Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.[NH2:14][CH2:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([NH:14][CH2:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:7]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(I)c1
Reactant: NCC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: O=C(CNC(=O)c1ccc([N+](=O)[O-])c(I)c1)OCc1ccccc1

Procedure:
As shown in scheme F, condensation of 3-iodo-4-nitrobenzoic acid with benzyl glycinate in presence of DCC and catalytic amount of DMAP gave benzyl 2-(3-iodo-4-nitrobenzamido)acetate, which on oxidation using oxidizing agents such as acetic anhydride-hydrogen peroxide gave benzyl 2-(3-iodyl-4-nitrobenzamido)acetate (intermediate 7). The intermediate 7 is treated either with K18F or K19F in the presence of kryptofix[2.2.2] or 18-crown-6 to yield benzyl 2-(3-fluoro-4-nitrobenzamido)acetate, which on reduction with hydrogen gas or hydrogen source in the presence of Pd/C gave 2-(4-amino-3-fluorobenzamido)acetic acid (compound 6). Reaction of 3-iodo-4-nitrobenzoic acid with thionyl chloride gave 3-iodo-4-nitrobenzoyl chloride, which on further treatment with 2,2,2-trichloroethyl glycinate in the presence of triethylamine gave 2,2,2-trichloroethyl 2-(3-iodo-4-nitrobenzamido)acetate. Oxidation of 2,2,2-trichloroethyl 2-(3-iodo-4-nitrobenzamido)acetate with acetic anhydride-hydrogen peroxide gave 2,2,2-trichloroethyl 2-(3-iodyl-4-nitrobenzamido)acetate (intermediate 8). Reaction of intermediate 8 either with K18F or K19F gave 2,2,2-trichloroethyl 2-(3-fluoro-4-nitrobenzamido)acetate, which on reduction with zinc dust gave compound 6. In an analogous manner, treatment of 3-iodo-4-nitrobenzoyl chloride with glycine in presence of sodium carbonate gave 2-(3-iodo-4-nitrobenzamido)acetic acid, which on oxidation with acetic anhydride-hydrogen peroxide and followed by treatment with KOH gave potassium 2-(3-iodyl-4-nitrobenzamido)acetate (intermediate 9). The intermediate 9 is treated either with K18F or K19F to yield 2-(3-fluoro-4-nitrobenzamido)acetic acid, which on reduction with iron powder in presence of acetic acid gave compound 6. Reduction of 2-(3-fluoro-4-nitrobenzamido)acetic acid with iron powder in the presence of acetic anhydride-acetic acid gave 2-(4-acetamido-3-fluorobenzamido)acetic acid (compound 7).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24](O)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[F:27][C:28]([F:37])([F:36])[CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([N:33]3[CH2:32][CH2:31][N:30]([CH2:29][C:28]([F:36])([F:37])[F:27])[CH2:35][CH2:34]3)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: FC(F)(F)CN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21)N1CCN(CC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.5 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (100 mg, 0.27 mmol) in DMF (2 mL) were added 1-(2,2,2-trifluoroethyl)piperazine (50 mg, 0.30 mmol), diisopropylethylamine (DIPEA) (105 μL, 0.60 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (125 mg, 0.33 mmol). The solution obtained was stirred at room temperature for 18 h then diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by preparative HPLC yielding Compound 56 as a solid (41 mg).
Reaction SMILES: [C:1]([N:5]1[C:9]([CH3:10])=[C:8]([C:11]([O:13]C)=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([N:5]1[C:9]([CH3:10])=[C:8]([C:11]([OH:13])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cnn(C(C)(C)C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)cnn1C(C)(C)C

Procedure:
A solution of methyl 1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylate in MeOH (20 mL) was treated with 2 M aqueous NaOH solution (7.95 mL, 15.9 mmol) for 48 h at room temperature. The solvent was removed under reduced pressure and the resulting residue was dissolved in H2O (20 mL). The resulting solution was then acidified to pH˜2 using 2 M HCl. The resulting precipitate was isolated by filtration, washed once with H2O (20 mL), and the solid was dried under high vacuum to yield 1-tert-Butyl-5-methyl-1H-pyrazole-4-carboxylic acid. 1H-NMR (400 MHz, d6-DMSO) δ: 12.16 (br. s., 1H), 7.67 (s, 1H), 2.69 (s, 3H), 1.59 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Br:13]Br.ClCCl.O>C(Cl)(Cl)Cl>[Br:13][C:6]1[CH:5]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: BrBr
Reactant: Oc1ccc(OC(F)(F)F)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Oc1ccc(OC(F)(F)F)cc1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.) solution of 4-trifluoromethoxyphenol (3-5.6 g, 0.2 mol) in chloroform (280 ml) was added dropwise a solution of bromine (32 g, 0.2 mol) in chloroform (50 ml). The solution was stirred at 0° C. for 1 hour and at room temperature for 2 hours. Dichloromethane (200 ml) and water (400 ml) ware added and the organic phase was washed further with water(400 ml), brine (200 ml) and dried (MgSO4). The solvent was removed and the residue was purified by distillation at reduced pressure to give the title compound. 1H NMR (250 MHz, CDCl3)δ 7.38 (1H, d, J=2. 1 Hz), 7.13 (1H, dd, J=9.1, 2.1 Hz), 7.03 (1H, d, J=9.1 Hz), and 5.53 (1H, s).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:10][C:9](=O)[N:8]([CH3:20])[C:7]1=O)=O)C.C1(C)C=CC=CC=1.O.[OH-].[Na+]>C1(C)C=CC=CC=1.C1COCC1.C1COCC1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C@@H:11]2[CH2:10][CH2:9][N:8]([CH3:20])[CH2:7][C@H:6]2[CH2:4][OH:3])=[CH:13][CH:14]=1
Reactant: CCOC(=O)[C@@H]1C(=O)N(C)C(=O)C[C@H]1c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CC[C@@H](c2ccc(F)cc2)[C@H](CO)C1
Temperature: 25 °C

Procedure:
To a cooled 50:50 mole mixture of NaAlH4/LiAlH4 (0.22 mol) in toluene/THF under argon is added (+/−) trans-3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione (0.083 mol) in THF holding the temperature below 15° C. After addition is complete, the reaction is allowed to warm to room temperature. After 30 minutes at room temperature reaction is heated to >40° C. for 2 hr. Reaction is then cooled to <5° C. and toluene (50 ml) is added. Water (9 ml) is then added slowly holding the temperature below 15° C. Additional H2O or aqueous NaOH is used as necessary. The solid inorganic salts are removed by filtration. These solids are washed with additional THF or toluene. The filtered solution is then concentrated to give (+/−) trans-4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine in essentially the same yield and similar impurity profile as with LiAlH4 as shown by HPLC analysis. The product can be recovered by standard procedures such as trituration with a less polar solvents.
Reaction SMILES: [NH4+:1].[Cl-].C[Al](C)C.F[C:8](F)(F)[C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH2:20][C:21]#[N:22])[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[C:9]1([CH3:8])[CH:14]=[CH:13][C:12]([C:15]2([CH2:20][C:21]([NH2:22])=[NH:1])[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1
Reactant: [NH4+]
Reactant: N#CCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C2(CC(=N)N)CCCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a stirred suspension of NH4Cl (1.3 g, 23.69 mmol) in dry toluene (30 mL) was added trimethylaluminium (2M solution in toluene) dropwise at 0° C., stirred at 0° C. for 15 min, then stirred at room temperature for 2 h. The solution of [1-(4-trifluoromethyl-phenyl)-cyclopentyl]-acetonitrile (241) (2 g, 7.89 mmol) in toluene (10 mL) was added dropwise at the room temperature and the reaction mixture was heated at 80° C. for 16 h, the reaction mixture was cooled to 0° C., and the reaction mixture was poured into the slurry of silica gel (4 g) in CHCl3 (4 mL), stirred vigorously for 30 min at 0° C., the solid was filtered off through celite and washed with methanol (5×100 mL). The filtrate was concentrated and the crude product was taken up in 10% methanol in dichloromethane (200 mL) and stirred for 30 min. The solid was discarded by filtration and the filtrate was concentrated. The crude product was suspended in ether and a solid was collected by filtration and dried to get 2-(1-p-tolyl-cyclopentyl)-acetamidine (hydrochloride salt) (242) (1.4 g, 65.59%) as a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH:22]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][N:22]([C:11](=[O:13])[C:10]([CH3:15])([CH3:14])[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:34]
Reactant: CC(C)(COCc1ccccc1)C(=O)O
Reactant: CCOC(=O)CNc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C(=O)C(C)(C)COCc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3-(benzyloxy)-2,2-dimethylpropanoic acid from Step B (415 mg, 1.99 mmol) in DCM (20 mL) was added one drop of DMF (cat.) followed by the drop wise addition of oxalyl chloride (329 mg, 2.59 mmol) over 10 minutes, while at ambient temperature. After the evolution of gas has ceased, the reaction was cooled to 0° C., prior to the introduction of ethyl anilinoacetate (429 mg, 2.39 mmol) and triethylamine (302 mg, 2.99 mmol). After 2 hours at 0° C., the reaction was allowed to warm to ambient temperature and then stir for an additional 1 hour. The reaction mixture was applied directly to a silica gel column for purification, eluting with a gradient of CH2Cl2:MeOH—99.5:0.5 to 98:2. Product containing fractions were pooled and concentrated in vacuo to give the title compound. MS: m/z=370 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=[O:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17](O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:17]([O:13][C:12](=[O:14])[CH:11]1[CH2:15][CH2:16][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)OCc2ccccc2)CC1
Reaction time: 6 h

Procedure:
To a solution of N-t-butoxycarbonyl isonipecotic acid (12.0 g, 52.3 mmol) from example 3 step A, in anhydrous CH2Cl2 (100 ml), was added benzyl alcohol (6.0 ml, 58 mmol), followed by EDC (11.04 g, 57.6 mmol), and DMAP (642 mg, 5.25 mmol). The resulting mixture was stirred for 6 hrs, then diluted with CH2Cl2 (150 ml) and washed successively with water, 10% aqueous citric acid, saturated NaHCO3, and brine and dried (MgSO4). Concentration in vacuo afforded a colorless oil which was chromatographed (SiO2, 20% EtOAc in hexanes) to afford the product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].[H-].[Na+].[Na+].[I-].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][C:23]=1[C:32]([F:35])([F:34])[F:33]>CN(C=O)C.CCOC(C)=O.O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][C:23]=2[C:32]([F:34])([F:33])[F:35])[C:6]=1[CH3:14]
Reactant: COC(=O)Cc1c(C)[nH]c2ccccc12
Reactant: CS(=O)(=O)c1ccc(CBr)c(C(F)(F)F)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2C(F)(F)F)c2ccccc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a stirring solution of (2-methyl-1H-indol-3-yl)-acetic acid methyl ester (2.0 g, 10.5 mmol) in dry DMF (25 ml) at 0° C., is added portionwise NaH (0.46 g, 11.5 mmol) as a 60% dispersion in mineral oil. The reaction mixture is stirred at 0° C. for 1.5 h then NaI (1.72 g, 11.5 mmol) and 1-bromomethyl-4-methanesulfonyl-2-trifluoromethyl-benzene (3.65 g, 11.5 mmol) are added. The reaction mixture is stirred at room temperature for 16 h. The reaction mixture is poured into water (100 ml) and EtOAc (50 ml) is added. An emulsion is formed which is filtered. Brine (20 ml) is added to the filtrate and the organic phase is separated and dried (MgSO4). Evaporation in vacuo affords a brown oil. Purification by flash chromatography on silica gel using 5:1 iso-hexane:EtOAc, increasing polarity up to 3:1 iso-hexane:EtOAc, gives the desired product; [M+H]+ 440.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][C:30](Cl)=[O:31].[CH2:33](O)[C:34](N)([CH2:37][OH:38])[CH2:35]O>C1COCC1>[O:38]1[C:37]([C:34]2[CH:35]=[C:6]([NH:7][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:30](=[O:31])[CH2:29][C:25]6[S:24][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:8]=[CH:12][CH:33]=2)=[CH:4][N:3]=[CH:2]1
Reactant: NC(CO)(CO)CO
Reactant: O=C(Cl)Cc1cccs1
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1
Solvent: C1CCOC1
Product: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Reaction time: 0.25 h
Yield: 98 %

Procedure:
To a stirred solution of {3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}amine (200 mg, 0.62 mmol) and TEA (64 mg, 0.63 mmol) in THF (25 mL) was added dropwise 2-thiopheneacetyl chloride (118 mg, 0.73 mmol). After stirring for 20 min., 15 min. LC/MS analysis indicated the reaction was complete and several equivalents of PS-trisamine were added and the mixture was stirred for 16 h followed by addition of 25 mg of TEA. The mixture was then filtered and the resin washed well with THF. The filtrate was concentrated and the crude partitioned between water and DCM. The layers were separated, and the aqueous was extracted with DCM. The organics were combined, filtered over MgSO4, filtered, reduced in vacuo to yield the title compound (270 mg, 98% yield). 1H NMR (400 MHz, d6-DMSO) δ 10.41 (s, 1H), 8.92 (d, J=6.9 Hz, 1H), 8.48 (d, J=5.3 Hz, 1H), 8.43 (d, J=9.0 Hz, 1H), 7.91 (s, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.67 (t, J=7.3 Hz, 1H), 7.49 (t, J=7.9 Hz, 1H), 7.40-7.43 (m, 1H), 7.31 (d, J=6.8 Hz, 1H), 7.24 (dt, J=1.1, 6.8 Hz, 1H), 7.07 (d, J=55 Hz, 1H), 6.99-7.01 (m, 2H), 3.91 (s, 2H) ppm. ES-LC/MS m/z=446, 448 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](O)([C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[C:9](=[O:21])[N:8]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=3[O:33][C:34]([F:37])([F:36])[F:35])(=[O:24])=[O:23])[C:5]2=[N:6][CH:7]=1.CS(OS(C)(=O)=O)(=O)=O.FC(F)(F)C(O)=O.[OH:54][C@H:55]1[CH2:59][NH:58][C@H:57]([C:60]([N:62]([CH3:64])[CH3:63])=[O:61])[CH2:56]1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CCN(CC)CC>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([N:58]3[CH2:59][C@H:55]([OH:54])[CH2:56][C@H:57]3[C:60]([N:62]([CH3:64])[CH3:63])=[O:61])([C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[C:9](=[O:21])[N:8]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=3[O:33][C:34]([F:35])([F:36])[F:37])(=[O:24])=[O:23])[C:5]2=[N:6][CH:7]=1
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(O)(c3cc(C)ccc3OC)c3cc(Br)cnc32)c(OC(F)(F)F)c1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Br)cnc32)c(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 1.7 %

Procedure:
To a solution of 290 mg of the compound obtained in Step 120-5 and 97 mg of Et3N in CHCl3 (2 ml), on ice, was added 101 mg of methanesulfonic acid anhydride and the reaction mixture was stirred at room temperature for one hour. The solution was cooled again under ice cooling, 97 mg of Et3N and 261 mg of (4R)-4-hydroxy-N,N-dimethyl-L-prolinamide trifluoroacetate was added, and the reaction mixture was stirred at room temperature for two hours. A saturated aqueous solution of NaHCO3 was poured, and the solution was extracted with EtOAc. The organic layer was washed with saturated brine, dried over Na2SO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by thin layer chromatography (silicagel 60 F254; 1 mm thick; mobile phase: CHCl3/MeOH=9/1; v/v) to obtain 6 mg of the title compound (amorphous).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1B1OC(C)(C)C(C)(C)O1)[C:5]#[N:6].Br[C:20]1[CH:21]=[C:22]([CH:26]([CH:33]2[CH2:35][CH2:34]2)[NH:27][S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:23]=[N:24][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([C:20]2[CH:21]=[C:22]([CH:26]([CH:33]3[CH2:35][CH2:34]3)[NH:27][S:28]([CH2:31][CH3:32])(=[O:29])=[O:30])[CH:23]=[N:24][CH:25]=2)=[C:2]([F:1])[CH:3]=1)#[N:6]
Reactant: CCS(=O)(=O)NC(c1cncc(Br)c1)C1CC1
Reactant: CC1(C)OB(c2ccc(C#N)cc2F)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NC(c1cncc(-c2ccc(C#N)cc2F)c1)C1CC1
Temperature: 100 °C
Yield: 55.6 %

Procedure:
(General Suzuki reaction procedure 2) A mixture of 3-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (333 mg, 1.35 mmol), N-((5-bromopyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide (430 mg, 1.35 mmol), PdCl2(PPh3)2 (77 mg, 0.10 mmol) and Na2CO3 (2M in water, 1.35 mL, 2.70 mmol) in DMF (6 mL) heated at 100° C. under N2 for 2 h. The solvent was removed in vacuo, and the residue was purified by flash column (EtOAc/Heptane, v/v, 0-50%) to give the title compound (270 mg, 56% yield); ESI-MS m/z: 360 [M+1]+. 1HNMR (MeOD, 400 MHz) δ 8.72 (1H, d, J=2.0 Hz), 8.71 (1H, d, J=2.0 Hz), 8.17 (1H, bs), 7.83-7.75 (3H, m), 3.95 (1H, d, J=8.8 Hz), 3.52 (3H, s), 3.05-2.92 (2H, m), 1.32-1.28 (1H, m), 1.30 (1H, t, J=7.2 Hz), 0.80-0.76 (1H, m), 0.67-0.61 (2H, m), 0.52-0.48 (1H, m). Enantiomers were separated by chiral HPLC (Chiralpak AS-H, EtOH/Heptane, v/v, 30/70) to the first peak (enantiomer 1, t=9.68 min), and the second peak (enantiomer 2, t=13.68 min).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@:15]4([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[C:4]([F:27])[CH:3]=1.O1CCCC1.C(P)(C)(C)C.C([Sn](CCCC)(CCCC)[C:43]1[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=1)CCC>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:27][C:4]1[CH:3]=[C:2]([C:43]2[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=2)[CH:7]=[CH:6][C:5]=1[C:8]1([C:11]([N:13]2[CH2:17][CH2:16][C@@:15]3([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[C:19](=[O:26])[O:18]3)[CH2:14]2)=[O:12])[CH2:10][CH2:9]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(Br)cc4F)CC3)C2)c2ccccc21
Agent: [Pd]
Agent: CC(C)(C)P
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(-c5ccncc5)cc4F)CC3)C2)c2ccccc21
Temperature: 120 °C

Procedure:
To a solution of (1R)-1′-{[1-(4-bromo-2-fluorophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (30 mg, 0.00007 mol, this compound was prepared by using a method that was analogous to that used for the synthesis of 238) in tetrahydrofuran (0.2 mL, 0.002 mol) were added tris(dibenzylideneacetone)dipalladium(0) (3 mg, 0.000003 mol), ti-tert-butylphosphine (1.7 mg, 0.0000083 mol), 4-(tributylstannyl)pyridine (30.7 mg, 0.0000835 mol), and the mixture was heated to 120° C. under microwave for 30 minutes. The reaction mixture was then filtered and the filtrate was diluted with methanol, and the product was isolated and purified by prep-HPLC. LC/MS (M+H+) 429.2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]([NH:24][C:25](=[O:31])OC(C)(C)C)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[C:19]([CH:20]([OH:22])[CH3:21])=[CH:18][CH:17]=[CH:16][N:15]3[CH:23]=2)=[CH:8][CH:7]=1.Cl.O1CCOCC1.C(N(CC)C(C)C)(C)C.[Cl:48][C:49]1[CH:50]=[C:51]([CH:66]=[CH:67][C:68]=1[O:69][CH:70]([CH3:72])[CH3:71])C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O>O>[Cl:48][C:49]1[CH:50]=[C:51]([CH:66]=[CH:67][C:68]=1[O:69][CH:70]([CH3:72])[CH3:71])[C:25]([NH:24][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]=[C:14]3[C:19]([CH:20]([OH:22])[CH3:21])=[CH:18][CH:17]=[CH:16][N:15]3[CH:23]=2)=[CH:10][CH:11]=1)[CH2:3][CH2:2][OH:1])=[O:31]
Reactant: CC(C)Oc1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Cl
Reactant: CC(O)c1cccn2cc(-c3ccc(C[C@@H](CCO)NC(=O)OC(C)(C)C)cc3)nc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(C(=O)N[C@H](CCO)Cc2ccc(-c3cn4cccc(C(C)O)c4n3)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
A mixture of 1,1-dimethylethyl [(1S)-3-hydroxy-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)propyl]carbamate (1.08 g, 2.54 mmol) and 4M HCl in 1,4-dioxane (8.0 mL, 32 mmol) was stirred at room temperature for 30 minutes. The reaction was concentrated to dryness, redissolved in DMF (25 mL), and to this solution was added N,N-diisopropylethylamine (1.64 g, 12.7 mmol) and pentafluorophenyl 3-chloro-4[(1-methylethyl)oxy]benzoate (0.963 g, 2.54 mmol). The mixture was stirred for 3.0 h at room temperature, diluted with water, and extracted into ethyl acetate. The extracts were washed with water and saturated sodium chloride, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (2% MeOH:EtOAc) to give the title compound (0.7 g, 53%) as a pale yellow powder. MS (ES+) m/e 522 [M+H]+.