Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C@@H:2]([CH2:8][N:9]([CH2:19][C@@H:20](Br)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[CH2:27]([N:34]1[C@H:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][N:9]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:19][C@@H:20]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)[C@H](Br)CN(C[C@H](Br)C(=O)OCC)S(=O)(=O)c1ccccc1
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@H]1CN(S(=O)(=O)c2ccccc2)C[C@@H](C(=O)OCC)N1Cc1ccccc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
To a solution of 112b (20g, 38.8 mmol) in toluene (100 ml) was added BnNH2 (12.48g, 116.5 mmol). The reaction mixture was stirred at 90° C. for 3h. Then the mixture was purified through a silica gel column eluting with PE:EA=50:1 to 10:1 to give 112c as a white crystal (10.7g, 60%) MS: [M+H]+: 461
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]([N:11]2[CH2:16][C:15]3([CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[O:14][CH2:13][CH2:12]2)=[O:10])[S:7][CH:8]=1)([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[CH:1]([C:4]1[N:5]=[C:6]([C:9]([N:11]2[CH2:16][C:15]3([CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[O:14][CH2:13][CH2:12]2)=[O:10])[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1csc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)n1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1csc(C(=O)N2CCOC3(CCNCC3)C2)n1
Reaction time: 0.33 h

Procedure:
A solution of tert-butyl 4-(4-isopropylthiazole-2-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 66, step a) (0.54 g) in DCM (20 mL) was treated with trifluoroacetic acid (5 mL) and the reaction mixture allowed to stand at 20° C. for 20 minutes. Toluene (40 mL) was added and the solvents removed under reduced pressure. The residue was azeotroped twice with acetonitrile to afford the subtitled compound. Yield 0.56 g.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4]C)C.[C:8]1(=[O:22])[N:12]([CH2:13][C:14](Cl)=[O:15])[C:11](=[O:17])[C:10]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:9]12.[CH2:23]([Cl:25])Cl>>[CH2:6]([N:3]1[C@H:4]([CH2:23][Cl:25])[C@H:13]([N:12]2[C:11](=[O:17])[C:10]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:9]3[C:8]2=[O:22])[C:14]1=[O:15])[C:7]1[CH:11]=[CH:10][CH:9]=[CH:21][CH:20]=1
Reactant: ClCCl
Reactant: CCN(CC)CC
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Product: O=C1[C@@H](N2C(=O)c3ccccc3C2=O)[C@@H](CCl)N1Cc1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of 3.34 g of the product Step A in 20 ml of methylene chloride was cooled to -50° C. and 2.8 ml of triethylamine were added all at once. A solution of 4 g of phthalimidoacetic acid chloride in 20 ml of methylene chloride was added thereto over 20 minutes. The mixture was stirred for one hour at 0° to -5° C. and was then poured into a decanting flask. The decanted organic phase was washed with 50 ml of demineralized water and 5 ml of a molar aqueous solution of sodium bicarbonate, and then twice with 30 ml of demineralized water. The wash water was re-extracted with 20 ml of methylene chloride and the combined organic phases were dried, rinsed and evaporated to dryness under vacuum. The 6 g of residue were chromatographed over silica gel and eluted with methylene chloride containing 5% ether. The fraction with an Rf=0.45 was evaporated to dryness and the residue was triturated with 10 ml of ether. The separated product was rinsed three times with 2 ml of ether and dried under vacuum to obtain 1.25 g of cis N-benzyl-3-phthalimido-4-chloromethyl-2-azetidinone melting at 149° C.
Reaction SMILES: [CH3:1][I:2].[Cl:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH2:6][O:7][C:8]1[C:9]2[N:10]([C:14]([CH2:18][N:19]([CH3:21])[CH3:20])=[C:15]([CH3:17])[N:16]=2)[CH:11]=[CH:12][CH:13]=1>CC(C)=O>[I-:2].[Cl:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH2:6][O:7][C:8]1[C:9]2[N:10]([C:14]([CH2:18][N+:19]([CH3:1])([CH3:21])[CH3:20])=[C:15]([CH3:17])[N:16]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CI
Reactant: Cc1nc2c(OCc3ccccc3Cl)cccn2c1CN(C)C
Solvent: CC(C)=O
Product: Cc1nc2c(OCc3ccccc3Cl)cccn2c1C[N+](C)(C)C
Product: [I-]
Reaction time: 24 h
Yield: 101.7 %

Procedure:
Methyl iodide (3.48 g) was added dropwise to a solution of 8-(2-chlorobenzyloxy)-3-dimethylaminomethyl-2-methylimidazo[1,2-a]pyridine (7.8 g) in acetone (100 ml) at room temperature and the mixture was stirred for 24 hours. The resulting precipitate was collected by filtration, washed with acetone, and dried in a desiccator to give 8-(2-chlorobenzyloxy)-3-trimethylammoniomethyl-2-methylimidazo[1,2-a]pyridine iodide (11.35 g).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[C:12]([F:13])=[CH:11][C:10]([OH:14])=[CH:9][C:8]=1[F:15])([CH3:6])([CH3:5])[CH3:4].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1COCC1>[C:21]([O:20][C:18](=[O:19])[CH2:17][O:14][C:10]1[CH:9]=[C:8]([F:15])[C:7]([C:3]([CH3:6])([CH3:4])[CH3:5])=[C:12]([F:13])[CH:11]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1c(F)cc(O)cc1F
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1cc(F)c(C(C)(C)C)c(F)c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
To a suspension of sodium hydride (75 mg, 1.9 mmol) in THF (5 ml) was added 4-tert-butyl-3,5-difluorophenol (290 mg, 1.6 mmol) at 0° C., followed by stirring for 30 minutes. Then, tert-butyl bromoacetate (370 mg, 1.9 mmol) was added and the mixture was refluxed at 90° C. for 1 hour. The reaction was quenched with saturated ammonium chloride aqueous solution and the product was extracted with EtOAc, washed with brine, dried over magnesium sulfate. Then, filtration, evaporation, and purification through silica gel column chromatography eluting with hexane/EtOAc (20:1 to 4:1) gave the tert-butyl(4-tert-butyl-3,5-difluorophenoxy)acetate (403 mg, 86%). The DCM (2.0 ml) solution of tert-butyl(4-tert-butyl-3,5-difluorophenoxy)acetate (400 mg, 1.34 mmol) and TFA (2.0 ml), was stirred for 1 hour at room temperature. Evaporation gave the residue which was triturated with Hexane to furnish the title compound as a white solid (253 mg, 77%). 1H NMR (300 MHz, CDCl3): δ 1.42 (9H, t, J=2.2 Hz), 4.63 (2H, s), 6.39 (2H, d, J=12.1 Hz). MS (ESI) m/z 243 (M−H)−.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[S:52][CH:53]=4)=[N:28]\[O:29][C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@H:21]3[S:20](=[O:64])[CH2:19][C:18]=2[S:65][CH2:66][S:67][C:68]2[N:72]=[CH:71][NH:70][N:69]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:73][Si]([N-][Si](C)(C)C)(C)C.[Li+].COS(C(F)(F)F)(=O)=O.Cl>O1CCCC1.O>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[S:52][CH:53]=4)=[N:28]\[O:29][C:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C@H:21]3[S:20](=[O:64])[CH2:19][C:18]=2[S:65][CH2:66][S:67][C:68]2[N:72]([CH3:73])[CH:71]=[N:70][N:69]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SCSc4nc[nH]n4)CS(=O)[C@H]23)cs1
Agent: COS(=O)(=O)C(F)(F)F
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cnnc1SCSC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(=O)OC(C)(C)C)n3)[C@H]2S(=O)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 27 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetylamino]-3-(1,2,4-triazol-3-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester 1-oxide (2.71 g: 2.63 mMol.) in tetrahydrofuran (50 ml) at -78° C. is added a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1M: 2.9 ml), and the mixture is stirred at -78° C. for 10 minutes, mixed with trifluoromethanesulfonic acid methyl ester (0.33 ml: 2.92 mMol.), and stirred at -78° C. for 30 minutes. The reaction mixture is mixed with 10% hydrochloric acid (2.1 ml), diluted with water, and extracted with ethyl acetate. The extract is washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (ethyl acetate) to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetylamino]-3-(4-methyl-1,2,4-triazol-3-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester 1 -oxide (0.73 g) as pale brown foam. Yield: 27%. NMR δ(CDCl3 -CD3OD) ppm: 1.51(s, 9H), 3.31(s, 3H), 3.85(s, 2H), 4.12, 4.70(ABq, J=14.6 Hz, 2H), 4.74(d, J=4.8 Hz, 1H), 6.26(d, J=4.8 Hz, 1H), 6.96(s, 1H), 7.01(s, 1H), 7.2-7.5(m, 25H), 8.11(brs, 1H). IR ν(CHCl3) cm-1 : 3400, 1805, 1722, 1690, 1545, 1507, 1497, 1450, 1372, 1040.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]([CH3:43])[C:12](=[O:42])[C:13]([CH3:41])=[C:14]2[C:19]=1[C:18](=[O:20])[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:16](=[O:30])[N:15]2[C:31]1[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=1)[C:34]([O:36]C)=[O:35].O[Li].O.O>C1COCC1.CO>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]([CH3:43])[C:12](=[O:42])[C:13]([CH3:41])=[C:14]2[C:19]=1[C:18](=[O:20])[N:17]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:16](=[O:30])[N:15]2[C:31]1[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=1)[C:34]([OH:36])=[O:35]
Reactant: COC(=O)c1cccc(-n2c(=O)n(Cc3ccc(OC)cc3)c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c32)c1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c3n(-c3cccc(C(=O)O)c3)c2=O)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 63.7 %

Procedure:
A mixture of methyl 3-(5-((2-fluoro-4-iodophenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzoate (0.500 g, 0.718 mmol) and LiOH.H2O (0.120 g, 2.87 mmol) in THF (5.0 ml), MeOH (5.0 ml), and Water (5.0 ml) was stirred at room temperature for 17 h. The solvents were evaporated in vacuo and the residue was acidified with 1 N HCl until solid was precipitated. The product was collected by filtration and triturated in pentane, drying of this solid under vacuum afforded titled compound (3d), (0.312 g, 63.7%); which was carried forward for the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14](/[CH:17]=[CH:18]/[CH2:19][CH2:20][CH2:21][C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:28][OH:29].C1[CH2:34][O:33]CC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH:18]([N:28]([OH:29])[CH:34]=[O:33])[CH2:19][CH2:20][CH2:21][C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(/C=C/CCCc1ncccn1)N1CCN(c2ccc(Br)cc2)CC1
Reactant: NO
Reactant: C1CCOC1
Product: O=CN(O)C(CCCc1ncccn1)CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1
Reaction time: 8 h

Procedure:
To a stirred solution of the 2-((E)-5-[4-(4-bromophenyl)piperazino]sulfonylpent-4-enyl)pyrimidine (451 mg, 1.0 mmol) in THF (10 ml) was added Hydroxylamine (50% solution in water, 500 μl) and the mixture stirred overnight. The solvents were removed in vacuo, azeotroping with toluene (3×) to give the N-[1-([4-(4-bromophenyl)piperazino]sulfonylmethyl)-4-pyrimidin-2-ylbutyl]hydroxylamine (497 mg, quantitative)
Reaction SMILES: [F:1][CH:2]([F:20])[C:3]1[CH:4]=[C:5]([C:9]2[C:10](=[O:19])[C:11]([C:16](O)=[O:17])=[CH:12][NH:13][C:14]=2[CH3:15])[CH:6]=[CH:7][CH:8]=1.[CH3:21][N:22](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.CN>CN(C=O)C>[CH3:21][NH:22][C:16]([C:11]1[C:10](=[O:19])[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH:2]([F:20])[F:1])[CH:4]=2)=[C:14]([CH3:15])[NH:13][CH:12]=1)=[O:17]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1[nH]cc(C(=O)O)c(=O)c1-c1cccc(C(F)F)c1
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c[nH]c(C)c(-c2cccc(C(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-(3-difluoromethyl-phenyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 16a, 931 mg, 3.33 mmol), TBTU (1.17 g, 3.64 mmol), triethylamine (0.94 mL, 6.70 mmol) in DMF (3 mL) is stirred for 30 min. Then, methylamine (5.23 mL of 2M solution in THF, 10.5 mmol) is added and the reaction mixture is stirred for 18 h at room temperature. The reaction mixture is concentrated under reduced pressure and purified by preparative reversed-phase HPLC (XBridge, gradient of acetonitrile in water, 0.3% NH4OH, 60° C.). Yield: 0.25 g (25% of theory); ESI mass spectrum: [M+H]+=293; Retention time HPLC: 0.59 min (Z011_S03).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].Cl[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][N:38]=1.C(N(CC)CC)C>CC(O)C.C(=O)([O-])O.[Na+]>[CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:31][CH2:32][N:33]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][N:38]=2)[CH2:34][CH2:35]1)=[O:28]
Reactant: Clc1ccncn1
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COc1c(C(=O)NC2CCN(c3ccncn3)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Yield: 41.9 %

Procedure:
A solution of the compound of Example 77 (200 mg, 0.42 mmol), 4-chloropyrimidine (58 mg, 0.51 mmol) and triethylamine (0.12 mL, 0.85 mmol) in 2-propanol (4.0 mL) was heated under reflux for 23 hr. The reaction mixture was diluted with saturated sodium hydrogen carbonate solution, and extracted twice with a mixed solvent of ethyl acetate-methanol. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate/methanol=0/100-5/95) and recrystallized from THF to give the title compound (97 mg, 42%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[C:19]([F:21])([F:20])[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.[CH3:29][N:30]([C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH:38]=1)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][N:30]([CH3:29])[C:37]1[CH:42]=[CH:41][C:40]([C:2]2[N:11]=[C:10]([NH:12][CH2:13][CH:14]3[C:19]([F:20])([F:21])[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:15]3)[C:9]3[C:4](=[N:5][CH:6]=[CH:7][N:8]=3)[CH:3]=2)=[CH:39][CH:38]=1)[CH3:36]
Reactant: CCOC(=O)CN(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(F)C(CNc2nc(Cl)cc3nccnc23)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CN(C)c1ccc(-c2cc3nccnc3c(NCC3CN(C(=O)OC(C)(C)C)CCC3(F)F)n2)cc1
Yield: 155.6 %

Procedure:
A solution of tert-butyl 3-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)-4,4-difluoropiperidine-1-carboxylate (173 mg, 0.42 mmol), ethyl 2-(methyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)acetate (200 mg, 0.63 mmol), Pd(PPh3)4 and Cs2CO3 in 4 mL of dioxane and 0.5 mL of water was stirred at 160° C. for 1 hour. The volatiles were removed in vacuo, and the residue was purified by chromatography with MeOH/H2O (1:8˜5:1) to give 373 mg of title compound.
Reaction SMILES: [CH2:1]([C:3]1[NH:8][C:7](=[O:9])[C:6]([SH:10])=[C:5]([NH:11][CH3:12])[N:4]=1)[CH3:2].Cl[CH2:14][C:15]([OH:17])=O.O.[OH-].[Na+].Cl>>[CH2:1]([C:3]1[NH:8][C:7](=[O:9])[C:6]2[S:10][CH2:14][C:15](=[O:17])[N:11]([CH3:12])[C:5]=2[N:4]=1)[CH3:2]
Reactant: O=C(O)CCl
Reactant: CCc1nc(NC)c(S)c(=O)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1nc2c(c(=O)[nH]1)SCC(=O)N2C
Yield: 77.2 %

Procedure:
2-Ethyl-5-mercapto-6-methylamino-3H-pyrimidin4-one (6.6g, 0.036 mole) from Example 112 and 3.37g (0.036 mole) of chloroacetic acid were added to approximately 120ml of water containing 4.27g (0.107 mole) of sodium hydroxide. The resultant solution was refluxed for approximately 4 hours, allowed to cool and acidified to about pH 2 with concentrated hydrochloric acid. The white solid was separated by filtration and dried (7.4g), then refluxed in approximately 100ml of acetic anhydride for about 2 hours and allowed to cool. The precipitate was removed by suction filtration, washed with diethyl ether and dried, providing 6.26g (78%) of 6,7 dihydro-2-ethyl-8-methyl-3H-pyrimido[5,4-b][1,4]thiazine-4,7-dione. The structural assignment was confirmed by infrared spectral analysis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[SH:9].Cl[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](Cl)[NH:12]1.[C:18](=O)([O-])[O-:19].[K+].[K+]>CC(C)=O>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][C:16]2[N:11]=[N:12][C:13]([O:19][CH3:18])=[CH:14][CH:15]=2)=[C:2]([F:1])[CH:7]=1
Reactant: Fc1cc(Br)ccc1S
Reactant: O=C([O-])[O-]
Reactant: ClC1=CC=CN(Cl)N1
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(Sc2ccc(Br)cc2F)nn1

Procedure:
A mixture of 2-fluoro-4-bromothiophenol (300 mg), 2,6-dichloro-pyridazine (149 mg), potassium carbonate (400 mg) and acetone (6 mL) was prepared and refluxed for two hours. The acetone from the mixture was evaporated and the resulting residue was dissolved in a solution of methanol (3 mL) and sodium metal (166 mg). The resulting solution was refluxed for 1 hour. Evaporation of methanol afforded 3-(4-bromo-2-fluoro-phenylsulfanyl)-6-methoxy-pyridazine, which was not isolated but was immediately used in Step 2.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S-:10][C:11]#[N:12].[NH4+].[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)[CH2:17][CH2:16]1.O>CC(C)=O>[NH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([CH2:21][N:18]2[CH2:19][CH2:20][CH:15]([NH:14][C:11]([NH:12][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[S:10])[CH2:16][CH2:17]2)=[CH:23]1
Reactant: N#C[S-]
Reactant: O=C(Cl)c1ccccc1
Reactant: NC1CCN(Cc2c[nH]c3ccccc23)CC1
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(NC(=S)NC1CCN(Cc2c[nH]c3ccccc23)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzoyl chloride (0.49 g, 3.5 mmol) was added to a solution of ammonium thiocyanate (0.29 g, 3.82 mmol) in dry acetone (4 cm3). The reaction mixture was heated under reflux for 10 minutes, then 4-amino-1-(indol-3-ylmethyl)piperidine (0.78 g, 3.41 mmol) was added. The suspension was stirred at room temperature for 1 hour then heated under reflux for 15 minutes and poured into water (20 cm3), precipitating an oil. The supernatant aqueous phase was decanted and the oil triturated with propan-2-ol under reflux to give the title compound as the hydrocyanate salt (0.18 g, 11.7%), m.p. 183°-185° C.
Reaction SMILES: [NH2:1][CH:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].Cl.[CH2:9](N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[O:26])=[CH:20][CH:19]=1>ClCCl>[CH3:9][O:6][C:5](=[O:7])[CH:2]([NH:1][C:25](=[O:26])[CH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)[CH2:3][OH:4]
Reactant: NC(CO)C(=O)O
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C(CO)NC(=O)Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
to a suspension of DL-Serine.HCl (2.0 g, 12.8 mmol) in dichloromethane (10 mL) at 0° C. were added dropwise triethylamine (3.58 mL, 25.7 mmol) and (4-methoxyphenyl)-acetyl chloride (1.96 mL, 12.8 mmol). The mixture was stirred at 25° C. for 12 hours. The reaction mixture was washed with a saturated aqueous sodium chloride solution, separated, and evaporated to dryness and purified by column chromatography (hexanes:ethyl acetate from 25 to 100%). 3-Hydroxy-2-[2-(4-methoxy-phenyl)-acetylamino]-propionic acid methyl ester was isolated as a white solid (2 g, 58%). ESI-MS m/z calc. 267.3, found 268.2 (M+1)+. Retention time of 1.83 minutes. 1H NMR (400 MHz, CDCl3) δ 3.64 (s, 2H), 3.78 (s, 3H), 3.83 (s, 3H), 3.93 (qd, J=14.6 and 4.0 Hz, 2H), 4.66 (m, 1H), 6.40 (m, 1H) 7.01 (d, J=8.7 Hz, 2H), 7.23 (d, J=8.7 Hz, 2H).
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH2:51]([O:55][C:56]([N:58]1[CH2:63][CH2:62][N:61]([C:64](=[O:88])[C@@H:65]([NH2:87])[CH2:66][CH2:67][CH2:68][O:69][Si:70]([C:83]([CH3:86])([CH3:85])[CH3:84])([C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[CH2:60][CH2:59]1)=[O:57])[CH2:52][CH2:53][CH3:54]>CN(C=O)C.C(Cl)CCl>[CH2:51]([O:55][C:56]([N:58]1[CH2:59][CH2:60][N:61]([C:64](=[O:88])[C@@H:65]([NH:87][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:30])[N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:19]=2)=[O:28])[CH2:66][CH2:67][CH2:68][O:69][Si:70]([C:83]([CH3:86])([CH3:85])[CH3:84])([C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[CH2:62][CH2:63]1)=[O:57])[CH2:52][CH2:53][CH3:54]
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 195 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 10 ml DMF were added 108 mg HOBt, 135 mg EDC and 0.2 ml DIPEA. After 20 minutes 255 mg 4-[(S)-2-Amino-5-(tert-butyl-diphenyl-silanyloxy)-pentanoyl]-piperazine-1-carboxylic acid butyl ester hydrochloride were added and the mixture stirred for 12 h. The reaction mixture was concentrated, diluted with ethyl acetate and washed with aqueous LiCl (4%), 0.1 M HCl and saturated aqueous NaHCO3. The crude product thus obtained was pure enough for the following transformation. Yield: 400 mg.