Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35]1([C:45](Cl)=[O:46])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][CH:36]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:45]([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)=[O:46])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Reactant: O=C(Cl)c1cccc2ccccc12
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C#N)cc4c3)C(=O)c3cccc4ccccc34)cc2)CC1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, 1-naphthalenecarbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:13]N1C(=O)CCC1=O.N(/C(C)(C)C#N)=N\C(C)(C)C#N>C(#N)C>[Br:13][CH2:12][C:11]1[C:2]([Cl:1])=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(C)c1Cl
Agent: CC(C)(C#N)/N=N/C(C)(C)C#N
Solvent: CC#N
Product: COC(=O)c1cccc(CBr)c1Cl
Temperature: 90 °C
Reaction time: 26 h
Yield: 66.9 %

Procedure:
To a solution of methyl 2-chloro-3-methylbenzoate (3.60 g, 19.4 mmol) in acetonitrile (60 mL) were added 1-bromopyrrolidine-2,5-dione (11.46 g, 64.3 mmol) and 2,2′-(E)-diazen-1,2-diylbis(2-methylpropanenitrile) (960 mg, 5.84 mmol), and the mixture was stirred at 90° C. for 26 hr. The insoluble material was filtered off from the reaction mixture, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→95/5), and the fractions containing the object product were concentrated under reduced pressure to give the title compound (3.42 g, 66%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]=[C:16]=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[NH2:18]/[C:19](/[CH3:28])=[C:20](/[CH2:26][CH3:27])\[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:19]([CH3:28])=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:26][CH3:27])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: CC(C)OC(=O)c1cc(N=C=O)c(F)cc1Cl
Reactant: CCOC(=O)/C(CC)=C(/C)N
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)=C(C)NC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F

Procedure:
using isopropyl 2-chloro-4-fluoro-5-isocyanatobenzoate and ethyl 3-amino-2-ethylcrotonate in dimethylformamide there is obtained isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-1-methyl-1-butenyl]ureido}-benzoate, m.p. 112°-115° C.,
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:26][CH2:25][C@H:24]4[C:27](O)=[O:28])=[N:21][CH:22]=3)[C:9]=2[F:30])[CH:5]=[CH:6][CH:7]=1.C([N:34](CC)C(C)C)(C)C.C(OC(Cl)=O)C(C)C.N.CO>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:26][CH2:25][C@H:24]4[C:27]([NH2:34])=[O:28])=[N:21][CH:22]=3)[C:9]=2[F:30])[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(Cc2ccc(N3CC[C@H]3C(=O)O)nc2)c(F)c1-c1cccc(Cl)c1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cc2ccc(N3CC[C@H]3C(N)=O)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 2.5 °C
Reaction time: 0.08 h

Procedure:
To a cooled (0-5° C.) and stirred solution of (S)-1-[5-(3′-chloro-2-fluoro-6methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-azetidine-2-carboxylic acid (I-143, 0.22 g, 0.54 mmol) in THF (2.5 mL) was added N,N-diisopropylethylamine (0.07 g, 0.57 mmol). The reaction mixture was stirred for 5 min, isobutylchloroformate (0.08 g, 0.57 mmol) was added, stirred at 0-5° C. for 45 min. Ammonia in methanol (7M sol, 1.0 mL, 7.0 mmol) was added, the reaction warmed to room temperature, and stirred for 0.5 h. The reaction mixture was diluted with water (5 mL). The organic layer was separated, the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using 5% methanol in dichloromethane, followed by preparative thin layer chromatography using 5% methanol in dichloromethane to afford 0.06 g (27%) of P-615 as an off-white solid. 1H NMR (DMSO-d6, 400 MHz): 7.99 (d, J=2.8 Hz, 1H), 7.51 (br s, 1H), 7.34-7.46 (m, 4H), 7.24-7.3 (m, 2H), 7.14 (br s, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.35 (d, J=8.4 Hz, 1H), 4.39 (dd, J=9.6, 6.8 Hz, 1H), 3.7-3.9 (m, 2H), 3.8 (s, 2H), 3.72 (s, 3H), 2.26-2.48 (m, 2H) ppm;
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:7]([C:9]3[CH:10]=[C:11]([CH2:20][OH:21])[CH:12]=[CH:13][C:14]=3[N:15]3[CH:19]=[N:18][CH:17]=[N:16]3)=[N:8][C:4]=2[CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:22]([CH3:24])([CH3:23])[CH3:25])[C:7]([C:9]3[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=3[N:15]3[CH:19]=[N:18][CH:17]=[N:16]3)[CH2:20][O:21][S:29]([CH3:28])(=[O:31])=[O:30])=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)n1c(-c2cc(CO)ccc2-n2cncn2)nc2cc(Br)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)n1c(-c2cc(COS(C)(=O)=O)ccc2-n2cncn2)nc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a round bottom flask is added [3-(5-bromo-1-tert-butyl-1H-benzoimidazol-2-yl)-4-[1,2,4]triazol-1-yl-phenyl]methanol (583 mg, 1.4 mmol) in CH2Cl2 (5 mL), followed by the addition of methansulfonyl chloride (0.15 mL, 1.9 mmol) and triethylamine (0.4 mL, 2.9 mmol). The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is quenched with saturated NaHCO3 (10 mL), extracted with EtOAc (3×10 mL). The organic layer is separated, washed with brine, dried under anhydrous Na2SO4 (500 mg), filtered and concentrated to afford methanesulfonic acid 3-(5-bromo-1-tert-butyl-1H-benzoimidazol-2-yl)-4-[1,2,4]-triazol-1-yl-benzyl ester (690 mg, 100%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].N1CCCC1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: C1COCCN1
Solvent: C1CCNC1
Product: O=C(CN1CCOCC1)c1ccc(Br)cc1

Procedure:
The title compound was prepared according to the procedure described in example 113, replacing 2-bromo-1-(3-bromophenyl)ethanone with 2-bromo-1-(4-bromophenyl)ethanone and pyrrolidine with morpholine. MS (ES) m/e 284 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[C:8](=[O:20])[CH:7]=1.[I:26]N1C(=O)CCC1=O.ClC(Cl)C(O)=O>CC#N>[F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[C:8](=[O:20])[C:7]=1[I:26]
Reactant: O=C1CCC(=O)N1I
Reactant: O=c1cc(OCc2ccc(F)cc2F)ccn1Cc1cccc(F)c1
Agent: O=C(O)C(Cl)Cl
Solvent: CC#N
Product: O=c1c(I)c(OCc2ccc(F)cc2F)ccn1Cc1cccc(F)c1
Temperature: 60 °C
Yield: 74 %

Procedure:
To a mixture of 4-(2,4-difluorobenzyloxy)-1-(3-fluorobenzyl)-1H-pyridin-2-one (0.15 g, 0.43 mmol) and N-iodosuccinimide (0.10 g, 0.46 mmol) in CH3CN (3 mL) was added dichloroacetic acid (13 mg, 0.10 mmol), and the reaction mixture was heated to 60° C. for 4 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in methylene chloride. The organic solution was washed with a saturated solution of NaHCO3 and then brine, dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent 90:10 methylene chloride/hexanes to 99:1 methylene chloride/methanol) provided 4-(2,4-difluorobenzyloxy)-1-(3-fluorobenzyl)-3-iodo-1H-pyridin-2-one as a white solid (0.15 g, 77%): mp 164-167° C.; 1H NMR (300 MHz, CDCl3) δ 7.65-7.55 (m, 1H), 7.35-7.26 (m, 2H) 7.15-6.80 (m, 5H), 6.05 (d, J=6 Hz, 1H), 5.22 (s, 2H), 5.16 (s, 2H). ESHRMS m/z 472.0033 (M+H C19H14F31NO2 requires 472.0018).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]2[CH:11]=[C:10](B3OC(C)(C)C(C)(C)O3)[CH:9]=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:28]1[CH:29]=[C:30]([NH:35][S:36]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)(=[O:38])=[O:37])[C:31]([Cl:34])=[N:32][CH:33]=1.C1COCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:34][C:31]1[C:30]([NH:35][S:36]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)(=[O:38])=[O:37])=[CH:29][C:28]([C:10]2[CH:9]=[CH:8][C:6]3[N:7]=[C:3]([NH:2][CH3:1])[S:4][C:5]=3[CH:11]=2)=[CH:33][N:32]=1
Reactant: CNc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: O=S(=O)(Nc1cc(Br)cnc1Cl)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CNc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4ccc(F)cc4)c3)cc2s1
Reaction time: 0.17 h
Yield: 21.3 %

Procedure:
To a microwave vial equipped with a stirbar and charged with N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine (0.22 g, 0.75 mmol), cesium carbonate (0.67 g, 2.1 mmol), PdCl2(dppf)*DCM (0.10 g, 0.12 mmol), N-(5-bromo-2-chloropyridin-3-yl)-4-fluorobenzenesulfonamide (0.250 g, 0.68 mmol) was added THF (3 ml). Then water (0.5 ml) was added into the mixture. The vial was capped and then placed into a CEM Microwave for 10 minutes at 100° C., while 100 watts of energy was supplied via Powermax® (Simultaneous heating while cooling technology). The progress of the reaction was monitored by LC/MS, which showed desired material in the mixture. The organic layer was extracted from the microwave vial by pipet and then diluted the organic with acetonitrile (15 ml) and TFA (0.1 ml). The crude was purified by reverse-phase HPLC. This gave N-(2-chloro-5-(2-(methylamino)benzo[d]thiazol-6-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (0.065 g, 21% yield) as a yellow crystalline solid. MS (ESI pos. ion) m/z: 449 (MH+). Calc'd exact mass for C19H14ClFN4O2S2: 448. 1H NMR (400 MHz, DMSO-d6): 2.97 (d, J=3.51 Hz, 3H), 7.42 (t, J=8.78 Hz, 2H), 7.46-7.53 (m, 2H), 7.81 (dd, J=8.53, 5.02 Hz, 2H), 7.94 (s, 1H), 8.03 (s, 1H), 8.13 (d, J=4.02 Hz, 1H), 8.54 (s, 1H), 10.45 (s, 1H).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH3:12][NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19].[C:20]([O:24][C:25]([N:27]1[CH2:31][C@@H:30]([O:32][C:33]2[C:42]3[C:37](=[C:38]([Cl:45])[C:39]([O:43][CH3:44])=[CH:40][CH:41]=3)[N:36]=[C:35]([N:46]3[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[N:47]3)[CH:34]=2)[CH2:29][C@H:28]1[C:55](O)=[O:56])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(C)C([C@@H]1C[C@@H](O)CN1C(OC(C)(C)C)=O)=O)CCCC=C>>[Cl:45][C:38]1[C:39]([O:43][CH3:44])=[CH:40][CH:41]=[C:42]2[C:37]=1[N:36]=[C:35]([N:46]1[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[N:47]1)[CH:34]=[C:33]2[O:32][C@@H:30]1[CH2:31][N:27]([C:25]([O:24][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:26])[C@H:28]([C:55](=[O:56])[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[CH3:12])[CH2:29]1
Reactant: C=CCCCCNC
Reactant: COc1ccc2c(O[C@H]3C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C3)cc(-n3ccc(C(F)(F)F)n3)nc2c1Cl
Agent: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@H](Oc2cc(-n3ccc(C(F)(F)F)n3)nc3c(Cl)c(OC)ccc23)CN1C(=O)OC(C)(C)C
Yield: 87 %

Procedure:
Compound 114 was synthesized from compounds 32a and 113 as white foam in 87% yield, following the procedure as described for compound 48.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[C:18](Cl)=[N:17][C:16]([N:20]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH3:21])=[CH:15][N:14]=1)[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O>CN(C=O)C>[CH2:1]([N:8]1[CH2:12][C:13]2[N:14]=[CH:15][C:16]([N:20]([CH2:22][CH:23]3[CH2:25][CH2:24]3)[CH3:21])=[N:17][C:18]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CC1CC1)c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CC1CC1)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reaction time: 2.5 h
Yield: 80.1 %

Procedure:
To a solution of 2-[benzyl({3-chloro-5-[(cyclopropylmethyl)(methyl)amino]pyrazin-2-yl}methyl)amino]ethanol (0.50 g) in DMF (3 mL) was added potassium tert-butoxide (0.19 g) at 0° C., and the mixture was stirred for 2.5 hr. Water (10 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 10→40% ethyl acetate/hexane) to give the title compound (0.36 g, 79%) as a pale-yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:16]([NH2:20])(=[O:19])[CH:17]=[CH2:18].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:18][CH2:17][C:16]([NH2:20])=[O:19])[CH2:12][CH2:11]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: C=CC(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccccc1N1CCN(CCC(N)=O)CC1
Temperature: 80 °C
Yield: 89501 %

Procedure:
A mixture of 1-(2-methoxyphenyl)piperazine hydrochloride (22 g, 96.2 mmol), acrylamide (7.5 g, 106 mmol) and potassium carbonate (20 mL, 5M, 100 mmol) in 110 mL of water was heated at 80° C. for 2 hours to give a suspension. The suspension was allowed to cool to room temperature and filtered. The filtered residue was washed with water (3×30 mL) and dried under reduced pressure at 85° C. for 16 hours to give 3-[4-(2-methoxyphenyl)-piperazin-1-yl]propionamide (22.67 g, 86.1 mol), m.p. 145°-146° C.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][CH:9]([F:38])[CH2:10][NH:11][C:12]1[N:13]=[C:14]2[CH2:36][CH:35]([CH3:37])[NH:34][CH2:33][C:15]2=[N:16][C:17]=1[N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH2:20][CH2:19]1.C(OC(=O)C)(=O)C.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[F:38][CH:9]([F:8])[CH2:10][NH:11][C:12]1[N:13]=[C:14]2[CH2:36][CH:35]([CH3:37])[N:34]([C:2](=[O:1])[CH3:4])[CH2:33][C:15]2=[N:16][C:17]=1[N:18]1[CH2:19][CH2:20][CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH2:22][CH2:23]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC1Cc2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2CN1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1Cc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NCC(F)F)nc2CC1C

Procedure:
A solution of N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (15 mg, 0.027 mmol), acetic anhydride (5.1 μL, 0.054 mmol), and DIPEA (14.2 μL, 0.081 mmol) in DCM (136 nL) was stirred at room temperature overnight. The crude reaction mixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 nm filter (Millipore® Millex-LCR), and purified via HPLC Method A to give the title compound as a TFA salt (8 mg) as a clear oil. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.13 (d, J=6.8 Hz, 1.4H), 1.23 (d, J=6.8 Hz, 1.6H), 1.92-2.03 (m, 2H), 2.09-2.17 (m, 2H), 2.18 (s, 1.4H), 2.22 (s, 1.6H), 2.54-2.67 (m, 1H), 2.95-3.04 (m, 2.4H), 3.13 (dd, J=16.7, 6.3 Hz, 0.6H), 3.34-3.44 (m, 2H), 3.74-3.83 (m, 2.4H), 3.99 (d, J=18.2 Hz, 0.6H), 4.40-4.49 (m, 1H), 4.55 (quin, J=6.6 Hz, 0.5H), 4.66 (d, J=16.7 Hz, 0.5H), 5.07 (d, J=17.7 Hz, 0.5H), 5.18 (m, 0.5H), 5.90-6.22 (m, 1H), 6.84-6.91 (m, 1H), 6.98 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.18 (td, J=9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 481.9.
Reaction SMILES: C[N:2](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][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[N:34]=[C:35]([NH:38]N)[S:36][CH:37]=1>>[CH3:23][S:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:38]([C:35]4[S:36][CH:37]=[C:33]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[O:26][CH3:25])[N:34]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)(=[O:22])=[O:21]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: COc1ccccc1-c1csc(NN)n1
Product: COc1ccccc1-c1csc(-n2nccc2-c2nn(-c3cccc(S(C)(=O)=O)c3)ccc2=O)n1
Yield: 21 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and [4-(2-methoxy-phenyl)-thiazol-2-yl]-hydrazine according to the method described for Example 91 in 21% yield. MS: M=506.2.13 (M+H)+
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Br:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: OB(O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=[N+]([O-])c1cnccc1-c1ccc(Br)cc1
Temperature: 100 °C
Yield: 76.1 %

Procedure:
4-Chloro-3-nitro-pyridine (6.9 g, 43.5 mmol), 4-bromophenyl boronic acid (8.05 g, 40.1 mmol), potassium carbonate (11.10 g, 80.3 mmol) and tetrakis triphenylphosphine palladium (2.31 g, 2.0 mmol) are taken up in DME (200 ml) and heated under reflux (100° C.) overnight. The mixture is cooled down to room temperature and filtered through Celite® pad, which is washed with EtOAc. The filtrate is concentrated to give a crude brown oil. Purification by flash chromatography (Silica gel-hexane/EtOAc) yields 4-(4-Bromo-phenyl)-3-nitro-pyridine (8.52 g) as a yellow oil (76% yield).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]3[N:21](CC4C=CC(OC)=CC=4OC)[C:22](=[O:33])[N:23]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]#[N:32])[C:15]=23)[CH2:9]1)(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]3[NH:21][C:22](=[O:33])[N:23]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]#[N:32])[C:15]=23)[CH2:9]1
Reactant: COc1ccc(Cn2c(=O)n(Cc3ccccc3C#N)c3c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)cc(C)nc32)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1cc(N2CCC[C@@H](N)C2)c2c(n1)[nH]c(=O)n2Cc1ccccc1C#N
Yield: 54.6 %

Procedure:
1.24 g (R)-1-[1-(2-cyanobenzyl)-3-(2,4-dimethoxybenzyl)-5-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]piperidine-3-carbamic acid tert-butyl ester (2.02 mmol) was dissolved in 8 mL anisole, to which 1.5 mL trifluoroacetic acid was added, and reacted for 24 h at 90° C. The reaction solution was evaporated to dryness. The residue was dissolved in a small amount of water, and washed with ethyl acetate. The aqueous phase was adjusted to basic with saturated sodium carbonate solution, and extracted with dichloromethane for five times. The dichloromethane phase was combined, dried and evaporated to dryness to afford 0.4 g titled product with a yield of 54.5%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:35]=[C:34]([CH2:36][OH:37])[O:33][N:32]=2)=[CH:27][CH:26]=1)([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:13][N:12]=1)[CH:8]([CH3:10])[CH3:9].CCN(C(C)C)C(C)C.O>C(Cl)Cl>[CH3:1][S:2]([O:37][CH2:36][C:34]1[O:33][N:32]=[C:31]([C:28]2[CH:29]=[CH:30][C:25]([C:7]([CH3:6])([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:13][N:12]=3)[CH:8]([CH3:10])[CH3:9])=[CH:26][CH:27]=2)[N:35]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)C(C)(c1ccc(-c2noc(CO)n2)cc1)c1ccc(OCc2ccccn2)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)C(C)(c1ccc(-c2noc(COS(C)(=O)=O)n2)cc1)c1ccc(OCc2ccccn2)cn1
Reaction time: 1.5 h

Procedure:
Methanesulfonyl chloride (27.0 μL, 0.348 mmol) was added to a stirred solution of 3d (100 mg, 0.232 mmol) and DIPEA (101 μL, 0.580 mmol) in DCM (2.00 mL) at 0° C. After approximately 1.5 h, the reaction mixture was poured into water and extracted three times with EtOAc. The combined organic extracts were washed with water, brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound 3e, which was used without further purification in the subsequent reaction.
Reaction SMILES: O.C(=O)([O-])[O-].[K+].[K+].[NH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[C:29](=[O:30])[C:28]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)=[CH:27][N:26]([CH2:38][C:39]([F:42])([F:41])[F:40])[CH:25]=3)=[O:23])=[CH:17][CH:16]=2)=[CH:13][C:12](Br)=[CH:11][N:10]=1.[CH3:44][O:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1B(O)O>COCCOC.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[NH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[C:29](=[O:30])[C:28]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)=[CH:27][N:26]([CH2:38][C:39]([F:42])([F:41])[F:40])[CH:25]=3)=[O:23])=[CH:17][CH:16]=2)=[CH:13][C:12]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=2[O:45][CH3:44])=[CH:11][N:10]=1
Reactant: Nc1ncc(Br)cc1-c1ccc(NC(=O)c2cn(CC(F)(F)F)cc(-c3ccc(F)cc3)c2=O)cc1
Reactant: COc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: COc1ccccc1-c1cnc(N)c(-c2ccc(NC(=O)c3cn(CC(F)(F)F)cc(-c4ccc(F)cc4)c3=O)cc2)c1
Temperature: 80 °C
Reaction time: 20 h
Yield: 34.1 %

Procedure:
Water (0.1 ml), potassium carbonate (70 mg) and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane adduct (6.9 mg) were added to a solution of the compound obtained in Step 1 of Example 31 (95 mg) and 2-methoxyphenylboronic acid (31 mg) in 1,2-dimethoxyethane (1.5 ml), and the mixture was stirred at 80° C. for 20 hours. After leaving to cool, the reaction solution was diluted with ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [hexane:ethyl acetate=3:1->1:3 (v/v)] to give 34 mg of the title compound as a solid.
Reaction SMILES: [C:1]([N:5]([CH2:11][CH3:12])[C:6](=[O:10])[O:7][CH2:8]Cl)([CH3:4])([CH3:3])[CH3:2].[OH:13][C@@H:14]([C@H:16]1[C:36](=[O:37])[N:18]2[C:19]([C:33]([O-:35])=[O:34])=[C:20]([S:23]/[CH:24]=[CH:25]\[C:26]3[S:30][CH:29]=[N:28][C:27]=3[CH2:31][OH:32])[C@H:21]([CH3:22])[C@H:17]12)[CH3:15].[Na+]>>[OH:13][C@@H:14]([C@H:16]1[C:36](=[O:37])[N:18]2[C:19]([C:33]([O:35][CH2:8][O:7][C:6]([N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:11][CH3:12])=[O:10])=[O:34])=[C:20]([S:23]/[CH:24]=[CH:25]\[C:26]3[S:30][CH:29]=[N:28][C:27]=3[CH2:31][OH:32])[C@H:21]([CH3:22])[C@H:17]12)[CH3:15]
Reactant: CCN(C(=O)OCCl)C(C)(C)C
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CCN(C(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12)C(C)(C)C
Yield: 68.2 %

Procedure:
In the same manner as in step b) in Example 125, 273 mg of the title compound was prepared from 180 mg of chloromethyl N-t-butyl-N-ethylcarbamate and 300 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate.