Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=[C:13]2[N:12]=[C:11]([CH3:23])[C:10]=1[CH2:24]O.CS([Cl:30])(=O)=O.CCN(CC)CC>C(Cl)Cl>[Cl:30][CH2:24][C:10]1[C:11]([CH3:23])=[N:12][C:13]2[N:14]([CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=2)[C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: CCOC(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(CO)c(C)nc2n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(CCl)c(C)nc2n1
Reaction time: 10 h
Yield: 100.3 %

Procedure:
To a stirred solution of ethyl 5-(2,4-dichlorophenyl)-6-(hydroxymethyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylate (430 mg, 1.12 mmol) in CH2Cl2 (10 mL) was added MsCl (0.1 mL, 1.35 mmol) and Et3N (0.24 mL, 1.69 mmol). After 10 h, the reaction was concentrated under reduced pressure and diluted with EtOAc. The mixture was extracted with H2O and brine before drying over MgSO4. Filtration and concentration under reduced pressure gave ethyl 6-(chloromethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylate (448 mg, 100% crude yield) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:17]([C:18]#[C:19][CH2:20]O)=[CH:16][N:15]([CH2:22][C:23]3[C:28]([CH3:29])=[C:27]([O:30][CH3:31])[C:26]([CH3:32])=[CH:25][N:24]=3)[C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=1.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.[CH:43]([NH:46][CH:47]([CH3:49])[CH3:48])([CH3:45])[CH3:44]>C(Cl)Cl.CCN(CC)CC>[Cl:1][C:2]1[C:3]2[C:17]([C:18]#[C:19][CH2:20][N:46]([CH:47]([CH3:49])[CH3:48])[CH:43]([CH3:45])[CH3:44])=[CH:16][N:15]([CH2:22][C:23]3[C:28]([CH3:29])=[C:27]([O:30][CH3:31])[C:26]([CH3:32])=[CH:25][N:24]=3)[C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=1
Reactant: COc1c(C)cnc(Cn2cc(C#CCO)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Reactant: CC(C)NC(C)C
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C)cnc(Cn2cc(C#CCN(C(C)C)C(C)C)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Reaction time: 72 h

Procedure:
A solution of N-[4-chloro-5-(3-hydroxy-prop-1-ynyl)-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide (9.0 g, 19.7 mmol) and Et3N (2 mL) in DCM (50 mL) was treated with MsCl (15.3 mL, 19.7 mmol) at 0° C. for 20 min and evaporated to give a yellow solid, containg mostly the desired mesylate (10.7 g). An aliquot of this solid (106.8 mg, 0.2 mmol) was treated with diisopropylamine (20.3 mg, 28.1 μL) in DCM (2 mL) at 0° C. for 10 h, and then at 25° C. for 3 days. Evaporation and prepartive plate chromatography gave the title compound.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][NH:6][N:7]([CH3:18])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:9].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:5][N:6]1[C:1](=[S:2])[N:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:8](=[O:9])[N:7]1[CH3:18]
Reactant: CNN(C)C(=O)Nc1ccc(Cl)cc1
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)n(-c2ccc(Cl)cc2)c(=S)n1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 118.5 %

Procedure:
A solution of 3.8 g (0.33 mol) thiophosgene in 10 ml chloroform was added dropwise to a stirred solution of 7 g (0.033 mol) 1,2-dimethyl-4-(4-chlorophenyl)semicarbazide and 6.67 g (0.066 mol) triethylamine in 200 ml chloroform. After completion of the addition, the reaction mixture was heated under reflux for 2 hours and stirred at about 25° C. for 3 days. The reaction mixture was then washed with water, dilute hydrochloric acid solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 10 g of a semi-solid residue. The residue was diluted with 100 ml dichloromethane and filtered. The filtrate was chromatographed on 200 g of silica gel. Elution with 1% methanol in dichloromethane gave the product, 3.9 g, as light tan crystals, m.p. 143°-144° C. Infrared analysis showed strong carbonyl absorption at 5.8 micron. The product is tabulated in Table I as Compound No. 2.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[O:20]([C:27]1[S:28][CH:29]=[C:30]([CH:32]=O)[N:31]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:32][C:30]2[N:31]=[C:27]([O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[S:28][CH:29]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1csc(Oc2ccccc2)n1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1csc(Oc2ccccc2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 2-phenoxythiazole-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.86 min.; [M+H]+: 424.82 g/mol.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:38])[CH2:18][CH:19]2[CH2:24][C:23](=[O:25])[N:22]([CH2:26][C:27]3[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=3)[C:21](=[O:37])[CH2:20]2)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[OH-:39].[Li+].Cl>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:38])[CH2:18][CH:19]([CH2:24][C:23]([OH:25])=[O:39])[CH2:20][C:21]([NH:22][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:35][CH:36]=2)=[O:37])[CH2:13][CH2:12]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc(CN2C(=O)CC(CC(=O)N3CCN(c4ccccc4C(C)(C)C)CC3)CC2=O)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)CC(CC(=O)O)CC(=O)NCc2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.6 %

Procedure:
To a stirred solution of methyl 4-[(4-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}-2,6-dioxopiperidin-1-yl)methyl]benzoate (Example 74, 0.575 g, 1.11 mmol) in THF (5 mL) stirring at 0° C. was added 1 M lithium hydroxide solution (5 mL, 5 mmol). After 1 h the reaction mixture was warmed to room temperature and kept stirring for 3 h. The mixture was acidified with 1 M hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to provide the crude product. The product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=90:10 to 20:80) to provide 4-[({5-[4-(2-tert-butylphenyl)piperazin-1-yl]-3-(carboxymethyl)-5-oxopentanoyl}amino)methyl]benzoic acid (0.608 g, quant) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:23][O:24][CH2:25][C@@H:26]([O:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:27].CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:32]1[CH2:33][CH2:34][CH:29]([O:28][C@@H:26]([CH3:27])[CH2:25][O:24][CH3:23])[CH2:30][CH2:31]1)=[O:5]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: COC[C@H](C)OC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC[C@H](C)OC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Reaction time: 1 h
Yield: 70.7 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.2 g, 0.67 mmol), (S)-4-(1-methoxypropan-2-yloxy)piperidine (92) (0.151 g, 0.87 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (0.280 g, 0.87 mmol) were dissolved in DMF (10 mL), to this was added DIPEA (0.152 mL, 0.87 mmol) and the reaction was stirred for 1 hour. The solvent was evaporated to dryness and the gum was dissolved in acetonitrile (4 mL) and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound as a white foam; (0.215 g, 70.7% yield) 1H NMR (400.132 MHz, CDCl3) δ 1.13 (3H, t), 1.61-1.49 (1H, m), 1.78-1.65 (2H, m), 1.91-1.87 (1H, m), 3.17-3.01 (1H, m), 3.31-3.27 (1H, m), 3.39-3.35 (4H, m), 3.57-3.45 (2H, m), 3.72-3.67 (2H, m), 4.06-3.97 (1H, m), 4.27 (2H, s), 7.01 (1H, t), 7.31-7.26 (2H, m), 7.79-7.70 (3H, m), 8.49-8.45 (1H, m), 10.50 (1H, s); m/z (LC-MS, ESI+), RT=1.81 (M+H 454).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[N:6][C:7]=1[CH3:8].[CH:16](OCC)=[O:17].[H-].[Na+]>C(COC)OC>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([CH:16]=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)CCc1cnc(C)c(C)c1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1cnc(C)c(C)c1

Procedure:
Reaction of ethyl 3-(5,6-dimethyl-3-pyridyl)-propionate with ethyl formate and sodium hydride in dimethoxyethane at room temperature gave ethyl 3-(5,6-dimethyl-3-pyridyl)-2-formylpropionate, m.p. 148°-9°.
Reaction SMILES: Br[CH2:2][CH2:3][CH3:4].[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:2][CH2:3][CH3:4])[CH:10]=[CH:9]2
Reactant: CCCBr
Reactant: Brc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCn1ccc2cc(Br)ccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
1-Bromopropane (1.25 g, 10.2 mmol) was added to a solution of 5-bromo indole (2 g, 10.2 mmol) in DMF (30 mL) followed by cesium carbonate (6.63 g, 20.4 mmol), and the mixture was stirred at 100° C. for 2 h. Insoluble solids were filtered off, and filtrate was concentrated. Residue was partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography using 5% ethyl acetate in hexane as eluent to afford title compound (1.8 g, 74%) as oil. 1H NMR (400 MHz, CDCl3): δ 7.74 (d, J=1.6 Hz, 1H), 7.28 (m, 1H), 7.20 (m, 1H), 7.09 (d, J=3.2 Hz, 1H), 6.41 (d, J=2.4 Hz, 1H), 4.05 (t, J=7.2 Hz, 2H), 1.87 (m, 2H), 0.9 (t, J=7.2 Hz, 3H); ESI-MS m/z=238 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:16][C:17]1[C:22]2[N:23]=[C:24]([C:26]3[CH:31]=[C:30](OC)[CH:29]=[CH:28][C:27]=3OCOC)[O:25][C:21]=2[CH:20]=[CH:19][CH:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.BrCC1C2N=C(C3C=C[C:52]([O:55][CH2:56][O:57]C)=CC=3)OC=2C=CC=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:16][C:17]1[C:22]2[N:23]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:57][CH2:56][O:55][CH3:52])=[CH:28][CH:27]=3)[O:25][C:21]=2[CH:20]=[CH:19][CH:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: COCOc1ccc(-c2nc3c(CBr)cccc3o2)cc1
Reactant: COCOc1ccc(OC)cc1-c1nc2c(CN(Cc3ccccn3)Cc3ccccn3)cccc2o1
Product: COCOc1ccc(-c2nc3c(CN(Cc4ccccn4)Cc4ccccn4)cccc3o2)cc1

Procedure:
4-bis(2-pyridylmethyl)aminomethyl-2-(4-methoxymethoxyphenyl)benzoxazole (F21) was prepared in a similar manner for the preparation of 4-bis(2-pyridylmethyl)aminomethyl-2-(5-methoxy-2-methoxymethoxyphenyl)benzoxazole (F18) using 4-bromomethyl-2-(4-methoxymethoxyphenyl)benzoxazole (F15) (552 mg, 1.5 mmol) instead of 4-bromomethyl-2-(5-methoxy-2-methoxymethoxyphenyl)benzoxazole (F12) in 98% (704 mg); 1H-NMR (400 MHz, CDCl3) δ3.52 (s, 3H), 3.93 (s, 4H), 4.19 (s, 2H), 5.26 (s, 2H), 7.11–7.18 (m, 4H), 7.29 (t, 1H, J=8.0 Hz), 7.44 (d, 1H, J=8.0 Hz), 7.51 (d, 1H, J=8.0 Hz), 7.66 (d, 2H, J=7.6 Hz), 7.78 (d, 2H, J=7.6 Hz), 8.19 (d, 2H, J=9.2 Hz), 8.55 (d, 2H, J=5.0 Hz).
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[CH:31]=[O:32])=[CH:25][CH:24]=1>>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH:30]2[C:31](=[O:32])[O:13][C:12]3[NH:11][C:10]([C:14]4[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=4[F:21])=[N:9][C:8]=3[CH:1]2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:27][CH:28]=1
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Reactant: O=C/C=C/c1ccc(Br)cc1
Product: O=C1Oc2[nH]c(-c3cc(F)ccc3F)nc2C(c2ccccc2)C1Cc1ccc(Br)cc1
Yield: 64 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and (E)-3-(4-bromophenyl)acrylaldehyde. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 11 as a white solid (95 mg, 64%). Analytical data for 11: 1H NMR (500 MHz, CDCl3) δ 9.37 (d, J=8.0 Hz, 1H), 7.89 (ddd, J=9.1, 6.1, 3.2 Hz, 1H), 7.47-7.41 (m, 2H), 7.39-7.30 (m, 3H), 7.09-7.02 (m, 1H), 7.02-6.92 (m, 5H), 4.08 (d, J=6.9 Hz, 1H), 3.56 (ddd, J=9.8, 6.8, 5.0 Hz, 1H), 3.27 (dd, J=14.9, 4.9 Hz, 1H), 2.41 (dd, J=14.9, 9.9 Hz, 1H); 13C NMR (CDCl3, 126 MHz) δ 168.6, 159.1 (d, JCF=243.6 Hz), 155.4 (d, JCF=240.8 Hz), 148.9, 136.9, 136.8, 136.5, 131.7, 130.8, 129.3, 128.4, 127.9, 120.6, 118.3 (dd, JCF=12.4, 9.4 Hz), 117.1 (dd, JCF=25.7, 8.3 Hz), 116.6 (dd, JCF=24.5, 9.6 Hz), 114.5 (dd, JCF=26.9, 3.8 Hz), 110.7 (d, JCF=3.7 Hz), 47.1, 38.5, 32.3; IR (film) cm−1 1773, 1618, 1529, 1481, 1463, 1240, 1171, 1119, 1099, 1071, 1011, 765, 740, 699; LRMS (ESI): Mass calcd for [M+H]+ C25H18BrF2N2O2: 495.0. found 495.0; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 10% IPA/hexanes; 1.0 mL/min, 280 nm), Rt1 (major)=33.1, Rt2 (minor)=52.8 min; er=96:4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14])[CH2:6][N:7]=[C:8]=[O:9].[N+:17](=[C:19]1[N:23]=[CH:22][N:21]=[C:20]1[C:24]([NH2:26])=[O:25])=[N-:18]>CS(C)=O>[O:9]=[C:8]1[N:7]([CH2:6][C:5]2[CH:10]=[C:11]([O:15][CH3:16])[C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:18]=[N:17][C:19]2=[C:20]([C:24]([NH2:26])=[O:25])[N:21]=[CH:22][N:23]12
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Reactant: COc1cc(CN=C=O)cc(OC)c1OC
Solvent: CS(C)=O
Product: COc1cc(Cn2nnc3c(C(N)=O)ncn3c2=O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4,5-Trimethoxybenzyl isocyanate (Sigma Aldrich) (0.536 g, 2.4 mmol) was added drop wise to a suspension of 5-diazoimidazole-4-carboxamide (0.274 g, 2 mmol) in dry dimethylsulfoxide (2.5 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of ice and the solid product removed by filtration, washed with water and ethyl acetate, and then recrystallised from chloroform/hexane to give an off-white powder. Yield: 0.323 g, 45%. IR vmax/cm−1 1740, 1690, 1589. 1H NMR δH (DMSO-d6) 3.64 (3H, s, 4-OMe), 3.76 (6H, s, 3,5-OMe), 5.42 (2H, s, CH2Ar), 6.75 (2H, s, ArH), 7.68 (1H, br s, NH), 7.81 (1H, br s, NH), 8.84 (1H, s, 6-H). δC (DMSO-d6) 52.5, 56.4, 60.4, 105.9, 129.4, 131.3, 131.7, 134.9, 137.6, 139.7, 153.4, 162.0. MS Found 361.1300. Calc for (M+H): 361.1260. Found C, 49.5; H, 4.4; N, 23.2. Calc. for C15H16N6O5C, 50.0; H, 4.5; N, 23.3%.
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:38](OC)[O:39]C)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:18][C:17]=2[N:28]([CH3:37])[S:29]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)(=[O:31])=[O:30])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CC(C)=O>[CH2:1]([S:8][CH:9]([CH:38]=[O:39])[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][C:24]([F:26])([F:27])[F:25])=[CH:18][C:17]=2[N:28]([CH3:37])[S:29]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)(=[O:31])=[O:30])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)C(CNC(=O)c1cc2cc(OC(F)(F)F)cc(N(C)S(=O)(=O)c3cccs3)c2[nH]1)SCc1ccccc1
Solvent: O
Solvent: CC(C)=O
Product: CN(c1cc(OC(F)(F)F)cc2cc(C(=O)NCC(C=O)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.5 %

Procedure:
A mixture of N-[2-(benzylthio)-3,3-dimethoxypropyl]-7-[methyl(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxamide (600 mg), Amberlyst (registered trade mark) 15 ion exchange resin (120 mg), water (0.05 mL) and acetone (15 mL) was stirred at room temperature for 15 hr. The insoluble substance was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-3:1, volume ratio) to give the title compound (560 mg, yield 100%) as a colorless amorphous solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:3]([NH:5][C@@H:6]([CH2:13][C:14]1[CH2:18][CH2:17][CH2:16][CH:15]=1)[C:7]([C@@:9]1([CH3:12])[CH2:11][O:10]1)=[O:8])=[O:4].[C:28]([O:32][C:33]([NH:35][C@@H:36]([CH3:40])[C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:14]1([CH2:13][C@H:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:37](=[O:38])[C@@H:36]([NH:35][C:33](=[O:34])[O:32][C:28]([CH3:30])([CH3:29])[CH3:31])[CH3:40])[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:7]([C@@:9]2([CH3:12])[CH2:11][O:10]2)=[O:8])[CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1ccc(C[C@H](N)C(=O)N[C@@H](CC2=CCCC2)C(=O)[C@@]2(C)CO2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC2=CCCC2)C(=O)[C@@]2(C)CO2)cc1
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
To (S)-2-amino-N-((S)-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-(4-methoxyphenyl)propanamide (TFA salt, 2.00 g, 4.26 mmol) and (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (805 mg, 4.26 mmol) in DMF (10 mL) at 0° C. was added HATU (1.94 g, 5.11 mmol) followed by DIEA (4.37 mL, 25.6 mmol) and the mixture was stirred for 15 min then quenched with NaHCO3 (sat., aq.), extracted with EtOAc (2×), washed with brine, dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (1:1 hexanes/EtOAc) provided tert-butyl ((S)-1-(((S)-1-(((S)-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)amino)-3-(4-methoxyphenyl)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)carbamate (1.94 g, 84%) as a colorless oil. MS(EI) for C29H41N3O7, found 544.3 (MH)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][NH:11]2)[CH:6]=[C:7]([Cl:9])[CH:8]=1.CCN(C(C)C)C(C)C.Cl[C:30]([O:32][CH3:33])=[O:31]>C(Cl)Cl>[Cl:9][C:7]1[CH:6]=[C:5]([CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][N:11]2[C:30]([O:32][CH3:33])=[O:31])[CH:4]=[C:3]([Cl:2])[CH:8]=1
Reactant: COC(=O)C1CCNC(c2cc(Cl)cc(Cl)c2)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2cc(Cl)cc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.5 %

Procedure:
Methyl 2-(3,5-dichlorophenyl)piperidine-4-carboxylate hydrochloride (4.8 g, 14.79 mmol) was dissolved in DCM (41.5 mL) and DIPEA (6.46 mL, 36.97 mmol). Methyl chloroformate (1.374 mL, 17.74 mmol) was added and the reaction mixture was stirred at room temperature for 1 h, then diluted with DCM and washed with 0.3 M HCl and brine. The organic layer was filtered through a phase separator and evaporated to give dimethyl 2-(3,5-dichlorophenyl)-piperidine-1,4-dicarboxylate (5.3 g) as an oil. MS m/z 346 (M+H)+
Reaction SMILES: Br[C:2]1[C:6]([CH3:8])([CH3:7])[O:5]/[C:4](=[C:9]2/[C:10](=[O:19])[NH:11][C:12]3[C:17]/2=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)/[CH:3]=1.[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CN(C=O)C.C(OCC)(=O)C>[F:18][C:14]1[CH:13]=[C:12]2[C:17](/[C:9](=[C:4]3\[O:5][C:6]([CH3:8])([CH3:7])[C:2]([N:26]4[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][OH:20])[CH2:24][CH2:25]4)=[CH:3]\3)/[C:10](=[O:19])[NH:11]2)=[CH:16][CH:15]=1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1Br
Reactant: OCCN1CCNCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1N1CCN(CCO)CC1
Temperature: 100 °C

Procedure:
A mixture of (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (95 mg, 0.29 mmol) and 1-(2-hydroxyethyl)piperazine (0.40 mL, 3.3 mmol) in 6 mL of DMF was heated in 100° C. bath for 2 hours. The mixture was cooled, diluted with ethyl acetate (60 mL), washed with brine (3×50 mL), and concentrated to give the crude product, which was purified by silica gel chromatography with 5-20% methanol in chloroform to give (3E)-6-fluoro-3-{4-[4-(2-hydroxyethyl)piperazin-1-yl]-5,5-dimethylfuran-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one as a grey solid. Yield: 73 mg, 67%.
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH3:27])[C:10]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]=[CH2:19])[CH:13]=3)[C:6]2=[CH:5][CH:4]=1)[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH3:27])[C:10]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][CH3:19])[CH:13]=3)[C:6]2=[CH:5][CH:4]=1)[CH3:2]
Reactant: C=Cc1cc(-c2c(CCCCC(=O)O)c(C)nn3c(CC)ccc23)ccn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCc1cc(-c2c(CCCCC(=O)O)c(C)nn3c(CC)ccc23)ccn1
Yield: 92.8 %

Procedure:
A solution of 5-[7-ethyl-2-methyl-4-(2-vinyl-4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid (15 mg) in MeOH was added 10% Pd/C (2 mg). The mixture was stirred under under hydrogen atomosphere (1 atm) for 6 h. The reaction mixture was filtered through Celite and the filtrate was concentrarted in vacuo. The residue was triturated with hexane to give 5-[7-ethyl-4-(2-ethyl-4-pyridinyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid (14 mg) as an yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][C@@H:22]2[CH2:26][CH2:25][CH2:24][C@H:23]2[OH:27])=[CH:17][CH:16]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([O:21][C@@H:22]2[CH2:26][CH2:25][CH2:24][C@H:23]2[OH:27])=[CH:19][CH:20]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(O[C@@H]4CCC[C@H]4O)cc3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(O[C@@H]4CCC[C@H]4O)cc3)cc12
Temperature: 75 °C

Procedure:
A solution of (±)-methyl 6-chloro-5-(4-{[trans-2-hydroxycyclopentyl]oxy}phenyl)-1H-indole-3-carboxylate (32 mg, 0.083 mmol) in methanol (0.845 mL) was treated with 1 N aqueous sodium hydroxide (0.291 mL, 0.291 mmol). The solution was heated to 75° C. in a sealed vial for 24 hours. The cooled reaction mixture was poured into 0.3 N HCl (7 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified using reverse-phase chromatography to give the title compound. MS (ES−) 370.0 (M−H)−. Retention time: 1.66 min; Waters Xbridge dC18 5 μm 4.6×50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. (0.03% NH4OH). Flow: 2.0 ml/min.