Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(O[CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:27][O:26][CH2:25][CH2:24][CH2:23][CH2:22][N:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][CH:9]=[C:10]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1ccc(-c2ccccc2)[nH]1
Reactant: COCCCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccccc2)n1CCCCOC
Temperature: 60 °C
Reaction time: 12 h
Yield: 76.8 %

Procedure:
Ethyl 5-phenyl-1H-pyrrole-2-carboxylate (400 mg) and 4-methoxybutyl methanesulfonate (440 mg) were dissolved in DMF (10 ml), cesium carbonate (780 mg) was added and the mixture was stirred at 60° C. for 12 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9-1:4) was concentrated under reduced pressure to give the object product (430 mg).
Reaction SMILES: [CH3:1][C:2]([C@@H:18]1[C:24](=[O:25])[N:23]2[C@@H:19]1[CH2:20][C:21]([S:39][C:40]1[CH:41]=[CH:42][C:43]3[N:44]([N:46]=[N:47][N:48]=3)[N:45]=1)=[C:22]2[C:26]([O:28]CC1C=CC([N+]([O-])=O)=CC=1)=[O:27])([O:4]C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)[CH3:3].P([O-])([O-])(O)=O.[K+:54].[K+]>O1CCCC1.C(O)C.[H][H].O.[Pt](=O)=O>[OH:4][C:2]([C@@H:18]1[C:24](=[O:25])[N:23]2[C@@H:19]1[CH2:20][C:21]([S:39][C:40]1[CH:41]=[CH:42][C:43]3[N:44]([N:46]=[N:47][N:48]=3)[N:45]=1)=[C:22]2[C:26]([O-:28])=[O:27])([CH3:3])[CH3:1].[K+:54]
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Sc3ccc4nnnn4n3)C[C@H]12
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)[C@@H]1C(=O)N2C(C(=O)[O-])=C(Sc3ccc4nnnn4n3)C[C@H]12

Procedure:
A mixture of 4-nitrobenzyl (5R, 6R)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-3-(tetrazolo[1,5-b]pyridazin-6-ylthio)-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylate (0.4357 g), platinum (IV) oxide monohydrate (0.2179 g) in 0.047M aqueous dipotassium hydrogen phosphate (41.1 ml), tetrahydrofuran (52.3 ml) and ethanol (4.40 ml) was stirred for 3.7 hours in hydrogen gas under atmospheric pressure at ambient temperature. After the catalyst was filtered off, the filtrate was concentrated to half of the original volume. The aqueous concentrate was washed with diethyl ether (x3) and evaporated in vacuo. The residue was chromatographed on nonionic adsorption resin "Diaion CHP-20P" (Trademark, manufactured by Mitsubishi Chemical Industries) (220 ml) eluting with water (1.50 l), 5% aqueous isopropyl alcohol (400 ml) and 10% aqueous isopropyl alcohol (400 ml). The fractions, whose IV spectra showed λ max 233.0 nm and 282.5 nm, were combined and lyophilized to give crude product (0.1459 g), which was chromatographed again on "Diaion CHP-20P" (130 ml) eluting with water (340 ml), 5% aqueous isopropyl alcohol (360 ml) and 10 aqueous isopropyl alcohol (200 ml). The fractions containing the desired compound were collected and lyophilized to give potassium (5R, 6R)-6-(1-hydroxy-1-methylethyl)-3-(tetrazolo[1,5-b]pyridazin-6-ylthio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.1299 g) as a yellow powder.
Reaction SMILES: [Li]CCCC.I[C:7]1[C:8]([CH3:13])=[N:9][O:10][C:11]=1[CH3:12].[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>C1COCC1>[CH3:13][C:8]1[C:7]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH3:17])=[C:11]([CH3:12])[O:10][N:9]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1noc(C)c1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1c(C)noc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39.2 %

Procedure:
n-BuLi (1.6 M solution in hexanes, 6 mL, 9.6 mmol) was added to a cooled (−78° C.) solution of 4-iodo-3,5-dimethylisoxazole (1.47 g, 6.60 mmol) in THF (24 mL) under nitrogen. After 15 min, tributyltin chloride (26 mL, 9.60 mmol) was added and the reaction was stirred over night while warming to room temperature. The reaction was quenched by 1 M HCl, CH2Cl2 was added, the phases separated and the solvent were evaporated. The residue was purified by flash chromatography with heptane: CH2Cl2 (75:25-0:100) to give 3,5-dimethyl-4-(tributylstannyl)isoxazole (1.00 g, 39%).
Reaction SMILES: [N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=5)[C:18]4=[O:28])=[CH:13][C:12]=3[F:29])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:31][CH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH2:31][CH:32]6[CH2:37][CH2:36][O:35][CH2:34][CH2:33]6)[CH:23]=5)[C:18]4=[O:28])=[CH:13][C:12]=3[F:29])[CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=c1c2ccc(O)cc2ccn1-c1ccc(N2CC[C@@H](N3CCCC3)C2)c(F)c1
Reactant: BrCC1CCOCC1
Product: O=c1c2ccc(OCC3CCOCC3)cc2ccn1-c1ccc(N2CC[C@@H](N3CCCC3)C2)c(F)c1

Procedure:
2-((R)-4-[1,3′]Bipyrrolidinyl-1′-yl-3-fluoro-phenyl)-6-hydroxy-2H-isoquinolin-1-one was reacted with 4-Bromomethyl-tetrahydro-pyran by method K. The product with the molecular weight of 491.61 (C29H34FN3O3) was obtained in this way; MS (ESI): 492 (M+H+).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]([C:10]1[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][N:11]=1)[CH2:8]Br)([CH3:4])([CH3:3])[CH3:2].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K].O>CN(C)C=O>[Cl:16][C:15]1[C:10]([C:7](=[N:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:8][N:22]2[C:21](=[O:23])[C:20]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]3[C:18]2=[O:28])=[N:11][CH:12]=[C:13]([Cl:17])[CH:14]=1
Reactant: CC(C)(C)ON=C(CBr)c1ncc(Cl)cc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)ON=C(CN1C(=O)c2ccccc2C1=O)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.9 %

Procedure:
To 140 mg of 2-bromo-1-(3,5-dichloropyridin-2-yl)ethanone-O-(tert-butyl)oxime in 2 ml of N,N-dimethylformamide, 91 mg of potassium phthalimide was added, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was mixed with 10 ml of water and extracted with ethyl acetate (15 ml×1), the resulting organic layer was washed with water (10 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 2:8 to 4:6) as the eluent to obtain 162 mg of the desired product as a colorless resinous substance.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][C@@H:6]1[OH:20])=[O:4].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](OC(=N)C(Cl)(Cl)Cl)([CH3:30])[CH3:29])=[CH:24][CH:23]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1CCCCC1.FC(F)(F)S(O)(=O)=O>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:11])=[O:12])[CH2:7][C@@H:6]1[O:20][C:28]([C:25]1[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=1)([CH3:30])[CH3:29])=[O:4]
Reactant: COC(=O)[C@H]1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@@H]1O
Reactant: CC(C)(OC(=N)C(Cl)(Cl)Cl)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@@H]1OC(C)(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 31.8 %

Procedure:
(1R,2R,4R) and (1S,2S,4S)-4-(2-Chloro-benzenesulfonyl)-2-hydroxy-cyclopentanecarboxylic acid methyl ester (100 mg, 0.314 mmol, example 48, step 5) and 2,2,2-trichloro-acetimidic acid 1-(4-chloro-phenyl)-1-methyl-ethyl ester (270 mg, 0.514 mmol) were dissolved in a mixture of DCM (1 ml) and cyclohexane (2 ml). Then a solution of trifluoromethanesulfonic acid (0.836 μl, 0.00941 mmol) in DCM (0.1 ml) was added and the reaction mixture was stirred at room temperature for 6 h. Then saturated NaHCO3 solution was added and the mixture was extracted 3 times with ether. The combined organic layers were dried (Na2SO4) and evaporated. The remaining light yellow oil was purified by silica gel chromatography (heptane/EtOAc 4:1-3:1) to obtain the title compound (47 mg, 32%) as white solid. MS (EI): 488.1 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:13]([CH3:15])[CH3:14].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[N:11]=[C:10]([N:13]([CH3:15])[CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CNC
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)c1nc(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 94.5 %

Procedure:
A solution of 2,4-dichloro-quinazoline (102 g, 530 mmol) in THF (1.2 L) was cooled to 4° C. and 50% aqueous Me2NH (139 mL, 1.33 mol) was added. The mixture was stirred at ambient temperature for 80 min. The solution was alkalized with saturated aqueous NaHCO3 (pH=9), and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, and concentrated. The residue was suspended in 50% Et2O in hexane (250 mL) and stirred at ambient temperature for 30 min. The solid was collected by filtration, washed with 50% Et2O in hexane, and dried at 80° C. to give (2-chloro-quinazolin-4-yl)-dimethyl-amine (104 g, 94%) as a pale yellow solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH:23]1[C:35]2[CH:34]([CH2:36][O:37][C:38](Cl)=[O:39])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1>CC#N>[C:11]([O:10][C:8]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:38]([O:37][CH2:36][CH:34]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:27]3[C:35]2=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:39])=[CH:20][CH:21]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
Triethylamine (7.36 mL, 52.82 mmol, 1.1 eq) is added at 0° C. to a stirred solution of N—BOC-1,4-phenylene diamine (10.00 g, 48.02 mmol, 1.0 eq) in CH3CN (240 mL), followed by 9-fluorenylmethyloxycarbonyl chloride (14.90 g, 57.62 mmol, 1.2 eq). The resulting mixture is allowed to warm to room temperature. After 4 hours stirring at room temperature, the reaction mixture is filtered to afford 20.60 g of the crude product as a white powder which is used in the next step without any further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[C@@H:10]([OH:14])[C@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[C:20]([F:27])=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH2:23].CCCP(=O)=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[C@@H:10]([OH:14])[C@H:9]1[C:15](=[O:17])[NH:23][CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([Cl:18])[C:20]=1[F:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)[C@@H](O)[C@H]1C(=O)O
Reactant: NCc1cccc(Cl)c1F
Agent: CCCP(=O)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](F)[C@@H](O)[C@H]1C(=O)NCc1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,3S,4S)-4-fluoro-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (195 g, 0.782 mmol) in CH2Cl2 (10 mL) were added 3-chloro-2-fluoro-benzylamine (150 mg, 0.94 mmol), propylphosphonic anhydride (50% in EtOAc, 0.346 mL, 1.17 mmol) and DIPEA (0.41 mL, 2.35 mmol). The reaction mixture was stirred 1 h at RT, then quenched by addition of a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (×2). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1). MS (UPLC): 391.3/393.1 [M+H]+, 435.4/437.4 [M+HCOO]−; tR (HPLC conditions f): 1.95 min.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[N:16][O:17][CH3:18])[C:12]([NH:14][CH3:15])=[O:13].[Br:19][C:20]1[CH:21]=[C:22]([CH3:27])[C:23](F)=[N:24][CH:25]=1.O>C1COCC1>[CH3:18][O:17][N:16]=[C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][O:3][C:23]1[C:22]([CH3:27])=[CH:21][C:20]([Br:19])=[CH:25][N:24]=1)[C:12]([NH:14][CH3:15])=[O:13]
Reactant: Cc1cc(Br)cnc1F
Reactant: CNC(=O)C(=NOC)c1ccccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)C(=NOC)c1ccccc1COc1ncc(Br)cc1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.3 %

Procedure:
Sodium hydride (60%, 0.18 g, 4,5 mmol) was added to a solution of 2-hydroxymethyl-α-methyoxyimino-N-methyl-benzeneacetamide (1.0 g, 4.5 mmol) in dry THF (25 mL) and stirred for 10 minutes at 25° C. under N2 atmosphere. The pyridine product of Example 1 (0.86 g, 4.5 mmol) was added to this reaction mixture and stirred for 16 hours. Water (20 mL) was added and the resulting mixture was extracted with ether (3×50 mL), dried (anhydrous Na2SO4), filtered and concentrated in vacuo to yield crude residue (1.5 g), which was then triturated with ether/pentane to give α-(methoxyimino)-N-methyl-2-[[[5-bromo-3-methyl-2-pyridinyl]oxy]methyl]-benzeneacetamide (1.1 g) as a white solid. M.P. 115-116° C.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].[O-:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Na+].O>C1COCC1>[C:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: [O-]c1ccccc1
Reactant: C=CCCC(=O)Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(=O)Oc1ccccc1
Reaction time: 24 h
Yield: 90 %

Procedure:
4-Pentenoyl chloride (8.16 g, 69.1 mmol) was added dropwise to sodium phenoxide (8.02 g, 69.1 mmol) in THF (160 ml) at 20° C. After 24 hours at 20° C. H2O (100 ml) was added and the aqueous phase was extracted with Et2O (3×200 ml). The organic phase was washed with NaHCO3 (2×200 ml), brine (2×200 ml) to neutrality, then dried (Na2SO4), filtered, concentrated and bulb-to-bulb distilled to afford the desired title ester in 90% yield. B.p.: 70° C./0.04 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH:15]([C:17]([CH3:19])=[O:18])=[CH2:16]>O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:16][CH2:15][CH:17]([OH:18])[CH3:19])[CH2:11][CH2:12]2)=[CH:13][CH:14]=1
Reactant: Clc1ccc(CC2CCNCC2)cc1
Reactant: C=CC(C)=O
Solvent: O
Product: CC(O)CCN1CCC(Cc2ccc(Cl)cc2)CC1
Product: Cl
Temperature: 110 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of 4-(4-chlorobenzyl)piperidine (1.0 g, 4.78 mmol) in methyl vinyl ketone (1.0 ml) was added H2O (1 drop) and the resulting solution stirred at 110° C. for 2 h. The crude mixture was purified by filtration on silica gel using CH2Cl2/MeOH as eluant to afford the title compound (1.20 g, 90%) as a pale yellow oil: 1H NMR (CDCl3) 1.35-1.55 (m, 5H), 1.63 (d, J =12.3, 2H), 2.055 (t, J=9.6, 2H), 2.154 (s, 2H), 2.40 (d, J=6.3, 2H), 2.748 (s, 2H), 2.972 (d, J=11.4, 2H), 7.034 (d, J=8.1, 2H), 7.218 (d, J=8.1, 2H).
Reaction SMILES: ClC1C=[C:4]([CH:41]=[CH:42][C:43]=1F)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.COC(C1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O.[S:83]1C=CC=C1B(O)O>>[CH:26]1([N:25]2[C:24]3[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=3[N:22]=[C:21]2[C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:10]2[CH:9]=[C:8]([O:39][CH3:40])[CH:7]=[CH:6][C:5]=2[C:4]2[S:83][CH:43]=[CH:42][CH:41]=2)[CH:20]=[CH:19]3)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Reactant: OB(O)c1cccs1
Agent: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Product: COc1ccc(-c2cccs2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 27 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 2-thiopheneboronic acid (34 mg, 0.2625 mmol) to produce the title compound (26 mg, 27% yield).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][O:6][C:4](=[O:5])[CH2:3]1.[BrH:8].[C:9](O)(=O)[CH3:10]>>[Br:8][CH2:7][C@H:2]([OH:1])[CH2:3][C:4]([O:6][CH2:9][CH3:10])=[O:5]
Reactant: CC(=O)O
Reactant: Br
Reactant: O=C1C[C@H](O)CO1
Product: CCOC(=O)C[C@@H](O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
To a 50 mL round bottom flask equipped with a magnetic stirring bar and nitrogen (N2) inlet was charged 2.13 g (S)-3-hydroxybutyrolactone (Example 2) (95.7% pure by VPC) and 5.0 mL acetic acid. The flask was cooled using an ice bath and 9.0 mL of 33% hydrogen bromide (HBr) in acetic acid was charged dropwise over several minutes upon which the ice bath was removed and the mixture allowed to warm to room temperature and stirred overnight under N2. An additional 1.0 mL of 33% HBr in acetic acid was added when VPC indicated that the reaction was not complete, and the mixture was stirred overnight at room temperature. The reaction was quenched by pouring into ethyl alcohol (85 mL) and heated at reflux until the reaction was complete (8 hours). The solvent was removed and the residue taken up in ethyl acetate (100 mL), washed with dilute aqueous sodium bicarbonate (NaHCO3) solution (25 mL), water (25 mL), and brine (25 mL). The organic layer was distilled and the residue purified by silica gel chromatography to yield 1.74 g (41.5%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[C:9]1[CH:10]=[C:11]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:12]2[N:13]([C:15]([CH3:18])=[N:16][N:17]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O:28][CH2:29][CH2:30]Br.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH2:1]([N:8]([CH3:26])[C:9]1[CH:10]=[C:11]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:30][CH2:29][O:28][CH3:27])[CH2:22][CH2:21]2)[C:12]2[N:13]([C:15]([CH3:18])=[N:16][N:17]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nnc2c(NC3CCNCC3)cc(N(C)Cc3ccccc3)nn12
Reactant: COCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COCCN1CCC(Nc2cc(N(C)Cc3ccccc3)nn3c(C)nnc23)CC1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
N6-Benzyl-3,N6-dimethyl-N8-piperidin-4-yl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (0.05 g; 0.11 mmol) was slurred up in 0.3 ml DMA. 2-bromoethyl methyl ether (0.01 ml; 0.14 mmol) and DIPEA (0.04 ml; 0.23 mmol) were added and stirred at 50° C. for 16 hours. The crude material was purified by using reversed phase chromatography under basic conditions.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[CH2:9][NH:8][CH2:7][CH2:6]2.Br[CH2:17][C:18](Cl)=[O:19].[CH:21]([N:24](C(C)C)[CH2:25]C)(C)C>>[CH3:21][N:24]([CH3:25])[CH2:17][C:18]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:9]1)=[O:19]
Reactant: COc1cc2c(cc1[N+](=O)[O-])CNCC2
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)CBr
Product: COc1cc2c(cc1[N+](=O)[O-])CN(C(=O)CN(C)C)CC2
Reaction time: 4 h

Procedure:
A suspension of 6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (1.25 g, 6.00 mmol), bromoacetyl chloride (0.75 mL, 9.01 mmol), and polymer supported diisopropylethylamine (4.7 g, 18 mmol) was stirred for 4 hours, filtered, and taken to a residue under reduced pressure. The residue was redissolved in 2.0M methylamine in tetrahydrofuran (15 mL) and stirred overnight. The solution was concentrated under reduced pressure and purified by column chromatography to afford N,N-dimethyl-2-[6-(methyloxy)-7-nitro-3,4-dihydro-2(1H)-isoquinolinyl]-2-oxoethanamine as a mixture of apparent rotameric forms in DMSO (0.90 g, 3.07 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(N(C(C)C)CC)(C)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[NH2:45][C:46]1[S:47][C:48]([C:51]([F:54])([F:53])[F:52])=[N:49][N:50]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:45][C:46]2[S:47][C:48]([C:51]([F:54])([F:53])[F:52])=[N:49][N:50]=2)=[O:43])=[C:18]([F:23])[CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: Nc1nnc(C(F)(F)F)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nnc(C(F)(F)F)s4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (100 mg) was dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-5-trifluoromethyl-1,3,4-thiadiazole (70 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 62 mg of the title compound.
Reaction SMILES: [CH2:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]C1.[SH:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+].C[N:21](C)C=O>>[NH2:21][C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@H:1]1[S:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: C1CCCCCC1
Reactant: O=C(O)CCS
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: N[C@@H]1CCCC[C@H]1SCCC(=O)O
Temperature: 60 °C

Procedure:
(±)-7-(tert-Butoxycarbonyl)-7-aza-bicyclo-[4.1.0]- cycloheptane (0.5 g, 2.68 mmol) was dissolved in 2 mL dimethylformamide and βmercaptopropionic acid (0.318 g, 3 mmol). After the addition of cesium carbonate (1.95 g, 6 mmol), the mixture was stirred at 60° C. until the TLC indicated the full consumption of starting material (appro. 4 hrs). The reaction mixture was diluted with water, the pH was adjusted to 4 (with 2.4 M HCl) and finally extracted with methylene chloride. The solvent layer was washed with brine, dried and evaporated to give the crude (±)-trans-2-(tert-butocycarbonylamino)-1-[2-(carboxy)ethylthio]-cyclohexane, which was not purified but taken to the next stage. The crude from the above was dissolved in 10 ml ethyl acetate saturated with hydrogen chloride and stir at room temperature. The white precipitate that resulted was filtered and dried under vacuo yielding 0.636 g of (±)-trans-2-amino-1-[2-(carboxy)ethylthio]-cyclohexane.