Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:8])[N:5]([CH3:7])[CH:6]=1.[CH2:9]([N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:15]2=[N:14]1)[CH2:10][C:11]#[CH:12]>>[Cl:22][C:21]1[C:15]2[C:16](=[N:17][N:13]([CH2:9][CH2:10][C:11]#[C:12][C:2]3[N:3]=[C:4]([CH3:8])[N:5]([CH3:7])[CH:6]=3)[N:14]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: C#CCCn1nc2cccc(Cl)c2n1
Reactant: Cc1nc(Br)cn1C
Product: Cc1nc(C#CCCn2nc3cccc(Cl)c3n2)cn1C
Yield: 5.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 108(C), from 4-bromo-1,2-dimethyl-1H-imidazole (85 mg, 0.49 mmol) and 2-but-3-ynyl-4-chloro-2H-benzo[d][1,2,3]triazole (100 mg, 0.49 mmol, Example 146(B)). Microwave conditions: 100° C. for 15 min The crude residue was purified by C18 flash chromatography to yield 8.0 mg (27 μmol, 5%) of 4-chloro-2-(4-(1,2-dimethyl-1H-imidazol-4-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a brown semi-solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:12])[CH2:11][C:5]=2[CH:4]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([OH:12])[CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CC(=O)CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)CC(O)CCC2
Reaction time: 0.67 h

Procedure:
To a solution of 3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (220 g) in methanol (1300 ml) was added portionwise sodium borohydride (22.0 g) at 6° C.-30° C., and then the reaction mixture was stirred for 40 minutes and evaporated in vacuo. The residue was partitioned between ethyl acetate (1 l) and water (1 l). The organic layer was washed with 1N hydrochloric acid (500 ml), aqueous sodium hydrogen carbonate (500 ml), and brine (200 ml), and dried over magnesium sulfate. The solvent was evaporated in vacuo to give 3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ol as a white powder.
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[CH2:9]([N:11]1[CH2:15][CH:14]([N:16]2C(=O)[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])[CH2:13][N:12]1[CH2:27][CH3:28])[CH3:10].Cl.[F:30]C1C=CC(C(Cl)=O)=CC=1>>[F:30][C:23]1[CH:22]=[CH:19][C:18]([C:17]([NH:16][CH:14]2[CH2:15][N:11]([CH2:9][CH3:10])[N:12]([CH2:27][CH3:28])[CH2:13]2)=[O:26])=[CH:25][CH:24]=1
Reactant: CCN1CC(N2C(=O)c3ccccc3C2=O)CN1CC
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Product: CCN1CC(NC(=O)c2ccc(F)cc2)CN1CC

Procedure:
A solution of 10 g. (0.026 mole) of 1,2-diethyl-4-phthalimidopyrazolidine maleate in 25 ml. of 6 N hydrochloric acid was refluxed two hours, the resulting mixture was cooled and filtered. The filter cake was washed with water which was combined with the acidic solution. The acidic solution was made basic with dilute sodium hydroxide and cooled with ice. To the resulting solution was added 8.2 g. (0.052 mole) of p-fluorobenzoyl chloride and the mixture shaken for 10 minutes. The resulting mixture was extracted with chloroform, the chloroform diluted with an equal volume of isopropyl ether and the resulting solution extracted with dilute hydrochloric acid. The acid layer was made basic with dilute sodium hydroxide and extracted with chloroform. The chloroform was dried (sodium sulfate) and concentrated. The residue was crystallized from isooctaneisopropyl ether and recrystallized from isooctaneisopropyl ether containing a few drops of ethyl acetate and clarified by charcoal treatment. The product (2.0 g; 29%) melted at 114°-116° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:21][C@:8]2([O:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[CH2:9]2)[CH2:7][NH:6]1)=[O:4].[CH:22]1([O:27][C:28]([NH:30][C@@H:31]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:32](O)=[O:33])=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:21][C@:8]2([O:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[CH2:9]2)[CH2:7][N:6]1[C:32](=[O:33])[C@@H:31]([NH:30][C:28]([O:27][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:29])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@]2(CN1)CN(c1cccc(Cl)c1)C(=O)O2
Reactant: CC(C)(C)[C@H](NC(=O)OC1CCCC1)C(=O)O
Product: COC(=O)[C@@H]1C[C@@]2(CN(c3cccc(Cl)c3)C(=O)O2)CN1C(=O)[C@@H](NC(=O)OC1CCCC1)C(C)(C)C
Yield: 42.3 %

Procedure:
Following the same procedure as Example 1 step G using (5S,8S)-methyl-3-(3-chlorophenyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylate (30 mg, 97 μmol) and (S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoic acid (28 mg, 116 μmol, 1.2 eq.) gave 22 mg (41 μmol) of (5S,8S)-methyl-3-(3-chlorophenyl)-7-((S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylate (C3). 1H NMR (300 MHz, CDCl3) 7.35-6.8 (m, 4H), 5.21-5.06 (m, 1H), 4.86 (m, 1H), 4.55-3.56 (m, 8H), 2.65-2.48 (m, 1H), 2.0 (m, 1H), 1.7-1.1 (m, 9H), 0.9-0.7 (m, 9H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH3:22])=[O:9])[CH2:2]1.F[C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[S:14][C:10]([C:8]([NH:7][CH2:6][CH:3]3[CH2:4][CH2:5][N:1]([C:24]4[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=4[C:26]([O:28][CH3:29])=[O:27])[CH2:2]3)=[O:9])=[C:11]([CH3:22])[N:12]=2)=[CH:20][CH:19]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NCC1CCNC1
Reactant: COC(=O)c1ccccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccccc1N1CCC(CNC(=O)c2sc(-c3ccc(Cl)cc3)nc2C)C1
Temperature: 140 °C
Reaction time: 6 h
Yield: 57.9 %

Procedure:
N-(Pyrrolidin-3-yl methyl)-2-(4-chlorophenyl)-4-methylthiazole-5-carboxamide (168 mg, 0.500 mmol) and methyl 2-fluorobenzoate (0.127 mL, 1.00 mmol) were dissolved in dimethylsulfoxide (4 mL). To this solution, potassium carbonate (138 mg, 1.00 mmol) and tetrabutylammonium iodide (18.5 mg, 0.0500 mmol) were added and the mixture was stirred at 140° C. for 6 hours. Subsequently, the reaction mixture was allowed to cool and water was added. The mixture was then extracted with ethyl acetate and the extract washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=4:1->2:1) gave 136 mg (58%) of the desired compound as a colorless amorphous product.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[F:22][C:23]1[CH:24]=[C:25]([N+:30]([O-:32])=[O:31])[CH:26]=[CH:27][C:28]=1F>C(OCC)(=O)C>[F:22][C:23]1[CH:24]=[C:25]([N+:30]([O-:32])=[O:31])[CH:26]=[CH:27][C:28]=1[N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCN(c3ccccc3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 105 h
Yield: 96.33 %

Procedure:
50 ml of ethyl acetate, 13.5 ml of 4-phenyl piperazine, and 15.30 ml of diisopropyl ethyl amine were added into a 250 ml triple-neck flask. After magnetic stirring at room temperature, 9.0 ml of 3,4-difluoro-nitrobenzene was added. The reaction was carried out for 105 hours, followed by extraction with 150 ml of ethyl acetate for three times (150 ml×3). The extract was washed three times with saturated NaCl solution (150 ml×3), dried with anhydrous magnesium sulfate (MgSO4), and evaporated to dryness. An orange yellow solid was obtained which was recrystallized with a mixture of acetone and water in volumetric ratio of 9:1 to produce orange yellow crystals (23.66 g) with a yield of 96.33%.
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][Si](C)(C)C)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO.C(Cl)Cl.C(Cl)Cl>[F:1][CH:2]([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1
Reactant: C[Si](C)(C)C#Cc1ccc(OC(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CO
Product: C#Cc1ccc(OC(F)F)cc1
Reaction time: 1.5 h
Yield: 97 %

Procedure:
A solution of {[4-(difluoromethoxy)phenyl]ethynyl}(trimethyl)silane (10.0 g, 41.7 mmol) in MeOH/CH2Cl2 (1/1) was treated with cesium carbonate (16.3 g, 50 mmol) at room temperature, stirred for 1.5 h, diluted with CH2Cl2 and filtered through a pad of silica gel. The filtrate was concentrated to dryness to give the title compound (6.8 g, 97%) as an oil. MS (+) EI: 168.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([NH2:19])[C:13]=3[CH:12]=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[Cl:21][C:22]1[C:27]([C:28](O)=[O:29])=[C:26]([F:31])[C:25]([CH2:32][NH:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:24][CH:23]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:21][C:22]1[C:27]([C:28]([NH:19][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[CH:12]=[CH:11][N:10]=[C:9]3[O:8][CH:5]2[CH2:6][CH2:7][C:2]([CH3:20])([CH3:1])[CH2:3][CH2:4]2)=[O:29])=[C:26]([F:31])[C:25]([CH2:32][NH:33][C:34](=[O:39])[C:35]([CH3:37])([CH3:36])[CH3:38])=[CH:24][CH:23]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: CC1(C)CCC(Oc2nccc3c(N)cccc23)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)CCC(Oc2nccc3c(NC(=O)c4c(Cl)ccc(CNC(=O)C(C)(C)C)c4F)cccc23)CC1
Yield: 33.3 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 1-((4,4-dimethylcyclohexyl)oxy)isoquinolin-5-amine (Intermediate-28, 70 mg, 0.25 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 89 mg, 0.31 mmol), oxalyl chloride (59 mg, 0.47 mmol), DMF (1 drop) and DIPEA (97 mg, 0.75 mmol) in CH2Cl2 (3 mL) to afford 45 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.89 (s, 1H), 8.19 (t, 1H), 8.14 (d, J=8.4 Hz, 1H), 8.04 (d, J=5.7 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.67 (t, J=7.8 Hz, 1H), 7.48 (d, J=6.0 Hz, 1H), 7.43 (s, 1H), 7.37 (d, J=7.8 Hz, 1H), 5.28 (m, 1H), 4.34 (d, J=5.4 Hz, 2H), 1.90 (m, 2H), 1.78 (m, 2H), 1.53 (m, 2H), 1.34 (m, 2H), 1.15 (s, 9H), 1.00 (s, 3H), 0.97 (s, 3H); MS (m/z): 540.10 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:5](Br)=[CH:4][N:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.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>[NH2:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:5]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[CH:4][N:3]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(N)ncc2Br)CC1
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: [Na+]
Solvent: CC#N
Product: COc1ccc(-c2cnc(N)cc2NCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 150 °C
Yield: 149.2 %

Procedure:
Two capped 0.5 mL microwave reaction vials each containing a solution of tert-butyl 4-((2-amino-5-bromopyridin-4-ylamino)methyl)piperidine-1-carboxylate (30 mg, 0.078 mmol), 4-methoxyphenyl boronic acid (17.8 mg, 1.5 eq.), Pd(PPh3)4 (4.5 mg, 5 mol %), 0.5M aqueous sodium carbonate (0.23 mL, 1.5 eq.) in acetonitrile (0.78 mL) were heated at 150° C. for 20 min by microwave irradiation. After cooling, the contents of the two reaction vials were combined and solvents were removed in vacuo. The crude product was purified by chromatography using a Biotage SNAP silica (10 g) column, eluting with a gradient of methanol/NH3 (99/1) in dichloromethane, to give the title compound as a yellow solid (48 mg, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]([OH:15])=[O:14].[CH2:16]1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C.CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COc1ccc2[nH]cc(CC(=O)O)c2c1
Reactant: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1c[nH]c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A reaction mixture containing 2-(5-methoxy-1H-indol-3-yl)acetic acid (0.5 g, 2.44 mmol) and BOP-Cl (0.62 g, 2.44 mmol) in 7 mL of anhydrous CH2Cl2 was treated with triethyl amine (0.49 g, 4.87 mmol) and allowed to stir at ambient temperature for 5 min. The mixture was then combined with anhydrous methanol (0.34 mL) and continuously stirred overnight at room temperature. Following dilution with dichloromethane (30 mL), the organic solution was washed with water (2×15 mL), dried over Na2SO4, and filtered (using a commercial phase separator syringe with attached drying cartridge). The organic filtrate was collected and concentrated in vacuo and the crude ester was purified by flash chromatography on silica gel (ethyl acetate/hexane gradient) to afford the title compound as viscous yellow oil, which permanently crystallized upon storage at −20° C. (453 mg, 85%). C12H13NO3, Mr=219.24; 1H NMR (400 MHz, DMSO-d6) d: 3.60 (s, 3H), 3.70 (s, 2H), 3.74 (s, 3H), 6.72 (dd, J=2.4/8.8 Hz, 1H), 6.96 (d, J=2.4 Hz, 1H), 7.19 (d, J=2.4 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H), 10.77 (s, 1H); LCMS (ESI) tR: 1.95 min (>99%, UV254), m/z: 220.1 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]2[O:9][CH:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.[CH:13]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[Cl-].[Al+3].[Cl-].[Cl-].O>[N+](C)([O-])=O>[CH:13]1([C:18]([C:8]2[O:9][C:5]3[C:4]([F:12])=[CH:3][C:2]([F:1])=[CH:11][C:6]=3[C:7]=2[CH3:10])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)C1CCCC1
Reactant: Cc1coc2c(F)cc(F)cc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: Cc1c(C(=O)C2CCCC2)oc2c(F)cc(F)cc12
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a solution of 5,7-difluoro-3-methyl-1-benzofuran (1.0 g) synthesized above, and cyclopentanecarbonylchloride (867 mg) in nitromethane (20 mL) was added aluminum chloride (anhydrous) (1.19 g) at 0° C., and the mixture was stirred for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100:0-95:5, v/v) to give the title compound (1.25 g, 80%) as a colorless solid.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:38])C.[OH-].[Na+].Cl>C(O)C>[F:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][O:29][C:16]2[CH:15]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:39])=[O:3])=[C:8]([CH3:38])[CH:9]=3)[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=2)=[CH:36][CH:35]=1
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCc3ccc(F)cc3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#CCN3CCOCC3)cc(OCc3ccc(F)cc3)c2)ccc1OCC(=O)O
Reaction time: 1 h

Procedure:
{4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (200 mg; 0.36 mmol) was dissolved in ethanol (20 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 170 mg. HPLC-MS: m/z: 522.1 (M+); Rt: 1.77 min.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C@H:18]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:21][CH2:20][S:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[CH3:38][O:39][C:40](=[O:44])[CH2:41][NH:42][CH3:43]>>[CH3:38][O:39][C:40](=[O:44])[CH2:41][N:42]([CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C@H:18]1[N:22]([S:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH2:21][CH2:20][S:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:43]
Reactant: CNCC(=O)OC
Reactant: CS(=O)(=O)OCC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Product: COC(=O)CN(C)CC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1

Procedure:
Following the general method A as outlined in Example 16, starting from (3S)-3-({[(2S)-3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and methyl(methylamino)acetate, the title compound was obtained in 98.9% purity by HPLC.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH:20]([CH3:22])[CH3:21])[C:15]([C:23]([OH:25])=O)=[CH:14]3)=[O:10])[CH2:4]1.Cl.[F:28][C:29]1([F:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.Cl.C(N=C=NCCCN(C)C)C>C(N(CC)CC)C>[F:28][C:29]1([F:35])[CH2:34][CH2:33][N:32]([C:23]([C:15]2[N:16]([CH:20]([CH3:21])[CH3:22])[C:17]3[C:13]([CH:14]=2)=[CH:12][C:11]([C:9]([N:5]2[CH2:6][CH2:7][CH2:8][CH:3]([N:2]([CH3:1])[CH3:26])[CH2:4]2)=[O:10])=[CH:19][CH:18]=3)=[O:25])[CH2:31][CH2:30]1
Reactant: FC1(F)CCNCC1
Reactant: CC(C)n1c(C(=O)O)cc2cc(C(=O)N3CCCC(N(C)C)C3)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(C(=O)N3CCCC(N(C)C)C3)ccc21

Procedure:
The title compound was synthesized in analogy to Example 1, from 5-(3-dimethylamino-piperidine-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylic acid, 4,4-difluoropiperidine hydrochloride, triethylamine and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to afford the product as a light-brown oil (79%).
Reaction SMILES: C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.[CH2:28]([O:31][C:32]([N:34]1[C@H:38]([C:39]([N:41]([CH2:43][C:44]2[N:45]3[C:51]([CH2:52][NH:53][C:54]([O:56][CH2:57][CH:58]=[CH2:59])=[O:55])=[N:50][CH:49]=[C:46]3[S:47][CH:48]=2)[CH3:42])=[O:40])[CH2:37][C@H:36]([S:60][C:61]2[C@H:62]([CH3:85])[C@@H:63]3[C@@H:73]([C@H:74]([O:76][Si](C(C)(C)C)(C)C)[CH3:75])[C:72](=[O:84])[N:64]3[C:65]=2[C:66]([O:68][CH2:69][CH:70]=[CH2:71])=[O:67])[CH2:35]1)=[O:33])[CH:29]=[CH2:30].P([O-])([O-])([O-])=O>C1COCC1>[CH2:28]([O:31][C:32]([N:34]1[C@H:38]([C:39]([N:41]([CH2:43][C:44]2[N:45]3[C:51]([CH2:52][NH:53][C:54]([O:56][CH2:57][CH:58]=[CH2:59])=[O:55])=[N:50][CH:49]=[C:46]3[S:47][CH:48]=2)[CH3:42])=[O:40])[CH2:37][C@H:36]([S:60][C:61]2[C@H:62]([CH3:85])[C@@H:63]3[C@@H:73]([C@H:74]([OH:76])[CH3:75])[C:72](=[O:84])[N:64]3[C:65]=2[C:66]([O:68][CH2:69][CH:70]=[CH2:71])=[O:67])[CH2:35]1)=[O:33])[CH:29]=[CH2:30]
Reactant: C=CCOC(=O)NCc1ncc2scc(CN(C)C(=O)[C@@H]3C[C@H](SC4=C(C(=O)OCC=C)N5C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]5[C@H]4C)CN3C(=O)OCC=C)n12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=CCOC(=O)NCc1ncc2scc(CN(C)C(=O)[C@@H]3C[C@H](SC4=C(C(=O)OCC=C)N5C(=O)[C@H]([C@@H](C)O)[C@H]5[C@H]4C)CN3C(=O)OCC=C)n12
Temperature: 25 °C
Reaction time: 27.5 h
Yield: 81.8 %

Procedure:
Acetic acid (0.30 ml) and 1.75 ml of a 1 M tetra-n-butylammonium fluoride/THF solution are added to a solution of 300 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[N-[5-(allyloxycarbonylaminomethyl)imidazo[5,1-b]thiazol-3-yl]methyl-N-methylaminocarbonyl]pyrrolidin-3-yl]thio-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-1-methylcarbapen-2-em-3-carboxylate in 5.2 ml of anhydrous THF, and the mixture is stirred in an argon atmosphere at room temperature for 27.5 hr. 1/15 M phosphate buffer (pH 7.0) (10 ml) is added thereto, and the mixture is extracted twice with 30 ml of ethyl acetate. The combined organic layers are dried over a 1:1 mixture of anhydrous magnesium sulfate and potassium carbonate and filtered, and the solvent is removed under reduced pressure and by filtrate to give a colorless viscous material. The viscous material is successively purified by column chromatography on silica gel (ethyl acetate:methanol=97:3 to 95:5) and on Sephadex LH-20 (chloroform:methanol=1:1) to give 212.6 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[N-[5-(allyloxycarbonylaminomethyl)imidazo[5,1-b]thiazol-3-yl]methyl-N-methylaminocarbonyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate as a colorless amorphous material.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].Cl[CH2:33][CH2:34][CH2:35][N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]([F:46])([F:45])[C:37]1=[O:47].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:46][C:38]1([F:45])[C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:36]([CH2:35][CH2:34][CH2:33][N:9]2[CH2:10][CH2:11][C:6]3([N:5]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:4][N:3]([CH2:18][C:19]4[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=4)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:2]3=[O:1])[CH2:7][CH2:8]2)[C:37]1=[O:47]
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Reactant: O=C1N(CCCCl)c2ccccc2C1(F)F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCN4C(=O)C(F)(F)c5ccccc54)CC3)C2=O)c1
Temperature: 81 °C
Reaction time: 16 h
Yield: 46.9 %

Procedure:
A mixture of tert-butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (300 mg, 0.71 mmol, 1 equiv), 1-(3-chloropropyl)-3,3-difluoroindolin-2-one (206.5 mg, 0.71 mmol, 1 equiv), sodium iodide (42.7 mg, 0.285 mmol, 0.4 equiv), and potassium carbonate (295.2 mg, 2.136 mmol, 3 equiv) in 2-butanone was stirred at 81° C. for 16 h. After cooling the reaction mixture, the crude mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, concentrated, and the crude residue was purified using preparatory thin layer chromatography in 5% methanol in dichloromethane to afford the title compound as cream crystals (210 mg, 46.8%); 1H NMR (400 MHz, DMSO-d6): δ 1.52 (s, 9H); 1.60 (d, 2H, J=13.2 Hz); 1.84 (t, 2H, J=6.8 and 6.4 Hz); 2.38 (t, 2H, J=6.4 Hz); 2.51 (bs, 2H); 2.71 (bs, 4H); 3.80 (t, 2H, J=6.8 Hz); 4.58 (s, 2H); 4.60 (s, 2H); 6.78 (t, 1H, J=7.2 Hz); 6.83 (d, 2H, J=8.4 Hz); 7.21-7.25 (m, 3H); 7.36 (d, 1H, J=8 Hz); 7.48-7.59 (m, 3H); 7.70 (d, 1H, J=6.8 Hz); 7.79 (s, 1H); 7.82-7.84 (m, 2H); MS for C36H40F2N4O4 m/z 631.11 (M+H)+.