.58 (dd, Jo=8.2, Jm=1.6 Hz. 1H, Ar), 7.62 (d, Jo=2.3 Hz, 1H, Ar), 7.68 (d, Jm=1.6 Hz, 1H, Ar), 7.99 (d, Jo=8.2 Hz, 1H, Ar), 10.81 (s, 1H, NH).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:44][O:45][C:46]1[CH:74]=[C:73]([O:75][CH3:76])[CH:72]=[CH:71][C:47]=1[CH2:48][NH:49][CH:50]([CH2:53][CH2:54][CH2:55][C:56]1[CH:61]=[CH:60][C:59]([O:62][CH2:63][C@@H:64]2[CH2:68][O:67][C:66]([CH3:70])([CH3:69])[O:65]2)=[CH:58][CH:57]=1)[CH2:51][NH2:52]>CN(C=O)C>[CH3:44][O:45][C:46]1[CH:74]=[C:73]([O:75][CH3:76])[CH:72]=[CH:71][C:47]=1[CH2:48][NH:49][CH:50]([CH2:53][CH2:54][CH2:55][C:56]1[CH:57]=[CH:58][C:59]([O:62][CH2:63][C@H:64]2[CH2:68][O:67][C:66]([CH3:70])([CH3:69])[O:65]2)=[CH:60][CH:61]=1)[CH2:51][NH:52][C:10]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=1)=[O:12]
Reactant: COc1ccc(CNC(CN)CCCc2ccc(OC[C@@H]3COC(C)(C)O3)cc2)c(OC)c1
Reactant: Nc1nc(N)c(C(=O)O)nc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1ccc(CNC(CCCc2ccc(OC[C@H]3COC(C)(C)O3)cc2)CNC(=O)c2nc(Cl)c(N)nc2N)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid (161 mg, 0.86 mmol) and HATU (325 mg, 0.86 mmol) in DMF (10 mL) is added N-methylmorpholine (0.38 mL, 3.42 mmol) followed by N*2*-(2,4-dimethoxy-benzyl)-5-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-pentane-1,2-diamine (391 mg, 0.86 mmol) and the mixture is stirred at RT overnight. The solvent is removed in vacuo. To the crude residue is added water (10 mL), which is then decanted off to leave an orange solid that is washed with diethyl ether (10 mL) and dried in vacuo at 50° C. to afford the title compound. [M+H]+ 629.
Reaction SMILES: [BrH:1].[C:2]1([S:8]([CH2:11][CH2:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH2:24][CH2:25]OC>>[BrH:1].[CH3:19][N:18]1[CH2:17][CH2:16][CH2:15][C@@H:24]1[CH2:25][C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[C:13]([CH2:12][CH2:11][S:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)(=[O:10])=[O:9])[CH:14]=2)[NH:18][CH:17]=1
Reactant: O=S(=O)(CCc1ccc2[nH]ccc2c1)c1ccccc1
Reactant: COCCOC
Agent: Br
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(CCS(=O)(=O)c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
49% w/w Hydrobromic acid (27.86 ml, 0.25 mol) was added over 1 hour to a stirred solution of 3N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole (92.86 g, 0.24 mol) in 1,2-dimethoxyethane (2.08 l) at about 5° C. The cooling bath was removed and the resulting slurry was allowed to granulate by stirring at room temperature for a further 18 hours. Filtration, followed by washing with 1,2-dimethoxyethane and drying in vacuo, afforded the required product (97.9 g) as a solid, m.p. 150-151° C. Found: C,56.77; H,5.87; N,5.85. C22H26N2O2S; HBr requires C,57.02; H,5.87; N,6.04%.
Reaction SMILES: Cl.[C:2]([C:6]1[O:10][C:9]([CH2:11][N:12]2[C:17]3[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[S:20][C:16]=3[C:15](=[O:27])[N:14]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[C:13]2=[O:34])=[N:8][N:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH2:35]([O:37][C:38]1[C:47]([O:48][CH3:49])=[CH:46][C:45]2[C:44]([C:50]3[CH:58]=[CH:57][C:53]([C:54](O)=[O:55])=[CH:52][CH:51]=3)=[N:43][C@@H:42]3[CH2:59][CH2:60][S:61][CH2:62][C@@H:41]3[C:40]=2[CH:39]=1)[CH3:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:2]([C:6]1[O:10][C:9]([CH2:11][N:12]2[C:17]3[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[S:20][C:16]=3[C:15](=[O:27])[N:14]([CH:28]3[CH2:29][CH2:30][N:31]([C:54]([C:53]4[CH:57]=[CH:58][C:50]([C:44]5[C:45]6[CH:46]=[C:47]([O:48][CH3:49])[C:38]([O:37][CH2:35][CH3:36])=[CH:39][C:40]=6[C@H:41]6[CH2:62][S:61][CH2:60][CH2:59][C@H:42]6[N:43]=5)=[CH:51][CH:52]=4)=[O:55])[CH2:32][CH2:33]3)[C:13]2=[O:34])=[N:8][N:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: CC(C)(C)c1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nnc(C(C)(C)C)o5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(5-tert-butyl-1,3,4-oxadiazol-2-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (1.63 g; compound B98) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (1.39 g; compound C10) and HBTU (1.48 g) in DCM (40 ml) in the presence of DIPEA (2.38 ml) according to the procedure described in example 55 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluent: EtOAc/cyclohexane, 90/10 (v/v)] as a solid
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3](=O)[CH2:4][CH2:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)(=O)C.CO>[CH3:28][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:17][CH2:18]2)=[CH:11][CH:12]=1)[OH:26]
Reactant: CN(C)C(=O)CCC(=O)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)CCCC(O)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Yield: 61 %

Procedure:
Prepared analogously to example A51 from N,N-dimethyl-γ-oxo-4-[4-(phenylmethyl)-1-piperazinyl]-benzenebutanoic acid amide by reduction with lithium aluminium hydride in a yield of 61% of theory. Colourless, amorphous substance of Rf=0.62 (eluant: ethyl acetate/methanol 1/1 v/v).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:21][S:22][C:23]1[CH:28]=[CH:27][NH:26][C:25](=[O:29])[C:24]=1[N+:30]([O-])=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[Sn](Cl)Cl>C1COCC1.O.C(Cl)Cl>[C:36]([O:35][C:34](=[O:40])[NH:33][C@H:20]([CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:21][S:22][C:23]1[CH:28]=[CH:27][NH:26][C:25](=[O:29])[C:24]=1[NH2:30])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N[C@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CSc1cc[nH]c(=O)c1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl[Sn]Cl
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CSc1cc[nH]c(=O)c1N
Reaction time: 22 h
Yield: 62.9 %

Procedure:
A solution of tert-butyl{(2R)-1-{[tert-butyl(diphenyl)silyl]oxy}-3-[(3-nitro-2-oxo-1,2-dihydropyridin-4-yl)sulfanyl]propan-2-yl}carbamate (44, 507 mg, 0.87 mmol) and ammonium acetate (1.1 g, 14.0 mmol) in THF (12 ml) and water (3 ml) was treated with anhydrous tin(II) chloride (1.04 g, 5.5 mmol) and the mixture stirred at +65° C. for 22 h. The reaction mixture was diluted with DCM, washed with saturated NaHCO3, dried over MgSO4, filtered and concentrated. Purification was performed in a chromatographic column on silicagel, eluted with 30% to 100% EtOAc in hexane to afford title compound (303 mg, 63% yield) as a light green solid. MS: m/z=576.2 (MNa+).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([CH3:18])[C:10](=[O:17])[C:11]([CH3:16])([C:13]([OH:15])=[O:14])[O:12][C:7]=2[CH:6]=1.C1(NC2CCCCC2)CCCCC1.Br[CH2:43][C:44]([O:46][CH3:47])=[O:45].O>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([CH3:18])[C:10](=[O:17])[C:11]([CH3:16])([C:13]([O:15][CH2:43][C:44]([O:46][CH3:47])=[O:45])=[O:14])[O:12][C:7]=2[CH:6]=1
Reactant: COC(=O)CBr
Reactant: CN1C(=O)C(C)(C(=O)O)Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc21
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COC(=O)C1(C)Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2N(C)C1=O
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
7-(2-Chloro-4-trifluoromethylphenoxy)-2,4-dimethyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-2-carboxylic acid (Compound 23) (0.4 g) was dissolved in DMF (0.2 ml) and dicyclohexylamine (0.2 ml) was added thereto, followed by stirring at 60° C. for 15 minutes. Then methyl bromoacetate (0.2 g) was added, the mixture further stirred at 60° C. for 3 hours, to the reaction mixture was added water (20 ml), and the mixture was extracted twice with ethyl acetate (20 ml). The extract was washed with water and then with saturated aqueous sodium chloride, and then dried over magnesium sulfate, followed by an evaporation of the solvent under a reduced pressure. The residue was purified by silica gel chromatography (eluant: n-hexane/ethyl acetate=3/1) to give 0.3 g of the title compound (colorless crystals).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:19]=[C:18]([CH2:20]O)[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][C:6]=1[C:22]([F:25])([F:24])[F:23])[CH:2]([CH3:4])[CH3:3].[NH:26]1[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]1.CCN(CC)CC.[BH3-]C#N.[Na+]>O1CCOCC1.O=[Mn]=O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:19]=[C:18]([CH2:20][N:26]4[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]4)[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][C:6]=1[C:22]([F:24])([F:25])[F:23])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(-c2nc3ccc(CO)cc3o2)cc1C(F)(F)F
Reactant: O=C(O)C1CNC1
Agent: O=[Mn]=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)Cc1ccc(-c2nc3ccc(CN4CC(C(=O)O)C4)cc3o2)cc1C(F)(F)F
Temperature: 50 °C

Procedure:
To a solution of [2-(4-isobutyl-3-trifluoromethyl-phenyl)-benzooxazol-6-yl]-methanol (1 eq) in dioxane (0.2 M) is treated with MnO2 (10 eq). The resulting mixture is refluxed for 20 minutes and filtered through celite. After concentration, the residue is redissolved in MeOH (0.2 M) and is added azetidine-3-carboxylic acid (2 eq) and Et3N (1.8 eq). The resulting mixture is heated at 50° C. for 1 hour. After cooling to room temperature, NaBH3CN (3 eq) is added in portions. The final compound is purified by preparative LCMS. 1H NMR (400 MHz, CD3OD) δ 8.49 (s, 1H), 8.38 (d, J=8.4 Hz, 1H), 7.88 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.66 (d, J =8.4 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 4.57 (s, 2H), 4.34 (m, 4H), 3.70 (m, 1H), 2.76 (d, J=6.8 Hz, 2H), 2.03 (m, 1H), 0.95 (d, J =7.2 Hz, 6H). MS: (ES+): 433.2 (M+1)+.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][NH:5][CH:4]=[C:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O[CH2:36][CH2:37][F:38])(=O)=O)=CC=1.Cl>CN(C=O)C>[F:38][CH2:37][CH2:36][N:5]1[CH:6]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2](=[O:1])[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4]1
Reactant: CCOC(=O)c1c[nH]cc(-c2ccccc2)c1=O
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCF)cc(-c2ccccc2)c1=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
Ethyl 4-oxo-5-phenyl-1,4-dihydropyridine-3-carboxylate (190 mg) was suspended in DMF (2.5 ml). Cesium carbonate (509 mg) and 2-fluoroethyl 4-methylbenzenesulfonate (256 mg) were sequentially added and the mixture was stirred at 50° C. for three hours. A 1 N aqueous hydrochloric acid solution was added under ice cooling, and the organic layer was extracted with ethyl acetate, washed with water and brine and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=300:1->40:1 (v/v)] to give 181 mg of the title compound as an oily substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O-:9])=[O:8].[Na+].[C:11]([O:17][CH2:18]Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].CN(C)C=O>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9][CH2:18][O:17][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:8]
Reactant: O=C([O-])c1cnccn1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)OCOC(=O)c1cnccn1
Reaction time: 8 h
Yield: 77.9 %

Procedure:
A four-necked flask was charged with 127.5 g (0.873 mole) of sodium pyrazinecarboxylate, 119.3 g (0.792 mole) of chloromethyl pivalate and 146 g of dimethylformamide and the internal temperature was maintained under stirring at 105°-110° C. for 8 hours. The reaction mixture was then cooled and transferred to a separatory funnel. After addition of 500 g of toluene, the mixture was washed with 3 portions, or a total of 900 g, of water. From the toluene layer which separated the toluene was first distilled off and the residue was subjected to distillation under reduced pressure to give 147 g of pivaloyloxymethyl pyrazinecarboxylate. Yield: 78% (based on chloromethyl pivalate).
Reaction SMILES: [N:1]1([CH2:7]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1[N:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][N:11]=1.[C:18]([O-])([O-])=[O:19].[K+].[K+]>CC(N(C)C)=O>[CH2:16]([C:13]1[CH:12]=[N:11][C:7]([N:1]2[CH2:2][CH2:3][CH:4]([CH2:18][OH:19])[CH2:5][CH2:6]2)=[N:15][CH:14]=1)[CH3:17]
Reactant: CCc1cnc(Cl)nc1
Reactant: OCN1CCCCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCc1cnc(N2CCC(CO)CC2)nc1
Temperature: 130 °C

Procedure:
Piperidinemethanol (10.7 g, 93 mmol) is dissolved in DMA (60 mL), treated with 2-chloro-5-ethylpyrimidine (14.57 g, 102 mmol) and K2CO3 (19.3 g, 140 mmol) and heated to 130° C. overnight. The solid is filtered, washed with DMA and discarded. The filtrate is evaporated and the crude purified by flash chromatography (EtOAc/hexanes gradient) to afford (1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methanol A1a as yellow oil: 1H-NMR (400 MHz, CDCl3) δ=8.16 (s, 2H), 4.75-4.72 (m, 2H), 3.53 (d, J=6.0 Hz, 2H), 2.91-2.83 (m, 2H), 2.45 (q, J=7.6 Hz, 2H), 1.84-1.73 (m, 3H), 1.27-1.20 (m, 2H), 1.18 (t, J=7.6 Hz, 3H); MS calcd. for [M+H]+ C12H20N3O: 222.1. found: 222.1.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[SH:19][C:20]1[S:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.C(=O)(O)[O-].[Na+].Cl>O.CC(C)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:19][C:20]3[S:21][C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[N:24]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Sc1nc2ccccc2s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3nc4ccccc4s3)CS[C@H]12
Yield: 58.1 %

Procedure:
To a mixture of 7-aminocephalosporanic acid (23.1 g., purity 86.4%) and 2-mercaptobenzothiazole (14.7 g.) in water (800 ml.), sodium bicarbonate (13.5 g.) was added portionwise with stirring, and acetone (250 ml.) was added thereto. The mixture was stirred at 73° C. for 4.5 hours, cooled below 20° C. and adjusted to pH 3.4 with 6 N hydrochloric acid. The precipitating crystals were collected by filtration, washed with water and acetone in turn and dried under reduced pressure to give 7-amino-3-(benzothiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (18.7 g.).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].[CH2:13]([O:15][C:16](=[O:27])[CH:17](Cl)[C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]>C1COCC1.C(O)C>[CH2:13]([O:15][C:16]([CH:17]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[F:1])[C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:27])[CH3:14]
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1
Reactant: O=C(O)c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(OC(=O)c1ccccc1F)C(=O)c1ccccc1
Temperature: 0 °C
Yield: 37.5 %

Procedure:
2-Fluorobenzoic acid (6 g, 42.8 mmole) was dissolved in 300 mL of anhydrous THF and the resulting reaction solution was cooled to 0° C. To this solution was added sodium hydride (1.88 g of a 60% oil dispersion, 47.1 mmole). The reaction mixture was allowed to warm to room temperature over 1 h. The THF was removed by evaporation before addition of 2-chloro-3-oxo-3-phenyl-propionic acid ethyl ester (9.7 g, 42.8 mmole) in 250 mL of ethanol. Reaction solution was warmed at reflux for 24 h. The ethanol was removed by evaporation and the resulting product was dissolved in water and extracted with toluene. The toluene was washed with 2 N aqueous Na2CO3, and saturated NaCl. The resulting toluene layer was concentrated and purified by chromatography (5-8% ethyl acetate in hexanes gradient) providing 2-fluoro-benzoic acid 1-ethoxycarbonyl-2-oxo-2-phenyl-ethyl ester (Intermediate XVIIb, 5.3 g, 38% yield)
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C@@H:3]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:4][CH2:5][CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16].[C:28](=O)(ON1C(=O)CCC1=O)[O:29]N1C(=O)CCC1=O.C(N(CC)CC)C>ClC(Cl)C>[CH3:1][C:2]([CH3:27])([CH3:26])[C@H:3]([N:4]1[CH2:5][CH2:6][N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:16])[F:17])[C:28]1=[O:29])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)[C@@H](NCCNCc1ccccc1C(F)(F)F)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2ccccc2C(F)(F)F)C1=O)C(C)(C)C

Procedure:
A solution of Example 138A (225 mg, 0.595 mmol) and disuccinimidyl carbonate (0.183 g, 0.714 mmol) in dichloroethane (6 mL) was treated with triethylamine (99 μL, 0.714 mmol) at 25° C. for 16 h. The mixture was partitioned between 10% sodium carbonate and dichloromethane. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and the solvents were evaporated to give the crude title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:13]2[N:18]=[C:17]([CH:19]3[CH:23]([C:24](=[O:27])[NH:25][CH3:26])[CH2:22][CH2:21][N:20]3[CH2:28][CH2:29][N:30]([CH2:38][C:39]3[CH:47]=[CH:46][C:42]4[O:43][CH2:44][O:45][C:41]=4[CH:40]=3)C(=O)OC(C)(C)C)[CH:16]=[C:15]([CH3:48])[N:14]=2)[CH:12]=[CH:11][N:10]=[CH:9]1.O.[OH-].[NH4+]>C(Cl)Cl>[N:8]1([C:13]2[N:18]=[C:17]([CH:19]3[CH:23]([C:24]([NH:25][CH3:26])=[O:27])[CH2:22][CH2:21][N:20]3[CH2:28][CH2:29][NH:30][CH2:38][C:39]3[CH:47]=[CH:46][C:42]4[O:43][CH2:44][O:45][C:41]=4[CH:40]=3)[CH:16]=[C:15]([CH3:48])[N:14]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: CNC(=O)C1CCN(CCN(Cc2ccc3c(c2)OCO3)C(=O)OC(C)(C)C)C1c1cc(C)nc(-n2ccnc2)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)C1CCN(CCNCc2ccc3c(c2)OCO3)C1c1cc(C)nc(-n2ccnc2)n1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
2,2,2-Trifluoroacetic acid (5.00 mL, 67.3 mmol) was added dropwise over 5 minutes to a 0° C. solution of tert-butyl 2-(2-(2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl)-3-(methylcarbamoyl)pyrrolidin-1-yl)ethyl(benzo[d][1,3]dioxol-5-ylmethyl)carbamate (100 mg, 0.18 mmol) in CH2Cl2 (5 mL). The reaction mixture was warmed to rt over 30 minutes then water (20 mL) was added. The solution was brought to pH=9 with ammonium hydroxide (100 mL), extracted with CH2Cl2 (3×10 mL), the combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum to afford 50 mg (61%) of 2-(2-(1 H-imidazol-1-yl)-6-methylpyrimidin-4-yl)-1-(2-(benzo[d][1,3]dioxol-5-ylmethylamino)ethyl)-N-methylpyrrolidine-3-carboxamide as yellow oil. [M−H]+ 462.00.
Reaction SMILES: [CH2:1]([S:8][C:9]([CH3:38])([CH:33](OC)[O:34]C)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]([CH3:32])[S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:26])=[O:25])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CC(C)=O>[CH2:1]([S:8][C:9]([CH3:38])([CH:33]=[O:34])[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]([CH3:32])[S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:26])=[O:25])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)C(C)(CNC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1)SCc1ccccc1
Solvent: O
Solvent: CC(C)=O
Product: CN(c1cccc2cc(C(=O)NCC(C)(C=O)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
A mixture of N-[2-(benzylthio)-3,3-dimethoxy-2-methylpropyl]-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (1.00 g), Amberlyst (registered trade mark) 15 ion exchange resin (0.20 g), water (0.1 ml) and acetone (10 ml) was stirred overnight at room temperature. The insoluble substance was removed by filtration, and the filtrate was concentrated to give the title compound (0.83 g, yield 92%) as colorless crystals. melting point 149-150° C.